Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(O)C>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([CH2:12][NH2:13])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: NCC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 10.0 g (40 mmol) 1-diphenylmethyl-azetidin-3-carbonitrile in 20 ml abs. THF is added dropwise to a suspension of 3.1 g (80 mmol) lithium aluminium hydride in 80 ml abs. THF at RT and stirred overnight. The batch is carefully added to 2 ml ethanol and filtered. The filtrate is concentrated under vacuum and dispersed between CHCl3 and water. The aqueous phase is extracted twice, each with 50 ml CHCl3, and the combined organic phases are dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3CH3OH/NH4OH (90/10/0 to 90/10/1). Yield: 5.6 g (55%) of slowly hardening resin.
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]O.[OH-].[Na+]>CO>[CH:1](=[C:8]1[CH2:17][CH2:16][C:15]23[O:19][CH:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C1C(=Cc2ccccc2)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCC23OC2C=CC=C13
Yield: 102.2 %

Procedure:
Ten grams (0.043 mole) of 2-benzylidene-1-tetralone (prepared as described in U.S. Pat. No. 3,926,988) is dissolved in 650 ml of MeOH at 35°, stirred, and treated with 10.5 g (0.092 mole) of 30% H2O2, followed by 10.5 ml (0.042 mole) of 16% NaOH solution while maintaining the temperature at 35°-36°. After stirring for 4 hours at room temperature, the solution is concentrated to approximately 50 ml on a rotary evaporator (high vacuum, low heat), diluted with 250 ml of cold H2O (an oil separates), extracted with ether (200 ml; then 4×100 ml), the combined ether layers dried (MgSO4), and the solvent evaporated to give 11.0 g (100%) of a semi-crystalline residue. Crystallization (of 10.6 g) from 55 ml of (i-Pr)2O gives 8.3 g (80%) of colorless solid; m.p. 71°-73°. Lit m.p. 77°-77.5° [JACS, 79, 232 (1957)].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=[CH:9][C:8]=2[C:7](=[O:19])[CH2:6]1)=[O:4].BrC(Cl)(Cl)Cl.N12CCCN=C1CCCCC2>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:16])[F:17])=[N:12]2)=[C:7]([OH:19])[CH:6]=1)=[O:4]
Reactant: COC(=O)C1CC(=O)c2ccc(C(F)(F)F)nc2C1
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)c2ccc(C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 5-oxo-2-trifluoromethyl-5,6,7,8-tetrahydro-quinoline-7-carboxylic acid methyl ester (50.0 g) is dissolved in methylene chloride (500 mL) and treated drop wise with a solution of bromotrichloromethane (54.43 g) and 1,8-diazabicylo[5.4.0]undec-7-en (55.72 g) in methylene chloride (100 mL) at 0-5° C. After the addition is complete, the reaction mixture is allowed to warm to room temperature, and stirred for 1 h. The reaction mixture is diluted with ethyl acetate and then washed successively with diluted aqueous hydrochloric acid and brine. The ethyl acetate phase is dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue is purified by recrystallization from hexane/ethyl acetate to give 47.13 g of the title compound of the formula
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=4[Cl:26])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:27][N:28](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.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>[Cl:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:27]#[N:28])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=2)=[O:12])[CH2:14][CH2:15]1
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cccc(F)c2Cl)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4cccc(F)c4Cl)CC3)n2c1
Temperature: 130 °C
Yield: 55 %

Procedure:
A solution of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-3-fluorophenyl)piperidin-1-yl)methanone (80 mg, 0.18 mmol) in DMF (2.0 mL) with zinc cyanide (43 mg, 0.65 mmol) was sparged with Ar for 20 min. To the solution was added Pd(PPh3)4 (21 mg, 0.018 mmol) and the vessel was sealed and heated to 130° C. with microwaves for 30 min. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 60% EtOAc in hexanes) and freeze dried to give 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (38 mg, 55%): mp 158-163° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.51-9.50 (m, 1H), 8.12 (dd, J=9.5, 1.0 Hz, 1H), 7.81 (dd, J=9.5, 1.5 Hz, 1H), 7.41-7.34 (m, 1H), 7.31-7.24 (m, 2H), 5.16-5.09 (m, 1H), 4.78-4.71 (m, 1H), 3.47-3.37 (m, 2H), 3.12-3.03 (m, 1H), 2.00-1.64 (m, 4H); ESI MS m/z 384 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])=[CH:4][C:3]=1[C:20](=[O:33])[NH:21][CH2:22][C:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[C:20](=[O:33])[NH:21][CH2:22][C:23]12[CH2:30][CH:29]3[CH2:31][CH:25]([CH2:26][CH:27]([CH2:28]3)[CH2:32]1)[CH2:24]2
Reactant: CC(C)(C)OC(=O)CNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 12.5 %

Procedure:
To [2-[4-chloro-3-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)carbamoyl-phenylamino]-ethylamino]-acetic acid, 1,1-dimethylethyl ester (0.10 g, Example 2a) was added a solution of HCl in dioxane (5 ml of a 4M solution) and reaction mixture stirred at room temperature for 48 h before concentration under reduced pressure. The residue was recrystallised twice from propan-2-ol/ethyl acetate/ether mixture to afford the title compound as a white solid (0.006 g).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>>[CH2:21]([N:28]1[CH2:2][CH:3]2[CH:5]([C:4]2([CH3:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:6]1=[O:8])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Reactant: NCc1ccccc1
Agent: Cl
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CN(Cc3ccccc3)C(=O)C21
Yield: 55.4 %

Procedure:
A solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 10 g, 33.6 mmol) in benzylamine (21.6 g, 201.6 mmol) was heated to 160° C. for 16 h. The mixture was cooled, 2N hydrochloric acid was added (200 ml), and the mixture was extracted with dichloromethane (3×250 ml). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (600 g) column chromatography eluting with dichloromethane, then a gradient of dichloromethane:ethyl acetate ending with pure ethyl acetate. Appropriate fractions were combined and concentrated in vacuo to give the title compound as an amber oil (6 g, 55%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]1=[O:4].[CH2:15]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N(C(O)=O)=NC(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:15]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:1][C@H:2]2[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]2=[O:4])=[O:29])=[CH:31][CH:32]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Agent: O=C(O)N=NC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(C(=O)O[C@H]2CC[C@@H](CCCCCC)OC2=O)cc1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
In dehydrated benzene were dispersed 200 mg of (2S,5R)-hydroxy-5-hexyl-δ-valerolactone synthesized in the same manner as described in Referential Example 4, 250 mg of p-octyloxybenzoic acid and 200 μl of azodicarboxylic acid, and 270 mg of triphenylphosphine was added to the dispersion and reaction was carried out with stirring overnight. The reacted solution was concentrated, and the concentrate was separated and purified by the silica gel column chromatography using n-hexane/benzene as the developing solvent. The obtained product was recrystallized from methanol to obtain 180 mg of (2S,5R)-2-(4-octyloxybenzoyloxy)-5-hexyl-δ-valerolactone. The NMR spectrum of the obtained compound is shown in FIG. 1. The results of the measurement of the phase transition behavior by a differential thermal scanning calorimeter and a polarization microscope are shown below: ##STR23##
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1
Reactant: CI
Product: COc1cccc(N(C)c2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-amine and methyl iodide by a procedure similar to example 7 (60% yield). 1H NMR (CDCl3): 7.74-7.76 (m, 1H), 7.57 (ddd, J=8.4, 6.0 and 1.8 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 6.98-7.03 (m, 2H), 6.89 (dd, J=8.1 and 2.4 Hz, 1H), 6.75-6.81 (m, 2H), 3.65 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:16])[CH3:15]
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a solution of (2,4-dimethylphenyl)(2-methylpropyl)amine (300 mg, 1.692 mmol) in pyridine (5 mL), stirred in air at room temperature, was added 4-acetylbenzene-1-sulfonyl chloride (370 mg, 1.692 mmol) in one charge. The reaction mixture was stirred at 20° C. for 30 minutes, then left to stand overnight. The solvent was evaporated in vacuo then redissolved in methanol and passed through an aminopropyl (NH2) SPE cartridge, eluting with methanol, followed by 2M ammonia/methanol. The product containing fractions were combined and passed through a sulphonic acid (SCX) SPE cartridge eluting with methanol, followed by 2M ammonia/methanol. The product containing fractions were combined and evaporated under a stream of nitrogen to give the crude product. The crude was purified by flash (Si) chromatography (using a 0-50% ethyl acetate-cyclohexane gradient) to give the required product (282 mg) as a yellow gum. LCMS (M+1) 360, RT 1.35 mins.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[CH:20]=[CH:19][CH:18]=[C:16]([NH2:17])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cccc(N)c2)ccc1F
Temperature: 25 °C
Yield: 81 %

Procedure:
3-cyano-4-fluorophenyl boronic acid (0.144 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (5-60% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.099 g in 81% yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[C:2]1C=CC=CC=1.[CH2:26]([NH:33]CCN)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][CH2:2][CH2:1][NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCCNCc1ccccc1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Product: O=C(NCCNCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 61 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using N-benzylethane-1,2-diamine instead of benzylamine and obtained in 61% yield. 1H NMR (DMSO-d6) 11.96 (br s, 1H), 11.41 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.19-8.14 (m, 1H), 7.75 (d, J=5.5 Hz, 1H), 7.38-7.18 (m, 7H), 6.46-6.43 (m, 1H), 3.73 (s, 2H) 3.37 (dd, J=12.4, 6.6 Hz, 2H), 2.89 (t, J=6.6 Hz, 2H); MS (m/z) 393 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 90 from tert-butyl(±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (124 mg, 0.27 mmol) and corresponding 2,3-dichlorophenylboronic acid (104 mg, 0.54 mmol), to afford after chromatographic purification the title compound (157 mg, 99%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.30–7.40 (m, 1H), 7.20 (s, 1H), 7.18 (d, 1H, J=3.6 Hz), 6.99 (s, 1H), 6.94 (s, 1H), 3.80–3.90 (m, 1H), 3.60–3.80 (m, 1H), 3.10–3.50 (m, 7H), 2.80–3.00 (m, 1H), 1.70–1.90 (m, 2H), 1.47 (s, 9H) ppm. MS (CI, NH3): 445 (base, M+H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl[C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[C:13]1([C:11]2[O:12][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9][CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ncc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
Triethylamine (1.08 mL; 7.69 mmol) was added to a mixture of 2-amino-1-phenylethanone hydrochloride (0.550 g; 3.08 mmol) and ethyl 2-chloro-2-oxoacetate (0.369 mL; 3.23 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture was then stirred at room temperature for 22 hand diluted with dichloromethane (40 mL). The organic layer was washed successively with a saturated aqueous solution of sodium carbonate, and water. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure. The crude residue was dissolved in phosphorus (V) oxychloride (10 mL) and the solution was refluxed for 4 hours. After cooling, the volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was then carefully washed with a saturated aqueous solution of sodium carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 15 to 100% dichloromethane in heptane) to afford 0.146 g (22% overall yield) of ethyl 5-phenyloxazole-2-carboxylate as a solid.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@@H]2C[C@:17]3(O)[C@@:12](CO)([C@H:13]4[C@H:26]([OH:27])C[C@@]5(C)[C@](O)(CC[C@@H]5C5COC(=O)C=5)[C@@H:14]4[CH2:15][CH2:16]3)[C@H](O)C2)[C@H](O)[C@H](O)[C@H]1O.[OH-].[Na+].Cl.[CH3:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:47]=1[NH:53][CH2:54][CH:55]([OH:57])[CH3:56].C(Cl)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:52][C:48]1[CH:49]=[CH:50][CH:51]=[C:46]([CH3:45])[C:47]=1[N:53]([CH2:54][CH:55]([OH:57])[CH3:56])[C:26](=[O:27])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1
Reactant: Cc1cccc(C)c1NCC(C)O
Reactant: C[C@@H]1O[C@@H](O[C@H]2C[C@@H](O)[C@]3(CO)[C@H]4[C@H](O)C[C@]5(C)[C@@H](C6=CC(=O)OC6)CC[C@]5(O)[C@@H]4CC[C@]3(O)C2)[C@H](O)[C@H](O)[C@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Product: Cc1cccc(C)c1N(CC(C)O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
100 ml of a 2 n aqueous sodium hydroxide solution are added dropwise, under ice cooling and vigorous stirring, to a suspension of 21.6 g (0.1 moles) of 1-(2,6-dimethylphenyl-amino)-2-propanol hydrochloride in 100 ml of benzene, and then 12.2 ml (14.6 g, 0.1 moles) of benzoyl chloride are dropped into the mixture at room temperature. The resulting mixture is stirred at room temperature for 5 hours and allowed to stand overnight. The aqueous phase is separated, the benzene phase is washed twice with 50 ml of water, twice with 50 ml of a 1 n hydrochloric acid solution and then thrice with 50 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 26.6 g (94%) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-propanol are obtained as a white, crystalline substance; m.p.: 121°-122° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[C:22]([NH:25][CH2:26][CH:27]1[O:32][CH2:31][CH2:30][NH:29][CH2:28]1)(=[O:24])[CH3:23].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]2[CH2:30][CH2:31][O:32][CH:27]([CH2:26][NH:25][C:22](=[O:24])[CH3:23])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CC(=O)NCC1CNCCO1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1
Yield: 49.2 %

Procedure:
A mixture of 1 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.15 g of 2-acetylaminomethylmorpholine, 1 g of triethylamine and10 ml of pyridine was heated under reflux for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and ethyl acetate was added to the residue. The resulting crystals were collected byfiltration, and suspended in 20 ml of water. The suspension was extracted with chloroform, and the extract was dried and concentrated. Recrystallization of the residue from ethanol gave 720 mg of 5-amino-7-(2-acetylaminomethylmorpholino)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 228°-229° C.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=[O:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.Br.[CH3:48][C:49](O)=O>C1COCC1.C1([Mg]Br)C=CC=CC=1.CCOC(C)=O.Cl>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH:45]([OH:46])[C:49]1[CH:48]=[CH:13][CH:14]=[CH:9][CH:10]=1)[CH:27]=2
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Br
Agent: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cc2ccc(C(O)c3ccccc3)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate (0.020 g, 0.032 mmol) (from Example 15, step 5) in THF (0.50 mL), phenylmagnesium bromide in THF (3.0 M, 0.032 mL, 0.096 mmol) was added slowly at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature. The reaction mixture was diluted with EtOAc (10 mL), and 1 M HCl was slowly added to adjust the pH to 7. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) and HBr in AcOH (8.0 M, 1.0 mL, 8.0 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. To the residue was added 1 M NaOH, and the aqueous layer was extracted with DCM. The combined organic extracts were dried, filtered and concentrated under reduced pressure. The resulting crude product was purified by preparative LC-MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound. LCMS calc. for C27H29N6O2 (M+H)+: m/z=469.3. Found: 469.2.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:22][CH3:23])=[N:10][CH:11]=[C:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[CH2:1]([C:8]1[C:9]([O:22][CH3:23])=[N:10][CH:11]=[C:12]([N:14]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH3:26])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1ncc(NC(=O)OC(C)(C)C)cc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(N(C)C(=O)OC(C)(C)C)cc1Cc1ccccc1
Temperature: 25 °C

Procedure:
970 mg of 3-benzyl-5-tert-butoxycarbonylamino-2-methoxypyridine was dissolved in 10 ml of N,N-dimethylformamide, followed by. adding 200 mg of 60% oily sodium hydride thereto. After stirring at room temperature, 0.192 ml of methyl iodide was added thereto in an ice bath. After the returned to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 920 mg of the target compound.