Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:26]([O-:28])=[O:27])[CH2:19]C1C=CC=CC=1.C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH3:19])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: C[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. Next, 966 mg (2 mmol) of butyl-triphenylphosphonium phenylalanine salt and 15 mL of acetonitrile were dropped to the solution, and then the mixture was stirred for 20 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-alanine was obtained. An isolation amount and an isolation yield were 496.3 mg and 87%, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:34][OH:35].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:34][OH:35])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Reactant: NO
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A solution of compound A (17.9 g, 39.7 mmol), hydroxylamine (3.9 g, 119 mmol), pyridine (200 mL), and water (100 mL) were combined. After stirring overnight, water (50 mL) was added and the precipitate was filtered to yield compound B as an off-white solid (16.9 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[CH:18][C:8]=2[NH:7][C:6]1=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]3.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH:5]3[O:10][C:9]4[CH:11]=[C:12]5[C:17](=[CH:18][C:8]=4[NH:7][C:6]3=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]5)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: O=C1Nc2cc3c(cc2OC1CCCBr)CCCC3
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cc3c(cc2OC1CCCN1CCN(c2ccc(F)cc2)CC1)CCCC3
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
A mixture of 2-(3-bromopropyl)-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (3.1 g), 1-(4-fluorophenyl)piperazine (2.3 g), triethylamine (1.5 ml) and N,N-dimethylformamide (DMF)(100 ml) was stirred at 80° C. for 1.5 hour, which was diluted with ice-water and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), from which the solvent was distilled off. The residue was recrystallized from chloroform-ethyl acetate to give 2.4 g (59.3%) of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one as colorless crystals, m.p. 164°-165° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[CH3:14])([O-:3])=[O:2].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>C(O)C.O>[NH2:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[CH3:14]
Reactant: Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: Cc1c(N)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2,6-dinitro-4-fluorotoluene (8.1 g) in ethanol (130 mL) is treated dropwise with a solution of sodium sulfide nonahydrate (16.39 g) in water (90 mL). The mixture is allowed to stir at room temperature for 2.5 hours, then diluted with water (500 mL) and extracted with ethyl acetate (4×500 mL). The combined extracts are dried over sodium sulfate and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 15% ethyl acetate/hexanes to afford 2-amino-4-fluoro-6-nitrotoluene as a solid.
Reaction SMILES: [H-].[Na+].ClC1C=C(NC2C3C4CCC5C(=CN(CCO)N=5)C=4SC=3N=CN=2)C=CC=1OCC1C=CC=C(F)C=1.IC.[Cl:41][C:42]1[CH:43]=[C:44]([N:57](C)[C:58]2[N:59]=[CH:60][N:61]=[C:62]3[S:77][C:65]4[C:66]5[C:70]([CH2:71][CH2:72][C:64]=4[C:63]=23)=[N:69][N:68]([CH2:73][CH2:74][O:75][CH3:76])[CH:67]=5)[CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[CH:51]=1>O.CN(C=O)C>[Cl:41][C:42]1[CH:43]=[C:44]([NH:57][C:58]2[N:59]=[CH:60][N:61]=[C:62]3[S:77][C:65]4[C:66]5[C:70]([CH2:71][CH2:72][C:64]=4[C:63]=23)=[N:69][N:68]([CH2:73][CH2:74][O:75][CH3:76])[CH:67]=5)[CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[CH:51]=1
Reactant: COCCn1cc2c(n1)CCc1c-2sc2ncnc(N(C)c3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12

Procedure:
To 4 mL DMF cooled to 0° C. was added sodium hydride (16 mg (60%), 0.40 mmol). To the slightly yellow and heterogeneous mixture was added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]ethanol (100 mg, 0.19 mmol) as a 1 mL DMF solution, upon which the contents become brown and homogenous. The contents were allowed to stir with warming to it over 10 min., and added was iodomethane (0.01 mL, 0.23 mmol). The mixture was stirred for 90 min., after which time water (0.5 mL) was added. The contents were concentrated under reduced pressure to dryness, and the residue diluted with CH2Cl2 (10 mL). The organic layer was washed with water (3×10 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude residue was purified by reverse phase HPLC. The fractions for each respective product were combined and diluted with CH2Cl2 (50 mL), and neutralized with NaHCO3 (50 mL). The respective organic layers were dried over MgSO4, filtered, and the solvent removed under reduced pressure to afford the final pure products. Example 312 (15 mg, 15%) and N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-(2-methoxyethyl)-N-methyl-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (8 mg, 8%) were each collected as white solids. Data for example 312: 1H-NMR (CD2Cl2-d2) δ 8.50 (s, 1H), 7.39 (s, 1H), 7.20-7.28 (m, 1H), 7.07-7.17 (m, 2H), 6.90-6.99 (m, 2H), 6.72 (d, 1H), 6.62 (d, 1H), 4.99 (s, 2H), 4.08 (t, 2H), 3.80 (t, 2H), 3.42 (s, 3H), 2.48 (t, 2H), 2.20 (t, 2H); LCMS RT=3.32 min; [M+H]+=536.3. Data for N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-(2-methoxyethyl)-N-methyl-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine: 1H-NMR (CD2Cl2-d2) δ 8.52 (s, 1H), 7.40 (s, 1H), 7.20-7.29 (m, 1H), 7.07-7.17 (m, 2H), 7.00 (s, 1H), 6.90-6.99 (m, 1H), 6.70 (d, 1H), 6.60 (d, 1H), 4.99 (s, 2H), 4.10 (t, 2H), 3.60 (t, 2H), 3.42 (s, 3H), 3.02 (s, 3H), 2.48 (t, 2H), 2.21 (t, 2H); LCMS RT=3.67 min; [M+H]+=550.4.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH2:4][F:5]>CO.[Rh]>[F:5][CH2:4][CH:3]([O:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:2][F:1]
Reactant: FCC(CF)Oc1ccncc1
Agent: [Rh]
Solvent: CO
Product: FCC(CF)OC1CCNCC1
Yield: 80275.4 %

Procedure:
4-(1,3-difluoropropan-2-yloxy)pyridine (27) (0.098 mg, 0.57 μmol) and 5% rhodium on alumina (0.02 g, 2.56 μmol) in MeOH (50 mL) were stirred under an atmosphere of hydrogen at 5 bar and 25° C. for 16 hours. The catalyst was filtered and washed with MeOH and the solvent evaporated to afford the desired compound as a gum (0.082 g, 81%); 1H NMR (400.132 MHz, CDCl3) δ 1.43-1.48 (1H, m), 1.60-1.71 (1H, m), 1.82-2.15 (3H, m), 2.42 (1H, s), 2.84-2.92 (1H, m), 3.09-3.14 (1H, m), 3.25-3.30 (1H, m), 3.82-3.95 (1H, m), 4.35-4.44 (2H, m), 4.47-4.56 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[OH:11].Cl.CC(=NO)C(C)=NO.I[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[OH:9][CH2:8][C:7]1[C:2]([CH3:1])=[C:3]([O:11][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[C:4]([CH3:10])=[N:5][CH:6]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: Cc1ncc(CO)c(C)c1O
Agent: O=[Cu-]
Agent: CC(=NO)C(C)=NO
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ncc(CO)c(C)c1Oc1ccc(C#N)cc1
Temperature: 110 °C
Yield: 7 %

Procedure:
A mixture of 4-deoxypyridoxine hydrochloride (0.44 g, 2.8 mmol), copper (I) oxide (0.50 g, 3.5 mmol), dimethylglyoxime (0.15 g, 1.3 mmol), 4-iodobenzonitrile (1.08 g, 4.7 mmol), cesium carbonate (5.00 g, 15.3 mmol), and crushed molecular sieves 3° A (0.6 g) in anhydrous DMF (4 mL) were heated at 110° C. for 12 hours. The reaction mixture was evaporated to dryness, and the crude product purified by column chromatography on silica gel using a gradient of dichloromethane:methyl alcohol (1:0 to 9:1) as eluant to give 4-(5-hydroxymethyl-2,4-dimethyl-pyridin-3-yloxy)-benzonitrile (89) (50 mg, 7% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:17]([N:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:13]1)=[O:11].C[Mg+].[Br-].[CH3:32]COC(C)=O>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:13][CH:14]([C:16]2[C:17]([N:22]3[CH2:27][CH2:26][C:25]([OH:28])([CH3:32])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:15]1)=[O:11]
Reactant: O=C1CCN(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Reactant: CCOC(C)=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCN(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 1-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-one (150 mg, 0.40 mol, SCHEME 13, Ex. 13.1) in 20 mL of THF was added CH3MgBr (0.60 mol, 3 M in ether) dropwise at 0° C. The mixture was stirred for 1 h at RT and then quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give crude product which was purified by prep. TLC (EtOAc:Petrol ether=1:1) to give (1H-benzoimidazol-2-yl)-{3-[3-(4-hydroxy-4-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone (0.109 g, 0.28 mmol, 70% yield) as a white solid.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[N:15][C:14]=3[C:25](O)=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][CH:46]=1)[C:32]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])=[O:33]>>[C:38]1([S:35]([NH:34][C:32]([C:31]2[CH:30]=[C:29]([NH:28][C:25]([C:14]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[NH:17][C:13]=3[CH2:12][CH2:11][C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[O:26])[CH:46]=[CH:45][CH:44]=2)=[O:33])(=[O:37])=[O:36])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Reactant: Nc1cccc(C(=O)NS(=O)(=O)c2ccccc2)c1
Product: Cc1ccccc1-c1nc(C(=O)Nc2cccc(C(=O)NS(=O)(=O)c3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazole-4-carboxylic acid (Example 93) was reacted with N-(3-amino-benzoyl)-benzenesulfonamide using essentially the same procedure as in Example 20, step d. The crude product was purified by flash column chromatography (silica, ethyl acetate/hexane 2:1) to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.52 (1H, br s), 9.70 (1H, br s), 8.29 (1H, s), 7.98 (3H, m), 7.68-7.52 (SH, m), 7.42-7.28 (4H, m), 2.98 (2H, m), 2.54 (3H, s), 1.95 (3H, s), 1.67-1.35 (14H, m). Found: C, 67.65; H, 6.34; N, 8.49%; C36H38N4O4S.1.0 H2O requires: C, 67.48; H, 6.29; N, 8.74%.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[C:12](=[O:20])[C:8]3=[N:9]2)=[CH:4][CH:3]=1.[C:22](=[O:29])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH2:23].[H-].[Li+]>CN(C=O)C.C(Cl)(Cl)Cl>[C:25]([O:24][C:22]([NH:23][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[C:12](=[O:20])[C:8]3=[N:9]2)=[CH:4][CH:3]=1)=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=C1c2cc(F)ccc2-n2c1nc1cc(F)ccc1c2=O
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=O)c1cc(F)ccc1-3

Procedure:
A solution of 3,8-difluoroindolo[2,1-b]quinazoline-6,12-dione (0.1 mmol, Example 36), t-butyl carbamate (0.11 mmol) and lithium hydride (0.12 mmol) in DMF (0.1 mM) is stirred at 70° C. for 12 h. The resulting reaction mixture is diluted with chloroform, washed with 0.1N HCl, sodium bicarbonate solution, dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (1% MeOH/CHCl3) gives 3-(N-t-butyloxycarbonylamino)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)CCC.S(=O)(=O)(O)O>[CH2:9]([O:20][C:19]([CH:14]1[C:15]2[C:11](=[CH:10][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:17]([OH:18])[CH:16]=2)[CH2:12][CH2:13]1)=[O:21])[CH2:1][CH2:2][CH3:3]
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)C(C(=O)O)CC2
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
A solution of 12 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid in 100 ml of n-butanol and 8 drops of concentrated sulphuric acid is boiled for 6 hours under reflux in an anhydrous atmosphere. It is then evaporated to a volume of approx. 20 ml in vacuo and the evaporation residue is partitioned between 3 times 100 ml of methylene chloride and 3 times 100 ml of water. The organic phases are dried over sodium sulphate and evaporated in vacuo. The evaporation residue, when crystallized from cold ether-petroluem ether, gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid n-butyl ester in the form of yellow platelets of melting point 43°-44° C.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH2:5][OH:6].Cl[CH2:16][C:17](OCC)=[O:18]>C1COCC1>[F:14][C:9]1[CH:8]=[C:7]([CH:4]2[NH:3][C:17](=[O:18])[CH2:16][O:6][CH2:5]2)[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: NC(CO)c1ccc(F)c(F)c1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(c2ccc(F)c(F)c2)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (8.0 mmol, 0.19 g) in 10 mL THF at 0° C. was added a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol (7.51 mmol, 1.3 g) in 20 mL THF dropwise via an addition funnel and after 30 min ethyl chloroacetate was added dropwise via syringe. The orange colored reaction mixture was stirred for 2 hours at 0° C. and then for 2 hours at 35° C. The solvent was removed and the 5-(3,4-difluoro-phenyl)-morpholin-3-one was isolated as a thick yellow oil (0.5 g). 1H NMR showed that the product was about 85% pure and any attempts to purify it further by column chromatography were not successful. It was used in the next reaction as described below without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(OCC)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH:13][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[F:21])=[CH:6][C:7]=1[Si:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: O=C(Cl)c1ccccc1F
Reactant: C[Si](C)(C)c1cc(NN)nnc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(NNC(=O)c2ccccc2F)nnc1Cl
Temperature: -4 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a stirred mixture of 3-chloro-6-hydrazino-4-(trimethylsilyl)pyridazine (6.34 g, 29.3 mmol) and anhydrous triethylamine (4.9 ml, 35.2 mmol) in anhydrous diethyl ether (100 ml), cooled under nitrogen to −4° C., was added dropwise, over 13 min, 2-fluorobenzoyl chloride (3.5 ml, 29.4 mmol) keeping the temperature below 5° C. The thick mixture was then stirred for 30 min at 0-5° C., then quenched with anhydrous methanol (1 ml). The mixture was diluted with hexane (100 ml) and filtered. The collected solid was washed with diethyl ether (2×25 ml), then water (100 ml), then dissolved in dichloromethane (300 ml) and methanol (20 ml), washed with saturated aqueous NaCl (100 ml), dried (Na2SO4), and evaporated in vacuo to leave 9.72 g (98%) of the title compound as a pale brown solid; 1H NMR (360 MHz, CDCl3) δ 0.36 (9H, s), 7.07 (1H, s), 7.20 (1H, dd, J=11.7 and 8.2 Hz), 7.30 (1H, t, J=7.6 Hz), 7.55 (1H, m), 8.00 (1H, br s), 8.07 (1H, td, J=7.7 and 1.8 Hz), 9.19 (1H, br s); MS (ES+) m/e 339/341 [MH]+, 217/219 [M-COC6H4F+2H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:23][O:24]C3CCCCO3)=[O:22])=[N:17][CH:18]=2)[CH2:8]1.[ClH:34].CCO.C(OCC)(=O)C>C(O)C>[ClH:34].[ClH:34].[OH:24][NH:23][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:15]=[N:14][C:13]([NH:12][C@@H:9]2[CH2:10][CH2:11][N:7]([CH2:6][C:5]3[CH:31]=[CH:32][CH:33]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:8]2)=[CH:18][N:17]=1
Reactant: COc1cccc(CN2CC[C@@H](Nc3cnc(/C=C/C(=O)NOC4CCCCO4)cn3)C2)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(CN2CC[C@@H](Nc3cnc(/C=C/C(=O)NO)cn3)C2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (240 mg) in ethanol (3.6 mL) was added 2N HCl-EtOH (10.1 mL), which was stirred at room temperature for 1 hour. To the resultant was added ethyl acetate (9.6 mL), which was stirred for 1 hour. The precipitate was filtered to give (2E)-N-hydroxy-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride (223 mg) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13]3([C:14]#N)[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C[O:20]C(C1(CC2C=CC(Cl)=CC=2)CCC(CO)(C)C1=O)=O.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C(C(C(O)=O)O)O>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C(OCC)(=O)C.CO.CCCCCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13]3([CH:14]=[O:20])[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Reactant: CC12CCC(Cc3ccc(Cl)cc3)C1(C#N)OC2
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC12CCC(Cc3ccc(Cl)cc3)C1(C=O)OC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In 12 ml of toluene, 267 mg of Compound 5-1 obtained in Production Example 9 of Example 1 described above was dissolved. The solution thus obtained was then cooled to −78° C. To the solution thus cooled, 1.2 ml of hexane solution of 1.0M diisobutylaluminum hydride was added dropwise. Thereafter, the resulting mixture solution was stirred for 1 hour. After the reaction, 1 ml of methanol and 10 ml of 10% aqueous solution of tartaric acid were added to the reaction solution thus obtained. The resulting mixture solution was stirred for 0.5 hour while being allowed to reach room temperature. The reaction solution thus obtained was mixed with saturated brine, and extraction with ethyl acetate was then carried out. The organic layers thus extracted were blended with each other and then washed with saturated brine. Thereafter, the organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled away under a reduced pressure. The residue was purified by silica gel column chromatography to obtain 184 mg of Compound 15-1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[N:30]=[CH:29][CH:28]=[CH:27][C:21]=2[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:12][CH2:11]1.[Cl:31]N1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:31][C:28]1[CH:29]=[N:30][C:20]([NH:19][CH2:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH3:2])[CH2:15][CH2:14]2)=[C:21]([CH:27]=1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCNc2ncc(Cl)cc2C(=O)N(C)C)CC1
Temperature: 55 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
A mixture of 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide hydrochloride (0.287 g, 0.66 mmol), prepared as in Example 21, in 6 mL of DMF was heated to 50° C. and N-chlorosuccinimide (0.1 g, 0.73 mmol) was added. The mixture was stirred at 55° C. for 4 hours, diluted with water and basified with K2CO3 giving a precipitate. The precipitate was extracted with diethyl ether and the ether layer was washed twice with brine, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with 5% methanol/methylene chloride to give 5-chloro-2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.188 g, 0.435 mmol) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O[C@@H:18]1[CH:23]2C[CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1>C1(C)C=CC=CC=1>[N:20]12[CH2:21][CH2:22][CH:23]([CH2:18][CH2:19]1)[C@@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:25]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCCCCC(O)(C(=O)OC)c1cccs1
Solvent: Cc1ccccc1
Product: CCCCCC(O)(C(=O)O[C@H]1CN2CCC1CC2)c1cccs1

Procedure:
2.7 g of 2-Hydroxy-2-thien-2-ylheptanoic acid methyl ester (Intermediate I-9) (0.011 mol) were dissolved in 70 ml of toluene. To this solution were added 1.63 g (0.0128 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 0.18 g (0.0045 mol) of HNa (60% dispersion in mineral oil). The mixture was refluxed with continuous removal of distillate with replacement with fresh toluene when necessary for 1 hour. The cooled mixture was extracted with 1N HCl acid, the aqueous layer washed with ether, basified with K2CO3 and extracted with CHCl3. The organic layer was washed with water, dried over MgSO4 and evaporated. The yield was 2.85 g (76%) of the title product as a mixture of diastereomers, structure confirmed by 1H-NMR.