Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)[C:5](O)=[O:6])C.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O.C1COCC1>[C:24]([NH:3][CH:4]([CH2:5][OH:6])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:13][CH:14]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCN(C(Cc1ccc(-c2nc3ccccc3o2)cc1)C(=O)O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCC(Cc1ccc(-c2nc3ccccc3o2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a mixture of ethyl 2-[4-(benzoxazol-2-yl)benzyl]-N-trityl-glycine (8.8 g; 16 mmol), dry ether (80 ml) and dry THF (40 ml) is added lithium aluminum hydride (0.8 g; 21 mmol) at 0° C. The reaction is then cooled to 0° C. and 0.8 ml H2O is added slowly, followed by 0.8 ml of 15% NaOH and then 2.4 ml H2O . This is brought to 25° C. and stirred 15 hours. The reaction is filtered through a bed of celite and extracted with ether and THF. The filtrate is concentrated to an oil which solidifies upon treatment with MeOH and Et2O. The solid is recrystallized from MeOH to yield N-trityl-1-[4-(benzoxazol-2-yl)phenyl]-3-hydroxy-2-propanamine.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34]([OH:36])=O)=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[N:41]1([CH2:46][CH2:47][NH2:48])[CH2:45][CH2:44][CH2:43][CH2:42]1.C(N(CC)CC)C>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34]([NH:48][CH2:47][CH2:46][N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:36])=[N:4]1)[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CCn1nc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCn1nc(C(=O)NCCN2CCCC2)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a suspension of 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (Example 8c) (2.5 g, 5.10 mmol) in dichloromethane (50 mL) at room temperature was added thionyl chloride (0.446 mL, 6.12 mmol), and the mixture was heated to reflux for 1 h. After cooling to room temperature the mixture was added dropwise to a solution of 2-(pyrrolidin-1-yl)ethanamine (0.711 mL, 5.61 mmol) and triethylamine (1.066 mL, 7.65 mmol) in dichloromethane (50.0 mL) in an ice bath. The resulting mixture was then allowed to warm up to room temperature, and stirred for another 0.5 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo, and the residue was purified twice by automatic silica gel column chromatography (Combiflash RF), eluting with a mixture of [dichloromethane/methanol/ammonium hydroxide (80:20:2)]/dichloromethane (0-50%) to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydrocinnoline-3-carboxamide (2.2 g, 3.75 mmol, 73.6% yield) as a light yellow solid. LCMS: (M+H)+: 587.3.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[N:13]1([CH2:11][CH:7]2[NH:8][CH2:9][CH2:10][C:5]3([O:1][CH2:2][CH2:3][O:4]3)[CH2:6]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(C1CC2(CCN1)OCCO2)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C1CCN(CC2CC3(CCN2)OCCO3)C1
Yield: 42.8 %

Procedure:
A solution of the product of stage (v) (712 mg) in dry tetrahydrofuran (7.5 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (total of 363 mg) in dry tetrahydrofuran (15 ml) under nitrogen. The mixture was heated under reflux for 19 h, allowed to cool for 1 h and water (5 ml) was cautiously added dropwise. More water (10 ml) and aqueous sodium hydroxide (2N, 5 ml) were then added followed by chloroform (25 ml). The insoluble material was filtered off, washed thoroughly with chloroform and the filtrate layers separated. The aqueous layer was re-extracted with chloroform (2×25 ml) and the combined organic solution dried and evaporated to give crude title compound (750 mg) as an oil. This oil was purified by column chromatography on neutral activity I alumina (Type UGl, 22.5 g) eluting with ether-methanol (19:1) to give the title compound as an oil (287 mg). T.l.c. Alumina/ether-methanol (19:1) Rf 0.30.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.[CH3:35][NH2:36]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[N:36][CH3:35])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CN
Reactant: O=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Solvent: CO
Product: CN=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 90 %

Procedure:
A stirred solution of Example 23 (0.5 g, 1.0 mmol) in MeOH was refluxed with methylamine (1.6 mL, 1.5 equiv. 33% in EtOH) for one hour. Evaporation in vacuo gave (E)-1-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methyliminomethylphenyl)propene-1-one (0.46 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14](CCCOC3CCCCO3)[C:13](=[O:28])[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:49])([F:48])[O:40][C:41]1[CH:42]=[C:43]([OH:47])[CH:44]=[CH:45][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:28])[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[C:11]=2[N:10]=[C:9]1[O:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([O:40][C:39]([F:38])([F:48])[F:49])[CH:42]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 7-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (500 mg, 1.232 mmol, product of intermediate 18, step 4) in DMF (3 mL) was added 3-(trifluoromethoxy)phenol (280 mg, 1.55 mmol), followed by potassium carbonate (400 mg, 2.90 mmol). The mixture was stirred at 80° C. overnight. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (0.59 g, 87.3% yield) as brown oil. LCMS retention time 2.157 min; LCMS MH+ 549.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=2[O:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])[CH:8]=[CH:9][CH:10]=1.[ClH:28]>O1CCOCC1>[ClH:28].[OH:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=2[O:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(CCc2ccccc2OCCC2CCCN2C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCC1CCOc1ccccc1CCc1cccc(O)c1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
1.80 g of 2-(2-{2-[2-(3-methoxymethoxyphenyl)ethyl]phenoxy}ethyl]-1-methylpyrrolidine [prepared as described in step (a) above] were dissolved in 20 ml of a 4N solution of hydrogen chloride in dioxane, and the solution was allowed to stand at room temperature for 30 minutes. At the end of this time, the mixture was concentrated by distillation under reduced pressure, and the resulting oily residue was dissolved in 20 ml of methylene chloride. Ethyl acetate was slowly added to the solution until it just began to show signs of turbidity. The mixture was then allowed to stand overnight at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 1.25 g (yield 71%) of the title compound as colorless crystals, melting at 68°-70° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:30][S:31](O)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:4]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[NH:13][N:12]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CNS(C)(=O)=O)cc2F)n[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)-N6-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine (Example 18; 0.10 g, 0.25 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.25 mmol), DIEA (0.064 g, 0.50 mmol), DMAP (0.033 g, 0.27 mmol), and THF (5 ml). The resulting suspension was shaken vigorously at 60° C. for 8 hrs and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give (0.82 g, 67%). 1H NMR (400 MHz, CD3OD) δ 7.44-7.41 (m, 2H), 7.17 (d, J=10.7 Hz, 1H), 7.02-6.97 (m, 2H), 5.26 (s, 1H), 5.01-4.99 (m, 1H), 4.56-4.53 (m, 1H), 4.16-4.08 (m, 1H), 3.01 (s, 3H), 1.52 (d, J=7.0 Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 480. Found: [M+H]+ 481.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[F:15].[NH4+:17].[OH-]>>[NH2:13][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]([C:3]([NH2:17])=[O:2])=[C:5]([F:15])[C:6]=1[F:14]
Reactant: [NH4+]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Agent: [OH-]
Product: NC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Temperature: 25 °C
Reaction time: 192 h
Yield: 84.6 %

Procedure:
A mixture of 4-amino-2,3-difluoro-5-nitrobenzoic acid methyl ester (150 g, 0.646 mol) in 14 M NH4OH (1 L, 14 mol, ˜7 vol) was stirred at room temperature. After 8 days HPLC analysis showed the reaction was almost complete. The solid product was filtered off, washed with water (2×200 mL), and then dried at 50° C. in a vacuum oven to provide 4-amino-2,3-difluoro-5-nitrobenzamide (118.7 g, 85% yield) as a yellow powder. HPLC 93.3a %. 1H NMR (400 MHz, DMSO-d6) δ7.65 (2H, br s, NH2), 7.83 (2H, br s, NH2), 8.30 (1H, apparent dd, J 1.5, 7.2, Ar—H). 19F NMR (376 MHz, DMSO-d6) δ −130, −154. 13C (100 MHz, DMSO-d6) δ 110.7 (C, d, J 12), 123.8 (CH, s), 128.1 (C, s), 139.5 (C, dd, J 14, 4), 139.6 (CF, dd, J 243, 17), 151.7 (CF, dd, J 257, 11), 163.4 (C, s). IR νmax/cm−1 3496, 3419, 3385, 3179, 1653, 1279, 1240. MS APCI (−) 216 (M−1) detected.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C(N(CC)CC)C.[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>O1CCCC1>[F:20][C:8]1[C:9]([F:19])=[C:10]([C:15]([F:17])([F:18])[F:16])[C:11]([F:14])=[C:12]([F:13])[C:7]=1[N:6]1[C:2]([NH:1][C:36]([CH2:35][O:34][C:31]([CH3:32])=[O:33])=[O:37])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Yield: 12.4 %

Procedure:
To a stirred solution of 0.68 gram (0.0020 mole) of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-4-nitropyrazole and 0.42 gram (0.0042 mole) of triethylamine in 20 mL of tetrahydrofuran was added dropwise a solution of 0.55 gram (0.0040 mole) of acetoxyacetyl chloride in 8 mL of tetrahydrofuran. The reaction mixture was heated at reflux for two hours. An additional 0.43 gram of acetoxyacetyl chloride and 0.22 gram of triethylamine were added, and the mixture was heated at reflux for 20 minutes. The mixture was cooled and filtered,, and the filtrate was evaporated under reduced pressure, leaving an oil. This oil was purified by column chromatography on silica gel, eluted with ethyl acetate/n-hexane (50:50) to yield 0.11 gram of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonyloxymethylcarbonylamino-4-nitropyrazole as a waxy solid, Compound 14 of Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[N:7]O)[CH2:5][C:4]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[O:3]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>>[CH3:14][N:11]1[CH2:12][CH2:13][C:4]2([O:3][CH:2]([CH3:1])[CH:6]3[CH:5]2[NH:7]3)[CH2:9][CH2:10]1
Reactant: CC1OC2(CCN(C)CC2)CC1=NO
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Product: CC1OC2(CCN(C)CC2)C2NC12

Procedure:
The precursor amine compounds may in turn be prepared as described in greater detail below. Thus, for example, 2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane may be obtained by reaction of 4-aminomethyl-1-methyl-piperidin-4-ol with acetaldehyde in dry dichloromethane. 2,8-Dimethyl-1-oxa-4,8-diazaspiro[4.5]decane may be obtained by reaction of 1-amino-2-propanol with 1-methyl-4-piperidone under reflux. 1′,4-Dimethylspiro[3-oxa-6-azabicyclo[3.1.0]hexane-2,4′-piperidine] may be obtained by first preparing 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime from 1-methyl-4-piperidone via 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one per the procedure of Tsukamoto et. al., Chem. Pharm. Bull. 1995, 43, 842-852, followed by reduction of the oxime with Red-A1 (sodium bis(2-methoxyethoxy)aluminumhydride) and then basic workup to yield 1′,4-Dimethylspiro[3-oxa-6-azabicyclo[3.1.0]hexane-2,4′-piperidine]. 2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]dec-3-yl amine may be obtained by first preparing 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime from 1-methyl-4-piperidone via 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one per the procedure of Tsukamoto et. al., Chem. Pharm. Bull. 1995, 43, 842-852, followed by reduction of the oxime with lithium aluminum hydride/aluminum chloride. Compounds of formula I may then be prepared from these amines by an appropriate coupling reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[F:12][C:13]([F:18])([F:17])C([O-])=O.[Na+].O>CN1C(=O)CCC1>[F:12][C:13]([F:18])([F:17])[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 160 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
To a solution of 2-bromo-4-nitrotoluene (23.2 mmol) in NMP (200 mL) was added sodium trifluoroacetate (8.5 g, 62.5 mmol) and Cul (8.75 g, 46 mmol) and the reaction mixture was stirred at 160° C. for 4 hours. The solution was cooled and water (300 mL) was added. The solution was filtrated and the solid was washed with ethyl ether (250 mL×3). The organic phase was washed with water and brine, dried, filtered, concentrated and purified through column chromatography to give 2-(trifluoromethyl)-4-nitrotoluene (3.12 g).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][C@H:35]([CH2:40][OH:41])[CH2:36][CH:37]([CH3:39])[CH3:38]>O1CCCC1.CC(C)=O>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:34][C@H:35]([CH2:40][OH:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)C[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A solution containing 2.49 g (10 mmol) N-carbobenzoxy-L-proline and 1.01 g (10 mmol) N-methylmorpholine in approximately 100 ml tetrahydrofuran (THF) was cooled to -20° under nitrogen, and 1.37 g (10 mmol) isobutyl chloroformate was added with magnetic stirring. After five minutes, a solution of 1.17 g (10 mmol) L-leucinol in 5 mL THF was added, and the resulting reaction mixture was stirred for 30 minutes at 0°. THF evaporated under vacuum, and 30 mL water and 100 mL ethyl acetate were added to the resulting residue. After separation of aqueous and organic layers, the organic layer was decanted and retained. The aqueous layer was extracted with a second aliquot (100 mL) of ethyl acetate, and the resulting organic phase was separated. The combined organic layers were washed with 50 mL of ice-cold, 5% aqueous citric acid, followed by 50 mL of an ice-cold, 5% sodium bicarbonate solution. An organic phase was separated, dried over anhydrous magnesium sulfate, and the ethyl acetate was evaporated to provide 3.25 g of crude product. Recrystallization from a mixture of 40 mL ethyl acetate and 25 mL n-hexane gave 2.03 g (5.8 mmol; 58%) of colorless N-carbobenzoxy-L-prolyl-L-leucinol, m.p. 95°-95.5°, α25D-72°, (C=1.03 g/100 mL acetone).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][O:7][CH2:8][CH:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[OH:10])[CH3:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>N1C=CC=CC=1>[C:21]([O:10][CH:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:8][O:7][CH2:6][CH2:5][N:3]([CH3:2])[CH3:4])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCOCC(O)c1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)OC(COCCN(C)C)c1cccc2ccccc12

Procedure:
2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethanol hydrochloride was reacted with acetic anhydride in pyridine in the presence of triethylamine to obtain oily 1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethane (compound No. 300).
Reaction SMILES: [OH:1][C@@H:2]([CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25][N:26]=[N+]=[N-])=[N:12][C:11]=2[N:10]([CH3:29])[C:8]1=[O:9].[H][H]>C(O)C.[Pd]>[OH:1][C@@H:2]([CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25][NH2:26])=[N:12][C:11]=2[N:10]([CH3:29])[C:8]1=[O:9]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(nc(CN=[N+]=[N-])n2Cc2ccccc2)n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H](O)CCCCn1c(=O)c2c(nc(CN)n2Cc2ccccc2)n(C)c1=O
Yield: 251.6 %

Procedure:
To a solution of (S)-1-(5-hydroxyhexyl)-7-benzyl-8-azidomethyl-3-methylxanthine (1.7 g, 1.65 mmol) in ethanol (100 ml) was added 10% palladium on carbon catalyst (0.6 g). The mixture was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. Removal of the catalyst by filtration and evaporation of the solvent under reduced pressure provided (S)-1-(5-hydroxyhexyl)-7-benzyl-8-aminomethyl-3-methylxanthine (1.6 g, 100% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd].[Br-].[Zn+2].[Br-]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(Cl)cc1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a solution of (E)-3-(4-chloro-phenyl)-acrylic acid ethyl ester (0.37 g, 1.73 mmol) in ethyl acetate (10 ml) were added palladium on activated charcoal (18 mg) and zinc bromide (80 mg, 0.35 mmol). The reaction vessel was then pressurized with hydrogen gas to a pressure of 1 atmosphere and the mixture was stirred for 18 h. The catalyst was then removed by filtration, washing with ethyl acetate, and the filtrate was concentrated in vacuo to yield a colourless oil which was used for the next step without further purification; MS (ISP): 214.2, 212.1 ([M+H]+.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]1([C:32]2[N:31]=[CH:30][C:29]([C:25]3[CH:24]=[C:23]([C:21]4[CH2:20][C:19](=[O:38])[NH:18][C:9]5[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:28]=[CH:27][CH:26]=3)=[CH:34][CH:33]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccc(C4CC4)nc3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M153) (300 mg, 0.556 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (125 mg, 53%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1cc(C)c2c(c1)C(=O)C(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 5,7-dimethyl-1H-indole-2,3-dione in tetrahydrofuran at 0° C. was added 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (40 mL). After stirred at room temperature overnight, a 5% HCI solution was added to the mixture and it was stirred 20 minutes. It was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and evaporated to dryness to afford the title compound as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[N:7][CH:8]=1.N[C:22]1C=NC(OC)=CN=1.ClC1C2C(=CC=CC=2)N=C(C)N=1>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:22])=[N:7][CH:8]=1
Reactant: COc1cnc(Nc2nc(C)nc3ccccc23)cn1
Reactant: COc1cnc(N)cn1
Agent: Cc1nc(Cl)c2ccccc2n1
Product: COc1cnc(N(C)c2nc(C)nc3ccccc23)cn1

Procedure:
(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The title compound was prepared from 2-amino-5-methoxy-pyrazine (105 mg, 0.84 mmol) and 4-chloro-2-methyl-quinazoline (150 mg, 0.84 mmol) by a procedure similar to Example 125c, yielding 106 mg of the title product.