Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.C(O)C.[C:14]([OH:18])(=[O:17])[CH:15]=O>O>[C:3]1([CH3:2])[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][N:10]=[CH:15][C:14]([OH:18])=[O:17])[CH:4]=1
Reactant: O=CC(=O)O
Reactant: Cc1cccc(NN)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cccc(NN=CC(=O)O)c1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 68.5 %

Procedure:
3-Methylphenylhydrazine hydrochloride (15.9 g, 100 mmol) was dissolved in water (450 mL) and ethanol (600 mL) with heating at 60° C. A solution of glyoxylic acid (9.21 g, 100 mmol) in water (100 mL) was added to the warm solution using water (3×15 mL) to rinse. The reaction mixture was stirred at 60° C. for 45 minutes and then cooled slightly and concentrated to remove ethanol. The aqueous mixture was neutralized with NaOH and then water was added (800 mL). The precipitate was filtered, washed with water (3×100 mL), washed with hexanes (100 mL) and dried to give the subtitle compound as a brown solid (12.2 g, 69%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8]/[N:9]=[C:10](/[C:16](=[O:18])[CH3:17])\[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:19]Br>>[Br:19][CH2:17][C:16](=[O:18])/[C:10](=[N:9]/[O:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[CH3:1])/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: BrBr
Reactant: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@@H]1C)C(C)=O
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@@H]1C)C(=O)CBr
Yield: 68 %

Procedure:
Ethyl (Z)-2-(cis-2-methylcyclohexyloxyimino)-3-oxobutyrate (0.46 g) was treated with bromine as described in Example 4c to give the title compound (0.41 g, 68%), νmax (film) 2930, 1740, and 1695 cm-1, δH (CDCl3) 0.95 (3H, d, J 6.7 Hz), 1.35 (3H, t), 1.3-2.1 (9H, m), 4.35 (2H, s), 4.38 (2H, q), and 4.40 (1H, m). [Mass spectrum: +ve ion (ammonia) MH+ (334)].
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Br[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1>C1(C)C=CC=CC=1.O>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:1][CH2:2][CH3:3])[N:7]=1
Reactant: CC[O-]
Reactant: Brc1cccc(Br)n1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cccc(Br)n1

Procedure:
Sodium ethoxide (1.5 g, 63 mmol sodium, in ethanol (30 ml)) was added to 2,6-dibromopyridine (15 g, 63 mmol) in toluene (150 ml) at ambient temperature under nitrogen, and the reaction heated under reflux for 5 hours. The cooled mixture was diluted with water (100 ml), and extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel using pentane/ethyl acetate (100:0 to 95:5) as eluant to give the title compound as a yellow oil, (quantitative).
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[C:10]([CH3:25])[C:11]([C:14]2(O)[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.S(Cl)(Cl)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH3:25])[C:11]([C:14]2[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH:15]=2)=[N:12][CH:13]=1
Reactant: Cc1cc(Br)cnc1C1(O)CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Br)cnc1C1=CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 49.5 %

Procedure:
Pyridine (42.7 ml) was added to a solution of 8-(5-bromo-3-methylpyridin-2-yl)-1,4-dioxaspiro[4,5]decan-8-ol (28 g) in dichloromethane (300 ml), thionyl chloride (19 ml) was added dropwise under ice cooling and the reaction solution was warmed to room temperature and stirred for an hour. After completion of the reaction, the reaction solution was poured into 10% aqueous solution of sodium carbonate, stirred and the resulting precipitate was collected by filtration and dried at 60° C. under air blow to give the titled compound (13.1 g) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]([NH2:19])([CH2:17][CH3:18])([CH3:16])[CH3:15]>C(#N)C>[CH3:15][C:14]([NH:19][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4])([CH3:16])[CH2:17][CH3:18]
Reactant: CCC(C)(C)N
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)CC
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.152 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added tert-amylamine (0.027 g, 0.228 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 5% MeOH/CH2Cl2 to provide the titled compound. MS (DCI) m/z 248 (M+H)+.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:34])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.[ClH:35].C(O)(C)C.[H][H]>C(O)(C)C.[C].[Pd]>[ClH:35].[NH2:11][C@H:12]([C:16]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:34])=[O:17])[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(C)[C@H](N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O
Yield: 84.2 %

Procedure:
To a solution of 1.70 g (3.55 m-mol) of 5'-O-(N-benzyloxycarbonylvalyl)-2'-deoxy-5-fluorouridine obtained in Example 26 in 50 ml of isopropyl alcohol were added 10% palladium-carbon (750 mg) and a solution of 16.0% hydrogen chloride-isopropyl alcohol (810 mg). The mixture was stirred for 3.5 hours in a stream of hydrogen under normal pressure at ordinary temperature. The catalyst was filtered off and the solvent was distilled off under reduced pressure from the reaction mixture and the residue was dissolved in isopropyl alcohol (5 ml). A small amount of ether was added to this solution and the resultant white precipitate was collected by filtration in a stream of dry nitrogen whereby 1.14 g (yield: 84.1%) of 5'-O-(valyl)-2'-deoxy-5-fluorouridine hydrochloride was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[N:5][S:6][C:7]=1[CH:8]=[CH2:9].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([CH3:32])[C:20]=1[CH3:33]>>[CH:8]([C:7]1[S:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:3]=1[CH2:2][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([CH3:32])[C:20]=1[CH3:33])=[CH2:9]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: C=Cc1snc(-c2ccc(CC)cc2)c1CCl
Product: C=Cc1snc(-c2ccc(CC)cc2)c1COc1ccc(CCC(=O)OCC)c(C)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 122 following Step 5 by coupling of 4-(chloromethyl)-3-(4-ethylphenyl)-5-vinylisothiazole with ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as a yellow oil. Mass spectrum (ESI, m/z): Calcd. for C27H31NO3S, 450.2 (M−H). found 450.2.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[O:13])=[CH:7][CH:6]=1)C.O.[OH-].[Li+].O>CCO.C1COCC1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[CH:6][CH:7]=2)=[C:16]([F:22])[CH:17]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
To a solution of 4-[3-(4-bromo-2-fluoro-phenyl)-ureido]-benzoic acid ethyl ester (0.7 g, 0.0018 mol) in EtOH (5 mL) and THF (4 mL), was added a solution of lithium hydroxide monohydrate in water (0.385 g, 0.009 mol, in 5 mL water) at room temperature. The reaction mass was stirred at room temperature for 5 h. The volatiles were evaporated under reduced pressure. The white solid was washed with diethyl ether. Subsequently, the reaction mixture was acidified with 2 N HCl [pH-6] at 0° C. to afford the solid compound. The solid material was collected by filtration and dried to obtain the title compound [0.55 g, 84%]; LC-MS (ESI): Calculated mass: 352.0; Observed mass: 352.9 [M+H]+ (RT: 1.49 min).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>CS(C)=O.CCOCC>[C:10]([C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)#[N:11]
Reactant: N#CCc1ccccn1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccccn2)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersed in oil) (4 g, 0.1 m) in DMSO (70 mL) under nitrogen at 15° C. was added dropwise a solution of 2-pyridyl acetonitrile (6 g, 51 mmol) and 1,5-dibromopentane (6.81 mL, 51 mmol) in ether (40 mL) and DMSO (10 mL) over 1 hour. The mixture was allowed to warm to room temperature and stirred for a further 24 hours under nitrogen. The reaction mixture was carefully quenched by the addition dropwise of isopropanol (10 mL), followed by water (100 mL) 10 minutes later. The reaction solution was taken up in EtOAc and washed with water. The aqueous layer was re-extracted with EtOAc, and the two organic layers were combined, dried (MgSO4), and concentrated in vacuo. The residue was purified on silica with a gradient of heptane to 9:1 heptane/EtOAc to give 1-cyano-1-(2-pyridyl)cyclohexane (6.77 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]([OH:16])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C([O:49][C:50](=[O:71])[C@H:51]([OH:70])[CH2:52][N:53]([CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[C:66]([Cl:68])[CH:65]=[CH:64][C:63]=2[F:69])=[CH:58][CH:57]=1)[NH2:54])C.CCN(C(C)C)C(C)C.CCO.[Li+].[OH-].O>>[Cl:68][C:66]1[CH:65]=[CH:64][C:63]([F:69])=[C:62]([C:59]2[CH:60]=[CH:61][C:56]([CH2:55][N:53]([CH2:52][C@@H:51]([OH:70])[C:50]([OH:71])=[O:49])[NH:54][C:14]([C:10]3[NH:11][C:12](=[O:13])[N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)=[O:16])=[CH:57][CH:58]=2)[CH:67]=1
Reactant: O=C(O)c1nn(-c2cccc(Cl)c2)c(=O)[nH]1
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2cccc(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
1-(3-Chlorophenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid (75.8 mg, 316 μmol) and HCTU (131 mg, 316 μmol) were combined in DMF (1.3 mL, 17.2 mmol). and stirred at room temperature for 15 minutes. (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (105 mg, 287 μmol) and DIPEA (150 mL, 862 μmol) were added, and the resulting mixture was stirred at room temperature for 15 minutes. The mixture was evaporated under reduced pressure. The residue was dissolved in EtOH (1.0 mL, 17.2 mmol) and a solution of 1 M LiOH in water (1.4 mL, 1.4 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then evaporated under reduced pressure. The residue was purified by reverse phase preparative HPLC to yield the title compound (75 mg, purity 100%) as a TFA salt. MS m/z [M+H]+ calc'd for C25H20Cl2FN5O5, 560.08. found 559.6.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:52]=[CH:53][CH:54]=2)[C:33]([NH:35][C:36]2[CH:51]=[CH:50][C:39]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[CH:38][CH:37]=2)=[O:34])O1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(OCC)(=O)C.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:52]=[CH:53][CH:54]=3)[C:33]([NH:35][C:36]3[CH:51]=[CH:50][C:39]([C:40]([O:42][CH2:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[O:41])=[CH:38][CH:37]=3)=[O:34])[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: CC1(C)OB(c2cccc(C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)c2)OC1(C)C
Reactant: COc1ccc(Nc2nc(Br)cn3ccnc23)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)OCc5ccccc5)cc4)c3)cn3ccnc23)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.5 %

Procedure:
A mixture of 6-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (1.82 g, 5.22 mmol) and benzyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (3.06 g, 5.22 mmol, 78% by mass) in 1 M aqueous sodium carbonate (8 mL) and 1,4-dioxane (24 mL) was sparged with nitrogen with stirring for 5 min. The resulting mixture was treated with tetrakis(triphenylphosphine)palladium(0) (1.20 g, 1.04 mmol) and stirred at reflux for 2.5 h. After this time, the reaction was cooled to ambient temperature, diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL) and the combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:4 ethyl acetate/methylene chloride) to afford benzyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)benzoate (2.02 g, 65%) as an off-white solid: mp 154-160° C.; 1H NMR (300 MHz, CDCl3) δ 10.72 (s, 1H), 9.57 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.08-7.94 (m, 7H), 7.69-7.60 (m, 3H), 7.50-7.34 (m, 5H), 6.92 (d, J=8.7 Hz, 1H), 5.36 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H); ESI MS m/z 600 [M+H]+; HPLC, 8.93 min, 95.9% (AUC).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-])=O.CO>O1CCCC1.[C].[Pd]>[NH2:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(C)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of methyl 5-methyl-4-nitrothiophene-2-carboxylate (95 g) and 10% palladium-carbon (50% containing water, 10 g) in tetrahydrofuran (250 mL)-methanol (250 mL) was stirred at 50° C. for 8 hr under a hydrogen atmosphere (0.3 MPa). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from diethyl ether to give methyl 4-amino-5-methylthiophene-2-carboxylate (58 g, yield 72%) as yellow crystals. melting point 91° C.
Reaction SMILES: [CH2:1]([C:6]1[CH2:7][CH2:8][C:9]2[CH2:10][NH:11][C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:18]=2[CH:19]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[C:17]1[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]1)=[N:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=CC2=C(CC1)CNC1=C2CCCC1
Reactant: [H][H]
Product: CCCCCc1ccc2cnc3ccccc3c2c1
Yield: 92.9 %

Procedure:
A mixture of 20 grams of 9-pentyl 1,2,3,4,5,6,7,8-octahydrophenanthridine, prepared as described in example 3, 108 grams of an alkylated benzene solvent and 4 grams of a 5% Palladium/Al catalyst were refluxed for 19 hours. Hydrogen gas was evolved during the reaction. The solvent was removed under diminished pressure to yield after work-up 18 grams of 9-pentyl phenanthridine; infrared spectrum, 6.41; 6.65; and 6.72 μ; C13 nuclear magnetic resonance spectrum, solvent CDCl3, ref. T.M.S.; δ in ppm.: ##STR9##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([N+:20]([O-])=O)=[CH:4][N:3]=1.Cl[Sn]Cl>C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NCc1ccc2ncccc2c1
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Nc1cnc(Cl)nc1NCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A suspension of 2-chloro-5-nitro-N-(quinolin-6-ylmethyl)pyrimidin-4-amine (2.25 g, 7.14 mmol), SnCl2 (7.18 g, 32 mmol) in ethanol (50 mL) and CHCl3 (10 mL) was refluxed for 5 h. The mixture was allowed to cool to room temperature and the solvent was evaporated. The residue was basified to pH 10 by saturated aqueous NaHCO3. The resulting suspension was stirred in ethanol (500 mL) for 2 h and filtered through a pad of silica gel. The filtrate was evaporated. Flash chromatography of the residue over silica gel, using 100% EtOAc to 10% MeOH-EtOAc with 0.5% NH3H2O, gave the desired product (1.02 g, 50%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 4.88 (s, 2H), 7.46-7.53 (m, 2H), 7.77-8.02 (m, 3H), 8.32 (d, 1H, J=8.0 Hz), 8.8 (m, 1H); LCMS (APCI) m/z 286.2 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]#[N:28])[N:18]=1>CN1C(=O)CCC1>[C:27]([C:19]1[N:18]=[C:17]([O:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2nc(C#N)cc3ccccc23)C1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (496 mg, 2.65 mmol) in NMP (4 mL) at 0° C. was treated with NaH (106 mg, 2.65 mmol) and stirred for 1 hour. Next, 1-chloroisoquinoline-3-carbonitrile (500 mg, 2.65 mmol) was added and the reaction mixture was stirred at RT for 15 minutes and then heated at 140° C. for 15 minutes in a microwave reactor. The crude reaction mixture, which contained the title compound, was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2]C1CCCN1.CC1CCCN1.[CH3:14][O:15][CH2:16][CH:17]1C[CH2:20][CH2:19][NH:18]1.N1CCC[C@H]1C(O)=O.CC1NC(C)CNC1>>[CH3:2][O:1][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][O:15][CH3:14]
Reactant: OCC1CCCN1
Reactant: COCC1CCCN1
Agent: CC1CCCN1
Agent: CC1CNCC(C)N1
Agent: O=C(O)[C@@H]1CCCN1
Product: COCCNCCOC

Procedure:
Following the procedure described above, but substituting pyrrolidine with 2-hydroxymethylpyrrolidine, 2-methylpyrrolidine, 2-methoxymethylpyrrolidine, proline, 3,5-dimethylpiperazine, an bis-(2-methoxyethyl)amine provide:
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:19]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]3[CH:45]=[CH:44][C:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:42][C:38]=3[C:39]([OH:41])=O)=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([C:64]([O:66][CH3:67])=[O:65])[CH2:60][CH2:59]1>ClCCl.O>[C:19]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]3[CH:45]=[CH:44][C:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:42][C:38]=3[C:39]([N:58]3[CH2:63][CH2:62][CH:61]([C:64]([O:66][CH3:67])=[O:65])[CH2:60][CH2:59]3)=[O:41])=[CH:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Reactant: COC(=O)C1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N2CCC(C(=O)OC)CC2)c1
Yield: 96.4 %

Procedure:
75 mg of N-[(3-dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDC), 27 mg of 1-hydroxy-1H-benzotriazole hydrate (HOBT) and 40 mg of triethylamine, are successively added to a suspension of 100 mg of 2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and 39 mg of methyl piperidine-4-carboxylate hydrochloride in 30 ml of dichloromethane. Water is added to the reaction mixture after 15 hours at room temperature. After phase separation, the aqueous phase is extracted with ethyl acetate. The combined dichloromethane and ethyl acetate phases are washed with saturated brine and dried over anhydrous sodium sulphate. Filtration and concentration result in a crude product which is purified by suction filtration through silica gel with cyclohexane/ethyl acetate 1:1 as mobile phase. 120 mg of product are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1C
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(C)c1
Yield: 97 %

Procedure:
3,4-Dimethylbenzoic acid (64.4 g, 429 mmol) was dissolved in methanol (600 ml), and sulfuric acid (9 ml) was added, which was followed by reflux under heating for 5 hours. The reaction mixture was concentrated to 160 ml and water was added. The mixture was extracted with ethyl acetate, and the organic extract was washed successively with water, 10% aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 68.0 g of methyl 3,4-dimethylbenzoate (yield 97%).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:8][N:7]2[C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][N:11]=[C:6]2[CH:5]([CH3:16])[NH:4]1.CC(C)(OC([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:25][C:26](O)=[O:27])=O)C>>[ClH:1].[ClH:1].[NH2:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:25][C:26]([N:4]1[CH:3]([CH3:2])[CH2:8][N:7]2[C:9]([C:12]([F:15])([F:13])[F:14])=[N:10][N:11]=[C:6]2[CH:5]1[CH3:16])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Reactant: CC1Cn2c(nnc2C(F)(F)F)C(C)N1
Agent: Cl
Product: CC1Cn2c(nnc2C(F)(F)F)C(C)N1C(=O)C[C@H](N)Cc1cc(F)ccc1F

Procedure:
The title compound is prepared by coupling 6,8-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine, hydrochloride from Example 8, Step C with (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1). Treatment of the coupled product with methanolic hydrogen chloride provides the title compound.