Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])#[N:2].C1(C)C=CC=CC=1.Cl.S(O)(O)(=O)=O.[NH2:23]O>C(N(CC)CC)C.CO>[NH2:2][C:1]1[CH:3]=[C:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[O:9][N:23]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)no1
Reaction time: 23 h
Yield: 143.8 %

Procedure:
To a suspension of cyanopinacolone (75.102 g) in a mixture of anhydrous toluene (150 ml) and anhydrous methanol (26.7 ml) is introduced gaseous hydrogen chloride (26.3 g) with cooling at 5° to 10° C. and stirring, and the whole mixture is allowed to stand at 10° to 12° C. for 23 hours. To the reaction mixture is dropwise added anhydrous methanol (750 ml), then triethylamine (185.178 g) with cooling and stirring to make a complete solution. The reaction mixture is treated with hydroxylamine sulfate (51.704 g) and stirred at 50° C. for 2 hours. Then, conc. hydrochloric acid (112.629 g) is dropwise added to the mixture, which is stirred at 50° C. for 1 hour. After evaporating the solvent under reduced pressure from the reaction mixture, the residue is made alkaline with 48% aqueous sodium hydroxide with cooling, and the aqueous solution is shaken with toluene. The organic layer is washed with water, subjected to azeotropic distillation under atmospheric pressure, and evaporated to dryness to remove the solvent, whereby 3-amino-5-t-butylisoxazole (79.480 g) is obtained. Melting point is 106° to 109° C. Yield is 94.5%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:18][C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH:15]=3)[O:10]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[Si]([N:32]=[C:33]=[N:34][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:18][C:17](=[N:34][C:33]#[N:32])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:20]4[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[CH:21]=4)[CH:15]=3)[O:10]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CC(=NC#N)c1cc(-c3cccc(C#N)c3)ccc1O2
Reaction time: 1 h

Procedure:
To a solution of 3-(1′-acetyl-4-oxospiro[chroman-2,4′-piperidine]-6-yl)benzonitrile (60 mg, 0.167 mmol) in anhydrous DCM (5 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.35 mL, 0.35 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.086 mL, 0.367 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (5 g), and stirred for 20 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give N-(1′-acetyl-6-(3-cyanophenyl)spiro[chroman-2,4′-piperidine]-4-ylidene)cyanamide as light brown solid which was used for next step without further purification. MS ESI +ve m/z 385 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[O:13]CCO1.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1.CCCCCC.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:24])[OH:20])=[C:3]([CH:9]=[O:13])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)c(C2OCCO2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(F)ccc1B(O)O
Temperature: -74 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 2.30 g (9.31 mmol) 2-(2-bromo-5-fluoro-phenyl)-[1,3]dioxolane in 15 ml tetrahydrofuran was added dropwise at −70° C. 6.11 ml (9.77 mmol) of a 1.6 M solution of n-butyllithium in hexane. The reaction mixture was stirred at −74° C. for 1 h. After dropwise addition of 2.65 ml (11.2 mmol) triisopropyl borate at −70° C. the reaction mixture was allowed to warm to 15° C. during a period of 2 h. Water (7 ml) was added, and the mixture was acidified to pH 1 by addition of 37% hydrochloric acid solution. After heating at 60° C. for 1 h, the mixture was cooled to room temperature and extracted with three 50-ml portions of diethyl ether. The combined organic layers were washed with 50 ml brine, dried over sodium sulfate and concentrated. Flash chromatography gave 1.2 g (77%) of the title compound as a light yellow liquid.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:5]=[N:4][N:3]=1.BrC1N=NN(C2CC2)N=1.[CH:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])=[O:21]>>[CH:8]1([CH2:7][N:6]2[C:2]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([CH:23]=3)[CH:20]=[O:21])=[N:3][N:4]=[N:5]2)[CH2:10][CH2:9]1
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Brc1nnnn1CC1CC1
Agent: Brc1nnn(C2CC2)n1
Product: COc1ccc(-c2nnnn2CC2CC2)cc1C=O

Procedure:
From a mixture of 5-bromo-1-cyclopropylmethyl-1H-tetrazole with 5-bromo-2-cyclopropyl-2H-tetrazole (1.91 g) and 3-formyl-4-methoxy-phenyl-boronic acid (1.86 g) to give the title compound (657 mg) as a yellow solid. NMR (CDCl3) δ 0.45 (2H,m); 0.70 (2H,m); 1.3 (1H,m); 4.05 (3H,s); 4.3(2H,d); 7.2 (1H,d); 8.0 (1H,m); 8.15 (1H,d); 10.55 (1H,s).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16](=[S:18])[NH2:17])[C:9]=2[CH3:19])[CH2:5][C:4](=[O:20])[C:3]=1[C:21](=O)[CH2:22][CH3:23].Cl.[CH2:26]([O:28][NH2:29])[CH3:27]>>[CH2:26]([O:28][N:29]=[C:21]([C:3]1[C:4](=[O:20])[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16](=[S:18])[NH2:17])[C:9]=2[CH3:19])[CH2:7][C:2]=1[OH:1])[CH2:22][CH3:23])[CH3:27]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C(N)=S)c2C)CC1=O
Reactant: CCON
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(C(N)=S)c2C)CC1=O

Procedure:
The reaction of 3-hydroxy-5-(3-thiocarbamoyl-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one with ethoxyamine hydrochloride was carried out following the same procedure as that described in Example 1 part (v) to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(3-thiocarbamoyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (24) as a tan oil. The compound was characterized by its proton nuclear magnetic resonance spectrum and the data are recorded in Table 3, Example 11.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:23])[O:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:25]([O:16][C:13]1[CH:14]=[C:15]2[C:5]3([O:4][N:3]([CH3:23])[C:2]([NH2:1])=[N:6]3)[CH2:7][CH:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:9][C:10]2=[CH:11][CH:12]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CN1OC2(CC(c3ccccc3)Oc3ccc(O)cc32)N=C1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(OCc4ccccc4)cc32)N=C1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 2.5 %

Procedure:
A mixture of 3′amino-2′-methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4)oxadiazol)-6-ol (30 mg, 0.096 mmol), (bromomethyl)benzene (21.45 mg, 0.125 mmol) and K2CO3 (16 mg, 0.115 mmol) was dissolved in acetone, then the mixture was stirred at room temperature for 24 hours. The mixture was filtrated and concentrated. The residue was purified by preparative HPLC to give 6-(benzyloxy)-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (140) (0.95 mg, 3%). 1H-NMR (MeOD): 7.32-7.56 (m, 10H), 6.91-7.23 (m, 3H), 5.12 (d, 2H), 5.23 (t, 2H), 3.31 (s, 3H) 2.73 (m, 1H), 2.32 (m, 1H);
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:7]([C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=1)=[N:6][N:5]([CH2:13][C:14](=O)[CH3:15])[CH:4]=2.[Si]([O:24][CH:25]([CH3:39])[CH2:26][N:27]1[CH:35]=[C:34]2[C:29]([C:30]([Cl:38])=[C:31]([Cl:37])[CH:32]=[C:33]2[Cl:36])=[N:28]1)(C(C)(C)C)(C)C.[N+:40](C1C(Cl)=C(Cl)C=C(Cl)C=1C=O)([O-])=O>>[NH2:40][C:14]([CH3:15])([CH2:13][N:5]1[CH:4]=[C:3]2[C:7]([C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=[C:2]2[Cl:1])=[N:6]1)[C:26]#[N:27].[Cl:36][C:33]1[C:34]2[C:29]([C:30]([Cl:38])=[C:31]([Cl:37])[CH:32]=1)=[N:28][N:27]([CH2:26][C:25](=[O:24])[CH3:39])[CH:35]=2
Reactant: CC(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1c(Cl)cc(Cl)c(Cl)c1[N+](=O)[O-]
Agent: CC(=O)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Product: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Yield: 58.5 %

Procedure:
2-Amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.16 g, 60%) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(4,6,7-trichloro-2H-indazol-2-yl)propan-2-one (0.25 g). 1-(4,6,7-Trichloro-2H-indazol-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part c and d except starting from 2-[2-(tert-butyldimethylsilanyloxy)propyl]-4,6,7-trichloro-2H-indazole (1.4 g, 69%) that was prepared using a procedure similar to that described in Example 132 part a except starting from [2-(tert-butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzypamine (2.2 g). [2-(tert-Butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzypamine (2.2 g, 44%) was prepared using a procedure similar to that described in Example 105 part a except starting from 2-nitro-3,4,6-trichlorobenzaldehyde (3 g) that was prepared as follows:
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:17](=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:30].CO>O1CCCC1>[C:10]([OH:12])(=[O:11])[CH3:9].[NH2:30][CH:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)C(OCc1ccccc1)C(=O)Cc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)O
Product: CC(C)(C)OC(=O)C(OCc1ccccc1)C(N)Cc1ccccc1
Temperature: 90 °C
Reaction time: 13 h

Procedure:
Ru(OAc)2((S)-dm-segphos) (0.138 g, 0.147 mmol), tert-butyl 2-benzyloxy-3-oxo-4-phenylbutanoate (5.00 g, 14.7 mmol), ammonium acetate (1.13 g, 14.7 mmol), methanol (25 mL) and tetrahydrofuran (25 mL) were placed in a 200 mL stainless steel autoclave, and the mixture was stirred at 90° C. under a hydrogen pressure of 3 MPa for 13 hours. After completion of the reaction, the solvent was removed by evaporation to give tert-butyl 3-amino-2-benzyloxy-4-phenylbutanoate acetate as a crude material (6.10 g). The ratio of anti and syn diastereoisomer (86:14) was determined by HPLC analysis using a CHIRALPAK AD-RH column (available from DAICEL CHEMICAL INDUSTRIES, LTD). The enantiomeric excess of the crude product was determined to be 98.6% ee (anti diastereoisomer) and 95.1% ee (syn diastereoisomer) by HPLC analysis using a CHIRALCEL OD-H column after conversion into tert-butyl 3-(4-nitrobenzoylamino)-2-benzyloxy-4-phenylbutanoate.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:9]12[CH2:18][CH2:17][CH2:16][CH2:15][C@:14]1([OH:19])[CH2:13][CH2:12][CH2:11][CH2:10]2)([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1.C(N(CC)CC)C>O1CCCC1>[C:23]([O:19][C@@:14]12[CH2:15][CH2:16][CH2:17][CH2:18][C@:9]1([C:6]([O:5][C:1](=[O:4])[CH:2]=[CH2:3])([CH3:8])[CH3:7])[CH2:10][CH2:11][CH2:12][CH2:13]2)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=C1CC(=O)O1
Reactant: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(O)CCCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(OC(=O)CC(C)=O)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 100 mmol of 4a-(1-acryloyloxy-1-methylethyl)-8a-hydroxy-cis-decalin prepared in the same manner as in Example 4, 110 mmol of diketene, 110 mmol of triethylamine, and 300 ml of tetrahydrofuran was stirred at room temperature for 2 hours. The resulting reaction mixture was subjected to chromatography on a silica gel to yield 8a-acetoacetyloxy-4a-(1-acryloyloxy-1-methylethyl)-cis-decalin represented by the following formula (yield: 89.1%). The conversion rate from 4a-(1-acryloyloxy-1-methylethyl)-8a-hydroxy-cis-decalin was 99%.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[CH2:33]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([C:49](O)=[O:50])[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:49]([CH:46]2[CH2:47][CH2:48][N:43]([C:41]([O:40][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:42])[CH2:44][CH2:45]2)=[O:50])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (2.00 g, 0.0107 mol) and N,N-diisopropylethylamine (2.2 g, 0.017 mol) in DCM (27.0 mL) was treated with and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.2 g, 0.017 mol), (1.5 g, 0.011 mol) and 1-[(benzyloxy)carbonyl]-4-piperidine carboxylic acid (3.8 g, 0.014 mol). The mixture was stirred at rt overnight then diluted with DCM (30 mL), washed with sat. NaHCO3 (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude material thus obtained was chromatographed over silica gel eluting with EtOAc:hexane 1:1 yielding 3.38 g of the title compound. 1H NMR (400 MHz, CDCl3); δ 1.68-1.78 (m, 2H), 1.91-1.94 (m, 2H), 2.44 (m, 1H), 2.89-2.92 (m, 2H), 4.24-4.26 (m, 2H), 4.70 (d, J=4.8 Hz, 2H), 5.14 (s, 2H), 6.85 (br, 1H), 7.30-7.37 (m, 5H), 8.34 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H). MS (ES+): m/z 389.17 [MH+].
Reaction SMILES: [I-].[C:2]([O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N+:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[N+:22]([O-])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].[H][H]>CO>[NH2:22][C:10]1[CH:11]=[C:12]([CH:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8]
Reactant: C[n+]1ccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1
Reactant: [H][H]
Agent: [I-]
Solvent: CO
Product: CN1CCC(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Yield: 140.9 %

Procedure:
0.48 g of platine (IV) oxide (2.12 mmol) is added to a solution of 26.8 g of 4-(4-(tert-butoxycarbonyl)-3-nitrophenyl)-1-methylpyridinium iodide (60.6 mmol) in 200 mL of methanol placed in a reactor made in stainless steel. The reaction medium is brought under 5 bar of hydrogen for 24 h. The catalyst is filtered and the filtrate is concentrated under reduced pressure to yield 24.8 g (98%) of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[C:49]([C:53]1[CH:58]=[CH:57][C:56]([S:59][CH2:60][CH2:61]CO)=[CH:55][CH:54]=1)([CH3:52])([CH3:51])[CH3:50]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:61][CH2:60][S:59][C:56]2[CH:57]=[CH:58][C:53]([C:49]([CH3:50])([CH3:52])[CH3:51])=[CH:54][CH:55]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(C)(C)c1ccc(SCCCO)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCSc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 67.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[4-(tert-butyl)phenyl]sulfanyl-1-propanol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (100 mg, yield 64%).
Reaction SMILES: Cl.N[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.C([N:15](CC)CC)C.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([NH:15][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][CH:11]=2)[CH2:7][C:8]1=[O:12])(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CCN(CC)CC
Reactant: Nc1ccc2c(c1)NC(=O)C2
Agent: Cl
Solvent: ClCCl
Product: O=C(NN1C(=O)Cc2ccccc21)c1ccncc1
Reaction time: 3 h

Procedure:
5.0 g. (27.1 mMol) 6-aminoindolin-2-one hydrochloride (Helv. Chim. Acta, 20, 373/1937) are suspended in 100 ml. methylene chloride, mixed with 3.7 ml. (27.1 mMol) triethylamine and stirred for 10 minutes. While cooling with ice, 6.73 g. (37.8 mMol) isonicotinic acid chloride hydrochloride and 5.24 ml. (37.8 mMol) triethylamine are added thereto. After 3 hours, the methylene chloride is distilled off and the residue is worked up with water and filtered with suction. The residue is stirred with hot ethanol. There are obtained 5.6 g. (82% of theory) of the title compound; m.p, 315°-320° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:14][C:15]([C@H:17]1[CH2:19][C@@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:4]1C=N[C:7]([O:10][CH2:11][CH2:12]C)=[CH:8][CH:9]=1.[NH2:26][C@H:27](C1C=CC(OCC)=CN=1)CO.BrC1C=CC(OCC)=CN=1>>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C@@H:3]([NH:14][C:15]([C@H:17]2[CH2:19][C@@H:18]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:16])[CH2:2][OH:1])=[N:26][CH:27]=1)[CH3:12]
Reactant: CCOc1ccc([C@@H](N)CO)nc1
Reactant: CCCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Agent: CCOc1ccc(Br)nc1
Product: CCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1

Procedure:
Prepared analogously to Compound 21 using IM46 and (R)-2-Amino-2-(5-ethoxy-pyridin-2-yl)-ethanol (prepared from commercially available 2-Bromo-5-ethoxy-pyridine CAS 42834-01-5 analogously to IM36). Compound 52 was further purified by SFC (Column: Chiralpack OJ250×30 mm, Mobile phase: Supercrital CO2/MeOH+NH4OH=55/45 at 50 mL/min, column temperature: 38° C., Nozzle Pressure: 100 Bar, Nozzle Temp=60° C., Evaporator temp=20 C, Trimmer temp=25° C., Detector: 220 nm). Yield=163 mg. 1H NMR (CDCl3 400 MHz, TMS): δ 8.15 (d, J=2.8 Hz, 1H), 7.08-7.31 (m, 6H), 7.06 (d, J=7.2 Hz, 2H), 5.11-5.15 (m, 1H), 4.00-4.08 (m, 3H), 3.87-3.90 (m, 1H), 2.47-2.52 (m, 1H), 1.63-1.76 (m, 3H), 1.43 (t, J=7.2 Hz, 3H), 1.27-1.31 (m, 1H); [α]20, D=182.0 (c=0.234 g/100 mL, EtOH)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][C:9](=O)[CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([SH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C(N)CN>C(#N)C>[CH2:12]([S:19][C:8]1([CH2:23][N+:20]([O-:22])=[O:21])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: SCc1ccccc1
Reactant: O=C1CCCC2(C1)OCCO2
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: NCCN
Product: O=[N+]([O-])CC1(SCc2ccccc2)CCC2(CC1)OCCO2
Yield: 72 %

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-9-one (6.00 g), benzylmercaptan (5.00 mL), nitromethane (20 mL), ethylenediamine (2.83 mL) and acetonitrile (25 mL) was heated under reflux for 3 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound (8.96 g, yield 72%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 121-122° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][C:13]1[C:18]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[CH:17][CH:16]=[CH:15][N:14]=1.N1C=CC=CC=1>CCOCC>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:20])=[O:5].[Cl:12][C:13]1[C:18]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Agent: OC(c1ccccc1)c1cccnc1Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
0.37 g phthalic anhydride, 0.50 g 2-chloro-α-phenyl-3-pyridinemethanol and 3 ml pyridine are heated at 100° C. for 7 hrs. The reaction mixture is diluted with ether and extracted twice with aqueous sodium carbonate. The aqueous extracts, after washing with ether, are acidified with 2N HCl, affording 0.5 g title product, m.p. 173°-4° C. (ethanol:water); neutralization equivalent: 372 (calculated 367.8); Cl 9.73 (9.64).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=[O:28])[O:23]C(C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:22]([OH:28])=[O:23].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2ccncc2)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccncc2)C[C@H](C)N3C(C)=O)cn1
Product: O=CO
Reaction time: 2 h
Yield: 45.7 %

Procedure:
A solution of 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(4-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see intermediate 59) (147 mg, 0.291 mmol) in dichloromethane (DCM) (3 mL) at room temperature under nitrogen was treated with trifluoroacetic acid (TFA) (0.449 mL, 5.83 mmol). The resulting mixture was stirred at this temperature for 2 h then concentrated in vacuo. The residue was co-evaporated with DCM then was dissolved in 1:1 MeOH:DMSO (1 ml×2) and purified by MDAP (modifier: formic acid). The desired fractions were combined and the solvent was removed under vacuo to give (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-4-pyridinyl-1,2,3,4-tetrahydro-4-quinolinamine formate salt (60 mg, 0.133 mmol, 45.7% yield).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([I:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CCOCC>[I-:19].[CH2:11]([N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3][C:2]=1[CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1nc2ccccc2o1
Reactant: CCCCCCCCI
Solvent: CCOCC
Product: CCCCCCCC[n+]1c(C)oc2ccccc21
Product: [I-]
Yield: 73.2 %

Procedure:
A stirred solution of 2-methylbenzoxazole (10.0 g, 75 mmol) and n-octyl iodide (18.0 g, 75 mmol) was heated at reflux for 18 h. After cooling, the yellow-brown solid was slurried in ether, filtered and washed with ether. The resulting solid was air dried to give (20.5 g, 73%) of 3-n-octyl-2-methylbenzoxazolium iodide.