Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.Cl.[CH2:16]([O:18][C:19](=[O:29])[C@H:20]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH2:21])[CH3:17].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.CO.ClCCl.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([NH:21][C@H:20]([C:19]([O:18][CH2:16][CH3:17])=[O:29])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:8]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])c(OC)c1)C(=O)OCC
Reaction time: 0.25 h

Procedure:
A solution of 3-methoxy-4-nitrobenzoic acid (10.0 g, 50.7 mmoles), (L)-glutamate diethyl ester hydrochloride (12.2 g, 50.7 mmoles), and 1-hydroxyenzotriazole (6.85 g, 50.7 mmoles) in dry dimethylformamide (250 mL) was stirred under nitrogen while triethylamine (5.13 g, 7.07 mL, 50.7 mmol) was added dropwise during 1 minute. After 15 minutes, 1,3-dicyclohexylcarbodiimide (11.5 g, 55.8 mmoles) was added in portions during 2 minutes. The reaction mixture was filtered after 18 hours and the solids were rinsed with dichloromethane (2×50 mL). The filtrate was spin evaporated and dried to an amber residue that was dissolved in dichloromethane (300 mL). The organic phase was washed successively with saturated bicarbonate solution, 5% citric acid, and 1:1 brine/water (1×300 mL each). The organic phase was then dried (MgSO4) and filtered to give a brown-orange solution that showed a major spot on tlc (silica, 2:1 hexane/ethyl acetate, Rf = 0.2). The solution was poured onto a silica gel column (500 g, pre-wet with dichloromethane) and rinsed with dichloromethane (500 mL). The product was removed by gradient elution using 10% and 15% added ethyl acetate (8×250 mL fractions each). Like fractions were combined by spin evaporation and dried (high vacuum) to give a clear yellow oil; yield, 11.5 g (59%); 1H-NMR (DMSO-d6) δ 1.15 and 1.18 (2t overlapped, 6H), 1.9-2.2 (m, 2H), 2.45 (t obscured by DMSO, 2H), 3.98 (s, 3H), 3.9-4.2 (2q overlapped, 4H), 4.46 (m, 1H), 7.58 (dxd, Jo =8 Hz, Jm =2 Hz, 1H), 7.71 (d, Jm =2 Hz, 1H), 7.97 (d, Jo =8 Hz, 1H), 9.00 (d, 1H); uv (MeOH) 327 nm max (2940), 295 min (2090), 257 sh (6640), 235 sh (9140), 203 max (29700); mass spec (CI) m/e 383 (100%). Anal. Calcd. for C17H22N2O8 (Mr 382.37): C, 53.40; H, 5.80; N, 7.33. Found: C, b 53.29; H, 5.85; N, 7.29.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([N+]1C=CN(C)C=1)CCC.C([N+]1C=CN(C)C=1)CCC.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Ni+2]>[CH2:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: c1ccccc1
Reactant: C=CCCCCCC
Agent: [Ni+2]
Agent: CCCC[n+]1ccn(C)c1
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCCc1ccccc1
Temperature: 60 °C

Procedure:
Nickel(II) bis-triflimide (0.06 g, 0.1 mmol) was dissolved in [bmim][NTf2] (1.0 g) in a round-bottomed flask equipped with a magnetic stirrer and reflux condenser. Benzene (3.90 g, 50 mmol) and oct-1-ene (1.12 g, 10 mmol) were added. The mixture was heated under reflux for 18 hours and was analysed by gas chromatographic analysis as in previous examples. The oct-1-ene peak disappeared and three isomers of octylbenzene were formed (70%, 20:26:54 2- to 3- to 4-isomer ratio) as well as octene dimer (30%). The less dense product phase was decanted from the ionic/catalyst phase and purified by Kugelrohr distillation. The ionic liquid and catalyst were prepared for reuse by heating at 60° C. under vacuum for 1 hour. The ionic liquid and catalyst were used for further reactions of benzene with oct-1-ene without loss of activity. This is an alkylation of benzene with an alkene using a metal bis-triflimide catalyst. Benzene and oct-1-ene react in the presence of 1% nickel(II) bis-triflimide in [bmim][NTf2] to form three isomers of octyl benzene and a small amount of hexadecene (unknown isomeric distribution). This is shown below: The Alkylation of Benzene with oct-1-ene.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[C:17](O)[N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:3][C:17]1[CH:18]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[Cl:6])[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2nc(O)cc(-c3ccccc3Cl)n2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc(Cl)cc(-c3ccccc3Cl)n2)n1
Yield: 86.6 %

Procedure:
Phosphoryl chloride (5 g) was added to the solution of 4-o-chlorophenyl-6-hydroxy-2-(6-methyl-2-pyridinyl)pyrimidine (5 g) in toluene (100 ml). The mixture was heated under reflux for 1 hour and left to stand to room temperature. Aqueous sodium carbonate solution was added thereto until the reaction solution became about pH 8 to be separated into two layers. Toluene layer was washed with water and dried over anhydrous magnesium sulfate. The toluene layer was concentrated under reduced pressure to obtain 4-chloro-6-o-chlorophenyl-2-(6-methyl-2-pyridinyl)pyrimidine (4.6 g).
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[CH3:43][NH:44][C:45]([C:47]1[NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[CH:55][C:49]=2[N:48]=1)=[O:46]>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:48]2[C:49]3[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=3[N:51]=[C:47]2[C:45]([NH:44][CH3:43])=[O:46])=[CH:37][CH:38]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CNC(=O)c1nc2ccccc2[nH]1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CNC(=O)c1nc2ccccc2n1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and N-methyl-1H-benzo[d]imidazole-2-carboxamide. M/e+ 416 for C23H19ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.40 (d, J=6.9 Hz, 1H), 7.90 (d, J=4.7 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.62 (dd, J=13.1, 8.0 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.18 (dd, J=8.4, 1.1 Hz, 2H), 6.98 (m, 1H), 6.73 (m, 1H), 6.67 (s, 2H) 3.12 (d, J=5.1 Hz, 3H) 1.83 (s, 1H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].C1([N-]C2CCCCC2)CCCCC1.[Li+].Br[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[CH2:35][C@H:34]([CH3:36])[N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:32]([CH3:44])[CH2:31]2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:1][C:2]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][N:30]2[CH2:35][C@H:34]([CH3:36])[N:33]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C@H:32]([CH3:44])[CH2:31]2)=[CH:27][CH:28]=1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Reactant: COC(=O)C(C)C
Agent: [Pd]
Agent: C1CCC([N-]C2CCCCC2)CC1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)c1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
A solution of methyl 2-methylpropanoate (188 ul, 1.64 mmol) in toluene (3 ml) was added to lithium dicyclohexylamide (362 mg, 1.93 mmol) under glove bag conditions. The suspension was stirred for 10 mins then added to a mixture of D43 (570 mg, 1.49 mmol) and bis(dibenzylideneacetone) palladium (0) (43 mg, 0.074 mmol). Tri(tert-butyl)phosphine (18 ul, 0.074 mmol) was added and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo and chromatography eluting with 0-90% EtOAc/petroleum ether gave the title compound as a yellow oil (395 mg). δH (CDCl3, 250 MHz) 7.29 (4H, m), 4.07 (2H, m), 3.66 (3H, s), 3.46 (2H, s), 2.61 (2H, m), 2.12 (2H, dd), 1.58 (6H, s), 1.46 (9H, s), 1.29 (6H, d). MS (ES): MH+ 405.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1C=CC=CC=1>[C:30](=[O:31])([O:29][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCOC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 1.07 g. of chloroformic acid n-heptyl ester as in Example 1. The 1.8 g. of yellow oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.782 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-heptyl carbonate obtained melts at 50.2°-50.5° and has a clearing point of 65.2°. UV (EtOH): ε270 = 25,900.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[N:13][C:12]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:24]1[C:29]2[CH:30]=[CH:31][C:32]([NH2:34])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([NH:34][C:32]3[CH:31]=[CH:30][C:29]4[O:24][CH2:25][CH2:26][O:27][C:28]=4[CH:33]=3)[N:14]=[N:13][C:12]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: CC(C)(C)c1ccc(-c2cc(Nc3ccc4c(c3)OCCO4)nnc2-c2ccccc2)cc1

Procedure:
Analogous to the procedure used to prepare Example 5(b), 4-(4-tert-butyl-phenyl)-6-chloro-3-phenylpyridazine, Example 78(d), (155 mg, 0.5 mmol) and 1,4-benzodioxan-6-amine (80 mg, 0.5 mmol, Aldrich) to give the product as a light yellow crystalline solid. MS (ESI, pos. ion) m/z: 438 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][N:14]([CH3:28])[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][CH:18]2[CH2:17][CH2:16][C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([N:14]([CH3:28])[CH3:13])[CH2:20][CH2:19]2)=[CH:5]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NCCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tryptamine (320 mg) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid (229 μl) and sodium triacetoxyborohydride (550 mg), the suspension was stirred for 3 days at RT. For working up, water (20 ml) was added to the reaction mixture. The organic phase was separated off and the aqueous phase was extracted once with ether and then rendered strongly alkaline with sodium hydroxide solution. The aqueous phase was milky-cloudy at pH 10. It was extracted with ethyl acetate (4×10 ml), the extracts were combined, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (674 mg) was recrystallized twice from ethyl acetate (5 ml). 22 mg of the nonpolar diastereoisomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained (m.p. 134-138° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[N:7][CH:8]=1.[H-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15]I.[Na+].[Cl-]>CN(C=O)C.O>[Cl:12][CH2:13][CH2:14][CH2:15][O:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[N:7][CH:6]=1
Reactant: ClCCCI
Reactant: COc1cncc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cncc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-methoxypyridin-3-ol (0.50 g, 4.01 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.19 g of an 80% dispersion in mineral oil, 6.33 mmol) in DMF (15 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (0.98 g, 4.81 mmol), and the resulting dark brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (0.75 g, 92.8%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2([CH2:14][C@H:15]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])OCC[O:10]2)=[N:3]1>CC(C)=O.CC#N.CC#N.Cl[Pd]Cl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:10])[CH2:14][C@H:15]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:3]1
Reactant: Cc1ccccc1[C@H](CC1(c2ccc(=O)n(C)n2)OCCO1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: CC(C)=O
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(S(C)(=O)=O)cc1
Yield: 55.4 %

Procedure:
To a solution of (R)-2-methyl-6-(2-(2-(4-(methylsulfonyl)phenyl)-2-o-tolylethyl)-1,3-dioxolan-2-yl)pyridazin-3(2H)-one (10 mg, 22 μmol) in acetone (1 ml) was added bis(acetonitrile)dichloropalladium(II) (1.4 mg, 5 μmol, Eq: 0.25), then after 24 h at room temperature another portion of bis(acetonitrile)dichloropalladium(II) (6 mg, 22 μmol) was added, then after 24 h the reaction mixture was evaporated. Chromatography (SiO2; gradient heptane/ethyl acetate 2:1 to ethyl acetate) afforded the title compound (5 mg, 55%). White solid, MS: 411.2 [M+H]+.
Reaction SMILES: C(=O)=O.CC(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:21][C:22]1[C:23](=[O:50])[N:24]([CH:47]([CH3:49])[CH3:48])[N:25]=[CH:26][C:27]=1[NH:28][CH2:29][CH:30]([OH:46])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][C:34]=1[CH2:43][CH2:44][CH3:45].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C.CS(C)=O>[Cl:21][C:22]1[C:23](=[O:50])[N:24]([CH:47]([CH3:49])[CH3:48])[N:25]=[CH:26][C:27]=1[NH:28][CH2:29][C:30](=[O:46])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][C:34]=1[CH2:43][CH2:44][CH3:45]
Reactant: CCCc1cc(C(=O)OC)ccc1OCC(O)CNc1cnn(C(C)C)c(=O)c1Cl
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: CCCc1cc(C(=O)OC)ccc1OCC(=O)CNc1cnn(C(C)C)c(=O)c1Cl
Reaction time: 0.33 h

Procedure:
A mixture of 1.11 g of dimethylsulfoxide and 20 ml of tetrahydrofuran was cooled with dry ice-acetone, and a mixture of 2.24 g of trifluoroacetic anhydride and 3.67 ml of tetrahydrofuran, was gradually dropwise added thereto. The mixture was stirred for 20 minutes, and then a solution obtained by dissolving 0.93 g of 4-chloro-5-[3-(2-n-propyl-4-methoxycarbonylphenoxy)-2-hydroxypropylamino]-2-i-propyl-3(2H)pyridazinone (Compound No. 44) in 8 ml of tetrahydrofuran, was dropwise added thereto. The mixture was stirred for 30 minutes. Then, 1.26 g of triethylamine was dropwise added. Then, the mixture was stirred for 30 minutes under cooling with ice and then for 1 hour at room temperature. Sodium hydrogen carbonate was added thereto, and tetrahydrofuran was distilled off under reduced pressure. The residue was extracted with chloroform, and the extract was washed with water, and dried over sodium sulfate. Then, the solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography by using benzene-ethyl acetate (1:1, v/v) as the developer. The solvent was distilled off, and the colorless crystals thereby obtained were further recrystallized from ethyl acetate-ethyl ether to obtain 0.52 g of the above identified compound as colorless crystals having a melting point of 133° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][NH:19]C(OCC=C)=O)=[CH:14][CH:15]=2)[C:10]([C:26](=[NH:35])[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCOCC1>C(Cl)Cl.[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][NH2:19])=[CH:14][CH:15]=2)[C:10]([C:26](=[NH:35])[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)NCCc1ccc2c(c1)c(C(=N)NC(=O)OC(C)(C)C)cn2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=N)c1cn(C(=O)OC(C)(C)C)c2ccc(CCN)cc12
Reaction time: 0.75 h

Procedure:
A solution of 1-tert-Butoxycarbonyl-3-(tert-butoxycarbonylcarbamimidoyl)-5-(2-[allyloxycarbonylamino]ethyl)indole (reference example 8) (0.199 g, 0.409 mmol), 50 mg tetrakis(triphenylphosphine)palladium (0), and 0.078 mL (0.90 mmol) morpholine in 20 mL CH2Cl2 is stirred for one hour. TLC showed some starting material present, so another 50 mg palladium catalyst is added. After stirring 45 minutes, the reaction mixture is concentrated, and the residue chromatographed (10:1 CH2Cl2:7N NH3 in MeOH) to provide the product as a yelow solid. 1H NMR (CDCl3): δ 1.57 (9H, s), 1.64 (9H, s), 2.88 (4H, m), 7.23 (1H, dd, J1=8.7 Hz, J2=1.2 Hz), 7.77 (1H, s), 8.16 (1H, d, J=8.7 Hz), 8.25 (1H, s). MS (EI) m/z 402 M+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([N:27]2[CH2:41][CH2:40][C:30]3([CH2:34][NH:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31]3)[CH2:29][CH2:28]2)[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:12])([F:11])[F:13])[N:5]=[C:4]([N:27]2[CH2:28][CH2:29][C:30]3([CH2:34][NH:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31]3)[CH2:40][CH2:41]2)[N:3]=1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(N)nc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2nc(N)nc(N3CCC4(CC3)CNC(C(=O)O)C4)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of ethyl 8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid.
Reaction SMILES: [CH3:1][Mg]Cl.[Cl:4][C:5]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8]>C1COCC1>[Cl:4][C:5]1[C:6]([C:7](=[O:8])[CH3:1])=[CH:13][CH:14]=[C:15]([CH3:17])[N:16]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(C)nc1Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C)nc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl magnesium chloride (3 M in THF, 10 mL) was slowly added at 0° C. to a solution of 2-chloro-N-methoxy-6,N-dimethyl-nicotinamide (2.4 g) in THF (100 mL). The reaction mixture was stirred at 0° C. for 1 h, then quenched with water. The resulting mixture was extracted with EtOAc, the combined organics dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, gradient from 0 to 25% in 25 minutes) to give 1-(2-chloro-6-methylpyridin-3-yl)-ethanone (0.85 g) as a brown oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.CC1C=CC(S(O[CH2:23][C@@H:24]([C@@H:39]2[C@:56]3([CH3:57])[C@H:42]([C@H:43]4[C@H:53]([CH2:54][CH2:55]3)[C@:51]3([CH3:52])[C:46]([CH2:47][C@@H:48]([O:65][CH:66]5[CH2:71][CH2:70][CH2:69][CH2:68][O:67]5)[CH2:49][C@@H:50]3[O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][O:60]3)=[CH:45][CH2:44]4)[CH2:41][CH2:40]2)[CH2:25][CH2:26][C:27]([F:38])([F:37])[C:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])([CH3:30])[CH3:29])(=O)=O)=CC=1>CCOCC>[O:60]1[CH2:61][CH2:62][CH2:63][CH2:64][CH:59]1[O:58][C@@H:50]1[C@@:51]2([CH3:52])[C:46](=[CH:45][CH2:44][C@@H:43]3[C@@H:53]2[CH2:54][CH2:55][C@@:56]2([CH3:57])[C@H:42]3[CH2:41][CH2:40][C@@H:39]2[C@H:24]([CH3:23])[CH2:25][CH2:26][C:27]([F:37])([F:38])[C:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])([CH3:30])[CH3:29])[CH2:47][C@@H:48]([O:65][CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][O:67]2)[CH2:49]1
Reactant: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
A mixture of 0.410 g (0.0108 mol) of lithium aluminum hydride, 50 mL of tetrahydrofuran and 2.98 g (0.0033 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate) was heated at reflux (60°) for 1 hr and cooled to 0° C. The mixture was diluted with 120 mL of ether and quenched with the dropwise addition of 0.82 mL of water and 0.65 mL of 10% aqueous sodium hydroxide solution. The mixture was then dried for 1 hr and filtered. The solids were triturated with ether and filtered. The combined filtrates were evaporated to dryness and chromatographed on 0.06-0.20 mm silica gel to yield [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-ene, [α]D16 +2° (c 1, CHCl3).
Reaction SMILES: [ClH:1].[N:2]1([C:9]2[CH:10]=[C:11]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH:28]([F:30])[F:29])[CH:22]=3)(=[O:20])=[O:19])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:31]=O>[BH4-].[Na+].C(#N)C>[ClH:1].[F:29][CH:28]([F:30])[O:27][C:23]1[CH:22]=[C:21]([S:18]([NH:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([N:2]3[CH2:8][CH2:7][CH2:6][N:5]([CH3:31])[CH2:4][CH2:3]3)[CH:10]=2)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCNCC1
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCN(C)CC1

Procedure:
The title compound was prepared from the title compound of Example 1 under reductive amination conditions employing an aqueous solution of formaldehyde and sodium borohydride in acetonitrile as solvent.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])[CH2:4][CH2:3]1.O=[CH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:27])[CH3:26])[CH2:20][CH2:19]1>>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH2:16][CH2:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:27])[CH3:26])[CH2:20][CH2:19]2)[CH2:3][CH2:4]1)=[O:9]
Reactant: O=C(c1cccs1)C1CCNCC1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3cccs3)CC2)CC1

Procedure:
From piperidin-4-yl-thiophen-2-yl-methanone hydrochloride (74 mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-acetamide (64 mg, intermediate AG). Yield: 75 mg (65%). Light yellow solid. MS (m/z): 363.4 ([M+H]+).