Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.Br[C:25]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:33]2[C:28](=[CH:29][C:30]([Cl:35])=[C:31]([Cl:34])[CH:32]=2)[NH:27][C:26]1=[O:36]>C(Cl)(Cl)Cl.C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:25]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[C:33]3[C:28](=[CH:29][C:30]([Cl:35])=[C:31]([Cl:34])[CH:32]=3)[NH:27][C:26]2=[O:36])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2C1(Br)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCNC2(c3ccccc3Cl)C(=O)Nc3cc(Cl)c(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A solution of 1.05 g of 4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperidine and 0.46 g of triethylamine in 10 ml of chloroform is added at RT to a solution of 1.8 g of the compound obtained in step C in 50 ml of THF and the mixture is stirred for 2 hours at RT. It is concentrated under vacuum, the residue is taken up with a 5% solution of potassium carbonate and extracted with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl, boiling THF is added to the organic phase, the latter is dried over sodium sulfate and the solvents are partially evaporated off. The crystalline product formed is filtered off to give 1.94 g of the expected product.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45][OH:46])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45][OH:46])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCO)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperidin-4-yl-ethanol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N4O3 [(M+H)+] 651.2863, observed 651.2863.
Reaction SMILES: [H-].[Na+].[C:3]12([CH2:13][OH:14])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>CN(C=O)C>[C:3]12([CH2:13][O:14][C:20]3[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[C:17]=3[C:18]#[N:19])[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH2:4]1)[CH2:12]2
Reactant: N#Cc1c(F)cccc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 94.4 %

Procedure:
To a cold (ice water) suspension of sodium hydride (206 mg; 5.0 mmol) in anhydrous DMF (4 mL) is added a solution of 1-adamantane methanol (830 mg; 4.9 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 40 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (702 mg; 5.0 mmol) in anhydrous DMF (3 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and extracted with ethyl acetate. The organics are separated and dried over magnesium sulfate. The solvent is removed and the resulting solid is dried under vacuum at 40° C. for 3 hours to give 1.32 grams of 2-(adamantan-1-ylmethoxy)-6-fluorobenzonitrile.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:20])[CH3:19].F[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:22][C:3]1([NH:2][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:19])[CH3:20]
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)Nc1ccc(C(F)(F)F)cn1

Procedure:
A solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (Intermediate 27; 1.50 g, 4.51 mmol), 2-fluoro-5-(trifluoromethyl)pyridine (CAS number 69045-82-5; 0.652 mL, 5.41 mmol) and DIPEA (2.36 ml, 13.5 mmol) in DMSO (10 ml) was subjected to microwave irradiation at 140° C. for 4 hours. The reaction was diluted with ethyl acetate (200 ml) and a saturated solution of sodium bicarbonate (100 ml). The aqueous layer was further extracted with ethyl acetate (100 ml). The combined organics were washed with water (50 ml), brine (50 ml), dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 10-20% diethyl ether/petrol) to afford the title compound as a single trans-enantiomer.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[C:21]([CH3:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][OH:24].C(O)(=O)C.N>CCO>[OH:24][CH2:23][C:22]1[C:21]([CH3:28])=[C:20]([CH:27]=[CH:26][CH:25]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1CO
Agent: N
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(CO)c3C)c2cc1OC
Yield: 48.6 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.15 g, 0.56 mmol), 3-amino-2-methylbenzylalcohol (0.1 g, 0.73 mmol), acetic acid (0.2 ml) in EtOH (10 ml) was refluxed for 4 h. After cooling the pH was adjusted to 9 with aqueous NH3. The resulting precipitate was filtered off and washed with cold EtOH and dried in vaccum at 40° C. to give 0.1 g (49% yield) of the title compound.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([NH:17][S:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:20])=[O:19])=[N:11][C:10]=1[C:29]([NH:31][CH3:32])=[O:30])C1C=CC=CC=1.CO>[Pd].C(OCC)(=O)C>[CH3:32][NH:31][C:29]([C:10]1[N:11]=[C:12]([NH:17][S:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)(=[O:20])=[O:19])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=1[OH:8])=[O:30]
Reactant: CNC(=O)c1nc(NS(=O)(=O)Cc2ccc(C)cc2)n(C)c(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(NS(=O)(=O)Cc2ccc(C)cc2)n(C)c(=O)c1O
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
A mixture of 5-(benzyloxy)-N, 1-dimethyl-6-oxo-2-(p-tolylmethylsulfonamido)-1,6-dihydro-pyrimidine-4-carboxamide (80 mg, 175 μmol), palladium on carbon (186 mg, 87.6 μmol), MeOH (5 ml) and ethyl acetate (5 ml) was placed under an atmosphere of hydrogen. After stirring for 1.5 hour, the reaction mixture was filtered and evaporated to dryness. Crystallization from MeOH provided the title product as an off-white solid (0.045 g; 70%). LCMS: m/z=367 (MH+).
Reaction SMILES: Br[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([C:14]#[N:15])[C:10](=[O:16])[C:9]=2[CH:17]=1)([CH3:4])[CH3:3].C(O)(=O)C>O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([C:14]#[N:15])[C:10](=[O:16])[C:9]=2[CH:17]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)(Br)c1ccc2occ(C#N)c(=O)c2c1
Solvent: O
Solvent: CC(=O)O
Product: C=C(C)c1ccc2occ(C#N)c(=O)c2c1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of 6-(1-bromo-1-methylethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile (2.0 g), acetic acid (20 ml) and water (5 ml) was heated at 100° C. for one hour, which was then concentrated. The concentrate was subjected to a silica-gel (100 g) column-chromatography, eluting with chloroform-acetone-formic acid (20:1:0.1). The initial eluate was recrystallized from ethanol to give colorless crystals (600 mg) of 6-isopropenyl-4-oxo-4H-1-benzopyran-3-carbonitrile, m.p. 142°-144° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[C:16](N)[CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:19].N([O-])=O.[Na+].[OH-].[Na+]>[Cu]Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[C:16]([Cl:19])[CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cc(N)ccn2)CC1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CCOC(=O)[C@H]1CC[C@H](c2cc(Cl)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cis/trans-4-(4-amino-pyridin-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:9) (0.638 g, 2.57 mmol) in concentrated hydrochloric acid (11.0 ml, 128 mmol) was added in small portions sodium nitrite (4.43 g, 64.2 mmol) at 0-5° C. The reaction mixture was allowed to warm to room temperature. Copper (I) chloride (10.7 g, 108 mmol) was added in one portion. Stirring for 2 h was followed by quenching with 32% sodium hydroxide solution (9.52 ml, 103 mmol) at 0-5° C. The reaction mixture was partitioned between dichloromethane (50 ml) and water (20 ml). The layers were separated. The aqueous layer was extracted with two 100 ml-portions of dichloromethane. The combined organic layers were washed with one 25 ml-portion of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.186 g, 27%) as colorless oil.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:11])[CH2:4][CH2:5][NH:6][C:7](=[O:10])[NH:8][NH2:9].[CH:12]([O-])([O-])OCC>>[CH3:2][CH:3]([CH3:11])[CH2:4][CH2:5][N:6]1[CH:12]=[N:9][NH:8][C:7]1=[O:10]
Reactant: CCOC([O-])[O-]
Reactant: CC(C)CCNC(=O)NN
Agent: Cl
Product: CC(C)CCn1cn[nH]c1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 13.0 g of 4-(3-methylbutyl)semicarbazide-hydrochloride (71.6 mmol) and 60 ml of ethyl orthoformate was stirred at 110° C. for two hours. After cooling, the mixture was subjected to column chromatography using silica-gel (eluate; ethyl acetate:hexane=1:2 to 2:1 to ethyl acetate to ethyl acetate:methanol=10:1). The desired fraction was concentrated. The crystals thus given was recrystallized from ethyl acetate-petroleum ether to give 7.0 g of 4-(3-methylbutyl)-3(2H,4H)-1,2,4-triazolone (63%) as colorless needles.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[C:23]([CH2:24][NH2:25])=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[NH2:25][CH2:24][C:23]1[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=[CH:21][N:22]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nccnc3CN)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2nccnc2CN)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [6-(3-aminomethyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (190 mg, 0.532 mmol) in THF (5 mL) and H2O (2 mL) was added LiOH (0.111 g, 2.66 mmol). The resulting solution was stirred at room temperature overnight. The mixture was diluted with H2O and acidified to pH 3 with 1N HCl. The resulting mixture was concentrated and the residue was purified by prep HPLC. The title compound was obtained (100 mg, 57%) as a white solid. 1H NMR (CD3OD) δ8.30 (d, 1H), 8.07 (d, 1H), 7.21 (d, 1H), 7.09 (d, 1H), 5.66 (dd, 1H), 4.47 (s, 2H), 3.14 (dd, 1H), 2.37 (s, 3H), 2.30 (dd, 1H). MS calcd for (C15H16BN3O5+H)+: 330. MS found: (M+H)+=330.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH2:19])(=[O:9])=[O:8])[CH:2]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1N
Product: Cc1cccc(S(=O)(=O)Nc2ccccc2N)c1

Procedure:
The sulfonamide was synthesized from 3-tolyl sulfonyl chloride (0.01 mol) and o-phenylene diamine (0.01 mol) by general Method C. It was purified by recrystallization from EtOH (0.73 g, 28%). EI-MS m/z 263 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([OH:22])=O)=[O:14])[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:63][CH2:64][CH2:65][NH2:66]>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:22])[NH:66][CH2:65][CH2:64][F:63])=[O:14])[N:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)O)n(-c2ccccc2)n1
Reactant: NCCF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reaction time: 12 h

Procedure:
To a solution of 1.3 g 5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 20 ml DMF were added 1.28 g HATU and 0.56 ml DIPEA. After 10 minutes 334 mg 2-fluoroethylamine hydrochloride were added. Additional 100 mg 2-fluoroethylamine hydrochloride and 400 mg HATU were added after 2 h. The reaction mixture was allowed to stir for further 12 h before being diluted with dichloromethane and extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using ethyl acetate/heptane 80:20 to ethyl acetate/heptane 100:0 as eluent. Yield: 1.5 g colorless oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.[CH2:11]([O:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](=O)[CH2:27][CH2:28][C:29](O)=[O:30])[CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH2:11]([O:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C@@:26]23[CH2:27][CH2:28][C:29](=[O:30])[N:10]2[C@@H:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:8][O:9]3)[CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CCC(=O)[C@H]1CC[C@H](COCc2ccccc2)CC1
Reactant: N[C@H](CO)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CC[C@@]2([C@H]3CC[C@H](COCc4ccccc4)CC3)OC[C@H](c3ccccc3)N12

Procedure:
To a stirred solution of (S)-(+)-phenylglycinol (6.85 g, 50 mmol) in toluene (150 mL) is added trans-4-[4-(benzyloxymethyl)cyclohexyl]-4-oxobutyric acid (15.2 g, 50 mmol), and the resulting mixture is heated to reflux for 4 hours with continuous water removal by using Dean-stark apparatus. The resulting mixture is concentrated, and the resulting residue is purified by silica gel column chromatography to afford trans-(3S,7aS)-7a-[4-(benzyloxymethyl)cyclohexyl]-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5-one.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5].[F-:20].[K+].C(O)CO>C(O)COCCO>[F:20][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5]
Reactant: CC(O)(CCCl)c1ccc(-c2ccc(F)cc2)cc1
Reactant: [F-]
Agent: [K+]
Solvent: OCCOCCO
Solvent: OCCO
Product: CC(O)(CCF)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A mixture of 27.9 g. of 1-chloro-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, 8.7 g. of KF, 10 ml. of ethylene glycol and 5 ml. of diethylene glycol is heated to 140° - 150° for 8 hours. It is cooled and worked up in the customary manner and gives 1-fluoro-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 90° - 92°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])([O-:3])=[O:2].[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
2-nitrobenzenamine (5.0 g, 36.2 mmol) was dissolved in 100 mL of THF under N2 atmosphere, 60% NaH (1.7 g, 43.4 mmol) was added at 0° C., and the mixture was stirred for 30 min at room temperature. (Bromomethyl)benzene (7.4 g, 43.4 mmol) was added at 0° C. and the reaction was stirred at 80° C. overnight. The solvent was evaporated in vacuo and the residue was purified by combi-flash (PE:EA=2:1) to give N-benzyl-2-nitroaniline as a yellow solid (2.92 g, 36%). 1H NMR (300 MHz, CD3OD): δ 4.65 (d, J=6 Hz, 2H), 6.69 (t, J=7.2 Hz, 1H), 6.94 (d, J=9 Hz, 1H), 7.25-7.50 (m, 5H), 8.09 (d, J=8.4 Hz, 1H), 8.62-8.68 (m, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]3[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:9]=3[CH:10]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.NC[C@H](O)C>>[CH3:1][C@@H:2]1[N:7]2[C:8]3[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:9]=3[CH:10]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1
Reactant: C[C@@H]1CNC(=O)c2cc3ccc(C(=O)O)nc3n21
Agent: C[C@@H](O)CN
Product: C[C@H]1CNC(=O)c2cc3ccc(C(=O)O)nc3n21

Procedure:
(9S)-9-Methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylic acid is synthesized using the similar procedure used to prepare (9R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylic acid (Intermediate J), replacing (S)-1-Aminopropan-2-ol with (R)-1-Aminopropan-2-ol in Step 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C@H:19]1[CH2:21][O:20]1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[OH:20][C@H:19]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:18][O:17][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:14][CH2:15][N:16]=3)[C:10]([NH2:13])=[N:11][C:12]=2[C:3]=1[O:2][CH3:1]
Reactant: C1CCNC1
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2CCCC2)ccc2c1N=C(N)N1CCN=C21
Yield: 77.8 %

Procedure:
A solution of 7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate F, 1.00 g, 3.47 mmol) and pyrrolidine (2.87 mL, 34.7 mmol, 10 equiv.) in DMF (18 mL) was in a microwave reactor for 45 min. at 140° C. The resulting mixture was concentrated under reduced pressure. The residue (2.5 g) was purified using MPLC to give N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (0.97 g, 78%): HPLC ret. time 0.71 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.82-1.92 (m, 2H), 1.94-2.03 (m, 2H), 3.02-3.14 (m, 3H), 3.27-3.33 (m, 2H), 3.52-3.61 (m, 2H), 3.80 (s, 3H), 4.06-4.16 (m, 4H), 4.23 (br sextet, J=4.3 Hz, 1H), 4.28-4.34 (m, 2H), 7.22 (d, J=9.4 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H); mass spectrum m/z 360 ((M+1)+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[N:30]([C:33]1[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36])=[C:31]=[O:32]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:31]([NH:30][C:33]3[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=3[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)c1ccccc1N=C=O
Product: COC(=O)c1ccccc1NC(=O)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and methyl 2-isocyanatobenzoate according to the procedure of Example 65. MS (ES) m/z 567.9.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:20]3[C:21]4=[C:22]5[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=[C:13]5[CH:12]=[CH:11][C:10]4=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1>[Br:33][C:9]1[C:10]2[C:21]3=[C:22]4[C:13](=[CH:12][CH:11]=2)[CH:14]=[C:15]([C:23]([CH3:26])([CH3:24])[CH3:25])[CH:16]=[C:17]4[CH:18]=[CH:19][C:20]3=[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:6][CH:5]=2)[CH:8]=1
Reactant: CC(C)(C)c1cc2ccc3ccc(-c4ccc(-c5ccccc5)cc4)c4ccc(c1)c2c34
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ccc3c(Br)cc(-c4ccc(-c5ccccc5)cc4)c4ccc(c1)c2c34
Temperature: 30 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Then, to a mixed solution of 8.65 g of 1-(4-biphenylyl)-7-t-butylpyrene, and 126 ml of tetrahydrofuran was added 4.1 g of N-bromosuccinimide under a nitrogen stream. This mixed solution was stirred at 30° C. for about 3 hours, and concentrated, 126 ml of methanol was added, and the mixture was stirred for about 1 hour, and filtered. To the resulting solid was added 30 ml of tetrahydrofuran, the mixture was heated and dissolved, 180 ml of methanol was added, and the mixture was stirred for about 1 hour, and filtered. After the resultant was purified by silica gel column chromatography, the solid obtained by evaporation was washed with 126 ml of methanol, and vacuum dried to obtain 8.8 g of 1-bromo-3-(4-biphenylyl)-7-t-butylpyrene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]=O.[BH4-].[Na+].O>C(O)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH2:25][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:25][C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccc2ccccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2nc(CNCCCN3CCN(CCCNCc4ccc5ccccc5n4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 2-quinolinecarbaldehyde (823 mg, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).