Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Na+].C([O-])(=O)C.[Na+].B(O)(O)O.Cl[C:23](=[CH2:26])[C:24]#[N:25]>O.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH:26]=[CH:23][C:24]#[N:25])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)[O-])cc1
Reactant: C=C(Cl)C#N
Agent: CC(=O)[O-]
Agent: OB(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(S(=O)(=O)C=CC#N)cc1

Procedure:
In a flask, 59.5 g. (0.31 mole) sodium 4-methoxybenzenesulfinate, 25.4 g. (0.31 mole) sodium acetate and 19.2 g. (0.31 mole) boric acid were dissolved in a mixture of 150 ml. water and 275 ml. isopropyl alcohol. There was then added, with stirring, dropwise, 33.9 g. (31 ml., 0.39 mole) 2-chloroacrylonitrile. The mixture was stirred for some time at room temperature. Water was then added and the mixture stirred for one hour. A precipitate formed, which was filtered, washed with water and ethanol, and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCc1cccc(Cl)c1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCc1cccc(Cl)c1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(3-chlorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a light yellow powder (59.6% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 7.94, 7.75, 7.64, 7.57, 7.37, 7.26, 7.24-7.19, 7.12, 7.00, 4.10, 3.95-3.66, 3.38, 2.90.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]=[C:12]([C:14](O)=[O:15])[N:13]=1.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:50][C@@H:51]1[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]1[OH:57]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]=[C:12]([C:14]([NH:50][C@@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[OH:57])=[O:15])[N:13]=1
Reactant: COc1ccc(-n2cc(C(=O)O)nc2-c2ccc(Cl)cc2Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(F)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(-n2cc(C(=O)N[C@@H]3CCCC[C@H]3O)nc2-c2ccc(Cl)cc2Cl)cc1
Yield: 23 %

Procedure:
In a 20-mL screw-cap vial, 182 mg (0.5 mmol) 2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid, 145 mg (0.55 mmol) TFFH, and 5.0 equiv. PS-DIEA (loading level: 3.50 mmol/g, 716 mg, 2.5 mmol) were heated in 10 mL 1,2-dichloroethane at 35° C. overnight. The formation of acyl fluoride was monitored by LC-MS. To the mixture, 1.1 equiv. (84 mg, 0.55 mmol) trans-2-aminocyclohexanol hydrochloride was added and the reaction continued overnight. The mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 1 mL MeOH and purified by preparative HPLC to give 53 mg of 2-(2,4-dichlorophenyl)-N-(trans-2-hydroxycyclohexyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamide (amber oil, 23% yield). 1H NMR (400 MHz, CD2Cl2) δ 7.90 (s, 1 H), 7.30-7.50 (m, 4 H), 7.10 (d, 2 H), 6.90 (d, 2 H), 3.85 (s, 3 H), 3.80 (m, 1 H), 3.50 (m, 1 H), 3.25 (bs, 1 H), 2.0 (m, 2 H), 1.75 (m, 2 H), 1.30-1.50 (m, 4 H); LC-MS m/z 460.2 (MH+), retention time 3.31 min (method 2).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:9]([C:5]5[O:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=5[CH3:8])=[O:11])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCc1nc(C)c(C(=O)O)o1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)o1
Yield: 71.8 %

Procedure:
In the same manner as in Example 259 and using 2-ethyl-4-methyl-1,3-oxazole-5-carboxylic acid (230 mg, 1.5 mmol), tetrahydrofuran (6 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (520 μL, 6.0 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (400 mg, 1.2 mmol) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (400 mg, 70%) was obtained as a white solid. melting point 228° C.
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[CH2:3][C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][C:7]([Cl:10])([CH3:9])[CH3:8].[OH-].[Na+]>ClCCl>[Cl:1][C:2]#[C:3][C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][C:7]([Cl:10])([CH3:8])[CH3:9]
Reactant: CC(C)(Cl)CCC(C)(C)CC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(Cl)CCC(C)(C)C#CCl

Procedure:
1.68 g of 1,1,1,6-tetrachloro-3,3,6-trimethylheptane is combined in 4 ml of dichloromethane with 10 ml of 40% aqueous sodium hydroxide solution and 0.52 g of "Aliquat" 336, and heated under reflux for 17 hours. Then the reaction mixture is allowed to cool, combined with 20 ml of dichloromethane, the organic phase is separated, washed with water, and dried over calcium chloride. The solution is then concentrated under vacuum, yielding 1,6-dichloro-3,3,6-trimethyl-1-heptyne as an oily crude product.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]([C:26]2[O:30][N:29]=[C:28]([CH3:31])[C:27]=2[Br:32])S(C2C=CC(C3C=CC=CC=3)=CC=2)(=O)=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1>[Br:32][C:27]1[C:28]([CH3:31])=[N:29][O:30][C:26]=1[NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][CH:5]=1)(=[O:8])=[O:9]
Reactant: Cc1noc(N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
N-(4-biphenylsuifonyl )-N-(4-bromo- 3-methyl- 5-isoxazolyl)-4-biphenylsulfonamide (0.150 g, 0.233 mmol) was dissolved in tetrahydrofuran (THF). Sodium hydroxide (0.120 g, 3.0 mmol) was added and the solution was warmed to 45° C. to dissolve the sodium hydroxide. Stirring was continued for 20 min. Tetrahydrofuran was removed under reduced pressure. The residue was dissolved in water, cooled to 0° C. and acidified to pH 3-4 with concentrated HCl. The solid precipitate was filtered off and dried in vacuo to give N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide (94% yield), which was further purified by recrystallization from chloroform/hexanes, m.p. 133°-135° C.
Reaction SMILES: [C:1]([CH:4]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:5]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2].[CH2:30](O)[CH2:31][OH:32].O.ClCCl>O1CCOCC1>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][N:6]1[C:7](=[O:8])[CH:4]([C:1]2([CH3:2])[O:32][CH2:31][CH2:30][O:3]2)[C:5]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C(C)=O)C(=O)N1Cc1ccc(OC)cc1OC
Reactant: OCCO
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)C(C2(C)OCCO2)C(=O)N1Cc1ccc(OC)cc1OC
Yield: 83 %

Procedure:
25.5 g (0.063 moles) of diethyl 3-acetyl-1-(2,4-dimethoxybenzyl)4-oxo-2,2-azetidine-dicarboxylate prepared according to Example 1e), 6.8 ml (0.126 moles, 7.8 g) of ethylene glycol and 15.8 ml (0.126 moles, 17.9 g) of borotrifluoride diethyl etherate in 100 ml of dry dioxane are allowed to stand at room temperature for 3 days, whereupon 150 ml of water and 150 ml of dichloromethane are added to the reaction mixture. Thereafter the organic phase is separated and shaken with 50 ml of a 5% aqueous sodium hydrogencarbonate solution and 50 ml of water. The organic phase is separated again, dried with magnesium sulfate, filtered and the filtrate is evaporated. 23.6 g (84%) of diethyl 1-(2,4-dimethoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2,2-azetidine-dicarboxylate are obtained.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:48][CH:49]([CH3:51])[CH3:50])[C:23]([NH:25][N:26]([C:32](=[O:47])[CH2:33][CH2:34][CH2:35][NH:36]C(OCC1C=CC=CC=1)=O)[CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[NH2:36][CH2:35][CH2:34][CH2:33][C:32]([N:26]([CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])[NH:25][C:23](=[O:24])[C@@H:22]([C@@H:12]([C:10](=[O:11])[NH:9][OH:8])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:48][CH:49]([CH3:50])[CH3:51])=[O:47]
Reactant: CC[C@H](C)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1)C(=O)CCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)CN(NC(=O)[C@H](CC(C)C)[C@H](CCCc1ccccc1)C(=O)NO)C(=O)CCCN
Yield: 70.6 %

Procedure:
A solution of 0.216 g of (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(4-benzyloxycarbonylaminobutyryl)-4-methyl-2′-(2(S)-methylbutyl)valerohydrazide in 5 ml of methanol was hydrogenated in the presence of 0.1 g of 10% palladium-on-carbon catalyst for 1 hour. The catalyst was removed by filtration and the methanol was evaporated. The residue was re-evaporated from diethyl ether and then triturated with a mixture of diethyl ether and hexane and there was obtained 0.104 g of 2′-(4-aminobutyryl)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methyl-2′-(2(S)-methylbutyl)valerohydrazide in the form of a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])[CH2:2]1.[CH3:15][N:16](C)C(Cl)=O.C[Si](C#N)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][C@H:3]([O:6][CH2:7][C:8]2[N:9]=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][CH:13]=2)[CH2:2]1
Reactant: [O-][n+]1ccccc1CO[C@H]1CCOC1
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1cccc(CO[C@H]2CCOC2)n1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
(S)-2-(Tetrahydrofuran-3-yloxymethyl)pyridine-1-oxide (24.08 g, 0.123 mol, 1 eq) was dissolved in anhydrous DCM (400 mL). N,N-Dimethylcarbamyl chloride (19.89 g, 0.185 mol, 1.5 eq) was added followed by trimethylsilyl cyanide (18.35 g, 0.185 mol, 1.5 eq). The solution was stirred at 40° C. for 24 hours (solution had turned red). The reaction was cooled to room temperature, then 2 M aqueous Na2CO3 solution was added (80 mL) and stirred overnight. The emulsion was filtered off, leaving the white precipitate behind. The layers were separated and the organic layer was evaporated to leave a brown oil. This was dissolved in ethyl acetate (160 mL), 2-M aqueous Na2CO3 solution (160 mL) was added and stirred for 2 hours. The layers were separated and the organic layer was washed with saturated brine (30 mL), dried over Na2SO4 and evaporated to a brown oil; LC-MS Retention time 1.82 min; (M+H)+ 205.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7]C)=O.[CH:16](N(C(C)C)CC)(C)[CH3:17].ClC(OCC1C=CC=CC=1)=O>C1COCC1>[NH2:2][C@H:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:4][C:5]1([OH:7])[CH2:17][CH2:16]1
Reactant: COC(=O)C[C@H](N)c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: N[C@@H](CC1(O)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
(S)-Methyl 3-amino-3-(4-fluorophenyl)propionate hydrochloride (4.5 g) was dissolved in THF (30 ml) and cooled to 0° C. After the addition of diisopropylethylamine (8.8 g), benzyl chloroformate (4.3 g) was slowly added dropwise and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated by rotary evaporation, dichloromethane (50 ml) was added and the mixture was washed twice with NH4Cl solution. Subsequently, the organic phase was dried with MgSO4, filtered and concentrated. The residue (5.72 g) was taken up in THF, titanium tetraisopropoxide (0.49 g) was added, and ethylmagnesium bromide (3 N, 17.9 ml) was added dropwise over the course of 1 hour. After 24 hours, the reaction solution was poured into cold 2 N sulfuric acid (150 ml) and extracted three times with dichloromethane. The combined organic phases were dried with MgSO4, filtered and concentrated. The residue was purified by preparative HPLC. The resulting (S)-1-(4-fluorophenyl)-2-(1-hydroxycyclopropyl)ethyl]carbamic acid benzyl ester (0.76 g) was dissolved in methanol (20 ml), 5% Pd/C was added and hydrogenation was effected under hydrogen pressure 2 bar. After filtration and concentration, the product (87 mg) was thus obtained with a molecular weight of 329.3 g/mol (C19H20FNO3), MS (ESI): m/e=330 (M+H+).
Reaction SMILES: C([O:8]C1C=CC(C(=O)C)=CC=1CO)C1C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([C:42](=[O:44])[CH3:43])[CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:35]([O:34][C:32]1[CH:31]=[C:30]([C:42]([CH:43]=[O:8])=[O:44])[CH:29]=[C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:33]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Product: O=CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
The title compound was prepared as a hydrate by the process of Description 54, replacing 1-(4-benzyloxy-3-hydroxymethylphenyl)ethanone. by 1-(3,5-dibenzyloxyphenyl)ethanone. γ (CDCl3) 6.40 (2H, s) 5.00 (4H, s), 2.40-3.50 (14H, m).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].CCN(CC)CC.[CH2:25]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl.CC(C)=O.CO>[CH2:25]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:16])[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(C)cc32)CC1
Yield: 83.4 %

Procedure:
Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (0.30 g), Et3N (0.5 mL) and 4-butylpiperidine (0.15 g, 1.0 mmol) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/acetone/MeOH 90:7:3) gave the title compound (0.26 g, 84%). 1H NMR (CD3OD) δ 7.00 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.81 (dm, J=8.0 Hz, 1H), 4.52 (ABq, J=14.4, 20.8 Hz, 2H), 3.99 (dd, J=6.0, 14.4 Hz, 1H), 3.90 (dd, J=8.4, 14.4 Hz, 1H), 2.97 (brd, J=11.2 Hz, 1H), 2.82 (brd, J=8.4 Hz, 1H), 2.39-2.10 (m, 2H), 2.31 (s, 3H), 2.07-1.88 (m, 2H), 1.73-1.62 (m, 2H), 1.35-1.18 (m, 9H), 0.94-0.08 (m, 6H); 13C NMR (CD3OD) δ 166.0, 143.8, 132.4, 128.3, 124.3, 116.6, 116.2, 67.4, 63.6, 55.0, 54.2, 44.8, 36.2, 35.6, 32.1 (br), 28.9, 28.8, 22.8, 20.0, 15.9, 13.2.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.N[CH2:10][C@@H:11]1CC[CH2:13][N:12]1CC.C(=O)C>>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][NH:12][CH3:13])[CH2:4]1
Reactant: CCN1CCC[C@H]1CN
Reactant: CN(C)[C@H]1CCNC1
Agent: CC=O
Product: CNCCN1CC[C@H](N(C)C)C1

Procedure:
By using (3S)-(−)-3-(dimethylamino)pyrrolidine (200 mg) as a starting material, the title compound (80 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:12]([CH2:34][CH2:35][CH2:36]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:66]=[N+:67]=[N-:68].[Li+].C(Br)(Br)(Br)Br>CN(C=O)C.CO>[CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:30])[CH3:31])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:12]([CH2:34][CH2:35][CH2:36][N:66]=[N+:67]=[N-:68])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CCCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CCCN=[N+]=[N-])[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
Utilizing the conditions of Hetz et. al., J.C.S. Perkin 1 1980, 306, to a solution of compound 39 (1 eq) in DMF is added triphenylphosphine (1 eq) and lithium azide (5 eq) at room temperature. Carbon tetrabromide (1 eq) is added and the reaction mixture is stirred until judged complete by tlc. MeOH is added to quench the reaction mixture and the solvent is evaporated under reduced pressure. The residue is purified by silica gel chromatography to yield the title compound, 40.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]([O:21][CH3:22])=[C:8]2[C:3]=1[C:4](=[O:29])[C:5](C(O)=O)=[CH:6][N:7]2[CH:23]1[CH2:25][CH2:24]1.[C-]#N.[Na+]>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]([O:21][CH3:22])=[C:8]2[C:3]=1[C:4](=[O:29])[CH:5]=[CH:6][N:7]2[CH:23]1[CH2:24][CH2:25]1
Reactant: CCOC(=O)CCNc1c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c2c1OC
Agent: [C-]#N
Agent: [Na+]
Product: CCOC(=O)CCNc1c(F)c(N)c2c(=O)ccn(C3CC3)c2c1OC
Temperature: 120 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-7-[2-(ethoxycarbonyl)ethyl amino]-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.30 g, 3.19 mmol) and NaCN (1.57 g, 32.0 mmol) in DSMO (25 mL) was stirred at 120° C. for 2 h. After cooling, the reaction mixture was poured in to ice-water (300 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, washed with water (3×100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.), hexane:EtOAc 1:1) to give ethyl 3-[(5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl)amino]propionate (723 mg, 63%) as a pale yellow solid.
Reaction SMILES: [C:1]([CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([O:3]CC)=[O:2].[OH-].[Na+]>CO.CCOC(C)=O>[C:1]([CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCC(CCP(=O)(OCC)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCC(CCP(=O)(OCC)OCC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.7 %

Procedure:
A solution 0.61 g (1.44 mmol) of (±)-diethyl 3-(carboethoxy)pentadecyl phosphonate (from Example 27, Step A) in 10 mL of MeOH was treated with 4.3 mL of 1 N NaOH. The resulting mixture was stirred at rt for 2 h then heated to 50° C. for 16 h. The reaction was diluted with 75 mL of EtOAc, washed with 50 mL of 2 N HCl, 50 mL of sat'd NaCl, dried and concentrated to give 0.62 g of the title compound: ESI-MS 393.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C([O-])(=O)C.[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C(=O)C>[CH3:17][O:16][C:11]1[C:10]2=[CH:9][CH:8]=[C:7]3[C:6]([O:5][CH2:4][C:3]4[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:2]3=4)=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(Br)c(COc2cccc3c(OC)cccc23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)COc1c-2ccc2c(OC)cccc12
Temperature: 130 °C
Yield: 98.8 %

Procedure:
To a 2000 ml recovery flask was added 1-[(2-bromo-5-methoxybenzyl)oxy]-5-methoxynaphthalene (3.0 g, 8.03 mmol), potassium acetate (2.4 g anh., 24.10 mmol), PdCl2(PPh3)2 (1.12 g, 1.60 mmol), and N,N-dimethylacetamide (500 ml 99%). The flask was purged with nitrogen, heated to 130° C. for 12 h, and concentrated under high vacuum. The dark solids were then dissolved in ether/CH2Cl2 (1/1 300 ml) and passed through a silica gel/celite plug. Evaporation under reduced pressure afforded 2.32 g (99%) product as a tan colored solid. mp 166-167° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.82 (3H, s), 3.97 (3H, s), 5.30 (2H, s), 6.98 (3H, m), 7.42 (1H, t, J=8.1 Hz), 7.69 (1H, d, J=8.5 Hz), 7.81 (2H, appd, J=8.6 Hz), 7.91 (1H, d, J=8.9 Hz); MS m/z 293 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:17]>C(O)(C)C>[NH2:17][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:15][C@H:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OC1CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c1c(I)nc2[C@H]1C[C@@H](O)C1
Temperature: 110 °C

Procedure:
In a Parr pressure reactor 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanol (4.159 g, 0.0119 mol) was dissolved with 2.0M ammonia in isopropyl alcohol (40 mL). The mixture was cooled to −20° C. and saturated with ammonia. The reaction was heated at 110° C. for 63 h at which point it was cooled and concentrated in vacuo. The crude product was purified using HPFC Jones 25 g silica gel column eluting with 5-8% MeOH: CH2Cl2 to yield the title compounds; MS (ES+): m/z 330.88 (100) [MH+], 331.89 (10) [MH++]; HPLC: tR=0.48 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.55-2.76 (m, 2H) 3.06-3.22 (m, 2H) 3.32-3.50 (m, 1H) 4.51-4.69 (m, 1H) 6.15 (br. s., 2H) 7.24 (d, J=5.05 Hz, 1H) 7.39 (d, J=5.05 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1.BrC1N=C(CO[CH2:38][CH2:39][N:40]2[CH2:43][C:42]3([CH2:46][CH2:45][CH2:44]3)[CH2:41]2)C=CC=1>>[CH2:41]1[C:42]2([CH2:46][CH2:45][CH2:44]2)[CH2:43][N:40]1[CH2:39][CH2:38][O:25][CH2:24][C:20]1[N:19]=[C:18]([NH:17][C:15]2[S:16][C:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([OH:11])([CH3:9])[CH3:10])=[CH:7][C:2]=3[F:1])=[CH:13][C:14]=2[C:26]([NH2:28])=[O:27])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C=O)n3)s2)c(F)c1
Reactant: Brc1cccc(COCCN2CC3(CCC3)C2)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(COCCN4CC5(CCC5)C4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to Example 251, Step 2 using 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-formyl-2-pyridinyl)amino)-3-thiophenecarboxamide (200 mg, 0.68 mmol) and 2-{2-[(6-bromopyridin-2-yl)methyoxy]ethyl}-2-azaspiro[3.3]heptane (211 mg, 0.68 mmol) as the starting materials.