Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.[CH3:23][N:24]1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:41][O:42][C:43]1[C:44]([O:52][CH2:53][CH2:54][CH3:55])=[C:45]([CH:49]=[CH:50][CH:51]=1)[CH2:46]CN.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:24]([CH2:46][C:45]2[CH:49]=[CH:50][CH:51]=[C:43]([O:42][CH3:41])[C:44]=2[O:52][CH2:53][CH2:54][CH3:55])[CH3:23])=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CCCOc1c(CCN)cccc1OC
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCN(C)CC3)c2)cccc1OC
Yield: 6 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting (3-methoxy-2-propoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (50 mg, 6%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.6 (br s, 1H), 8.16 (d, J=9.2 Hz, 1H), 7.86 (s, 1H), 7.43 (d, J=15.2 Hz, 1H), 7.08-6.93 (m, 3H), 6.70-6.63 (m, 3H), 4.77-4.63 (m, 2H), 3.87 (q, J=6.8 Hz, 2H), 3.79 (s, 3H), 3.48-3.31 (m, 5H), 3.09-2.86 (m, 6H), 2.72 (s, 3H), 2.44-2.35 (m, 2H), 1.71 (app sextet, J=7.0 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H); MS (ESI) m/e 468 (M+H)+.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=O)[CH2:2]1.Cl[Si](C)(C)[CH3:15].[CH3:18][OH:19]>C1COCC1>[CH3:18][O:19][C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([C:10]([O:12][CH3:15])=[O:11])[CH2:2]1)=[O:9]
Reactant: O=C(O)C1CCCC(C(=O)O)C1
Reactant: CO
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COC(=O)C1CCCC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 95 %

Procedure:
1,3-Cyclohexanedicarboxylic acid (45.0 g, 261.4 mmol) was dissolved in methanol (250 mL). Chlorotrimethylsilane (10.00 mL, 78.79 mmol) was added and the reaction was stirred at room temperature for 4 days. The reaction was checked by LC-MS with the product mass [M+H]+ 201 seen. The mixture was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (200 mL). The organic layer was then washed with saturated. NaHCO3, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a slightly viscous, clear and colorless oil. The oil was redissolved in anhydrous THF and concentrated to yield 49.5 g (95%) of cyclohexane-1,3-dicarboxylic acid dimethyl ester, which was used in the next step without further purification.
Reaction SMILES: Cl.N1C=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC)(OC)(OC)CCC.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][CH2:31][CH2:32][C:33]2[O:37][N:36]=[C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:34]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([CH2:4][CH2:5][CH3:6])[N:30]([CH2:31][CH2:32][C:33]3[O:37][N:36]=[C:35]([C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)[CH:34]=3)[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Reactant: c1ccncc1
Agent: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc2c(Cl)nc3ccccc3c2n1CCc1cc(-c2ccc(F)cc2)no1
Yield: 51.1 %

Procedure:
Under a nitrogen atmosphere, pyridine hydrochloride (1.6 g, 14 mmol), trimethyl orthobutyrate (1.62 g, 11.0 mmol), 2-chloro-N4-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}quinoline-3,4-diamine (2.10 g, 5.49 mmol), and toluene (50 mL) were combined and heated at reflux for four hours under a Dean-Stark trap. The volatiles were removed under reduced pressure. The resulting oil was dissolved in ethyl acetate, and the solution was washed sequentially with aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 4:6 hexane:ethyl acetate) to provide 1.22 g of 4-chloro-1-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-2-propyl-1H-imidazo[4,5-c]quinoline as a pale yellow solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH3:5])[CH3:4].[CH3:7][C:8]1[O:9][CH2:10][CH2:11][N:12]=1.[CH3:13][CH2:14][CH2:15][CH2:16][O-:17].[Na+]>C(Cl)Cl.C(O)CCC>[CH2:16]([O:17][C:8]1([CH3:7])[N:12]([CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])[CH2:11][CH2:10][O:9]1)[CH2:15][CH2:14][CH3:13]
Reactant: CC(C)=CCBr
Reactant: CC1=NCCO1
Reactant: CCCC[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: ClCCl
Product: CCCCOC1(C)OCCN1CC=C(C)C
Yield: 59 %

Procedure:
14.9 g (0.1 mol) of prenyl bromide and 8.5 g (0.1 mol) of 2-methyl-oxazoline were stirred in 50 ml of methylene chloride at 25° C. for 2 hours and the mixture was treated with 0.11 mol of a sodium butylate solution in n-butanol at 40° C. for 1 hour and worked up in the customary manner. 13.4 g (59 mmols, 59%) of 2-butoxy-2-methyl-3-(3-methyl-2-butenyl)-oxazolidine were obtained by distillation at a boiling point 78°-80° C./0.3 mm Hg.
Reaction SMILES: NC[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[CH3:20][CH2:21][N:22](CC)CC.C(Cl)(=[O:29])C>C(Cl)Cl>[OH:15][B:12]1[C:11]2[CH:16]=[CH:17][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:21](=[O:29])[CH3:20])=[CH:19][CH:18]=3)=[CH:9][C:10]=2[CH2:14][O:13]1
Reactant: CCN(CC)CC
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a 20 mL scintillation vial containing 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (150 mg, 0.59 mmol, 1.0 eq.) in DCM (5.0 mL) was added Et3N (180 μL, 1.3 mmol, 2.2 eq.), followed by acetyl chloride (84 μL, 1.2 mmol, 2.0 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-acetamide as a white solid. LCMS (m/z) 298 (M+H); 1H NMR(CHLOROFORM-d) δ: 7.55 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.6 Hz, 2H), 6.74-6.83 (m, 3H), 6.68 (d, J=1.4 Hz, 1H), 4.79 (s, 2H), 4.21 (d, J=5.8 Hz, 2H), 1.84 (s, 3H). Amount obtained, 165 mg, 94.3% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][CH:12]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(OCC)(=O)C>O>[C:21]([O:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(-c2ccc(CO)s2)s1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCc1ccc(-c2ccc(C=O)s2)s1
Yield: 95 %

Procedure:
5-Hydroxymethyl-5'-formyl-2,2'-bithiophene (0.2 g) and pyridine (1 ml) were mixed together. Acetic anhydride (1 ml) was added slowly into the mixture with stirring. Ethyl acetate (200 ml) and water (50 ml) were added 2 hours later. The ethyl acetate layer was washed with weak base, weak acid and water. The product was concentrated and purified by column chromatography, eluted with ethyl acetate/n-hexane (1/9). Light yellowish crystals were obtained. The melting point of the crystal was 89°-91° C. The yield was 95%.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH2:8])=[O:7])[CH2:2][CH2:3][CH3:4].O1CCCC1.[C:14](Cl)(=[O:18])[C:15](Cl)=[O:16].C(OCC)(=O)C>O>[CH2:1]([N:5]1[C:15](=[O:16])[C:14](=[O:18])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN1C(=O)NC(=O)C1=O
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
3.6 g of butylurea was added to 100 ml of anhydrous tetrahydrofuran and the suspension was stirred in an ice-water bath. 4.3 g of oxalyl chloride was added dropwise to the suspension, and the stirring was continued for 30 minutes in an ice-water bath. 100 ml of ethyl acetate and 30 ml of water were added to the reaction mixture and the organic layer was obtained by extraction, The water layer was further extracted with 60 ml of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated to dryness, the crude residue was recrystallized from ethyl acetate-hexane to give 5.1 g of 1-butylimidazolidinetrione in the form of colorless needle crystals. The resulting compound was suspended to 400 ml of 0.1N ammonium aqueous solution and stirred for 8 hours at room temperature. Further, 5 ml of 28% ammonium aqueous solution was added to the solution and stirred for 14 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in methanol. 3 ml of conc. hydrochloric acid was added thereto. The solution was concentrated under reduced pressure, and the solid precipitate was filtered off, washed with water sufficiently, and recrystallized from water-methanol to give 1.8 g of 5-butyloxaluric acid (compound 3) in the form of colorless needle crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.I[CH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[N:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccc(Cl)cc2n1C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
[3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid (0.062 g, 0.19 mmol) was dissolved in DMF (3 mL) and cooled to −10° C. and then sodium bis(trimethyl)amide solution (0.420 mL, 0.42 mmol, 1.0M solution) was added. The reaction was stirred for 1 hour then iodomethane (13 μL, 0.21 mmol) was added in one portion. Standard aqueous workup and purification by preparatory HPLC provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[C:4]([F:24])[C:5]([N+:21]([O-])=O)=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].[H][H]>C(O)C.O1CCCC1.[Ni].ClCCl>[NH2:21][C:5]1[C:4]([F:24])=[C:3]([F:25])[C:2]([Cl:1])=[C:11]2[C:6]=1[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]2[CH:12]1[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c(N)c2c1=O
Yield: 86.2 %

Procedure:
A suspension of 21.7 g (58.2 mmol) of ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-nitro-4-oxo-3-quinolinecarboxylate in 300 ml of ethanol and 300 ml of tetrahydrofuran was catalytically reduced using 3 g of Raney nickel in a hydrogen atmosphere of 50 psi. After twelve hours the mixture was diluted with dichloromethane and the catalyst was removed by filtration. The filtrate was concentrated to give 17.2 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:10][C:11]1[N:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH3:10][C:11]1[N:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=4)[O:28][N:27]=3)=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(OCc2ccc(CC(Cl)=NO)cc2)n1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(OCc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of 3-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 1-2-3 in anhydrous tetrahydrofuran (5 mL) was added (4-(6-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (222 mg, 0.76 mmol) described in Manufacturing Example 3-1-5 at room temperature. Triethylamine (142 μL, 1.0 mmol) was added dropwise to the reaction solution, and stirred overnight at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3 then 1:1) to obtain the title compound (10.5 mg, 11%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8]>C(OCC)(=O)C.O.C(OCC)C.Cl.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8]
Reactant: O=C(O)/C=C/C(=O)c1cc(Br)c(O)c(Br)c1
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCC(=O)c1cc(Br)c(O)c(Br)c1
Yield: 35.7 %

Procedure:
To a stirred solution of (E)-4-(3,5-dibromo-4-hydroxyphenyl)-4-oxobut-2-enoic acid (G) (2.852 g, 8.149 mmol) in ethyl acetate (27 mL) and water (3 mL) was added zinc power (5.7 g) portion wise until no further gas evolution was observed. At this point, the reaction mixture was diluted with diethyl ether (50 mL) and HCl (2 M solution, 8 mL) and the resulting mixture was filtered through a pad of Celite. After filtration, the organic solution was washed with HCl (2 M solution, 10 mL), followed by water (3×10 mL). The organic layer was then dried (MgSO4) and concentrated in vacuo to give a brown solid. This was then triturated with cold ethanol to give the title compound as a pale brown solid (1.025 g, 36%). 1H NMR δ (ppm) (DMSO-d6): 2.58 (2 H, t, J=6.12 Hz), 3.17-3.27 (2 H, m), 8.15 (2 H, s), 10.99 (1 H, s), 12.19 (1H, s)
Reaction SMILES: [NH2:1][C@:2]1([C:21](OC)=[O:22])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:9][CH:8]=2)[CH2:3]1.[BH4-].[Na+].[ClH:27]>CCO>[NH2:1][C@:2]1([CH2:21][OH:22])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:9][CH:8]=2)[CH2:3]1.[OH2:19].[ClH:27]
Reactant: COCCCCCCc1ccc([C@@H]2CC[C@](N)(C(=O)OC)C2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCCCCCCc1ccc([C@@H]2CC[C@](N)(CO)C2)cc1
Product: O

Procedure:
A solution of (1R,3R)-methyl 1-amino-3-(4-(6-methoxyhexyl)phenyl)cyclopentanecarboxylate (12.84 g, 38.5 mmol) in EtOH (50 mL) was added dropwise to a solution of sodium borohydride (4.37 g, 115 mmol) in EtOH (50 mL). After about 15 hours 2N HCl was added slowly to the reaction mixture. The mixture was partially concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated and the solvent was removed in vacuo and the residue was dissolved in warm dioxane (100 mL) and water (1 mL) after cooling to about room temperature. The resulting solid was collected by filtration and dried in vacuo to provide ((1R,3R)-1-amino-3-(4-(6-methoxyhexyl)phenyl)cyclopentyl)methanol, hydrochloric acid, monohydrate.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][CH:8]([OH:26])[CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])[CH3:6])=[O:4].[H-].[Na+].O>CN(C=O)C>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH:9]([CH:8]1[O:26][CH2:2][C:3](=[O:4])[N:5]([CH3:6])[CH2:7]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: CN(CC(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(C(Oc2ccccc2[N+](=O)[O-])c2ccccc2)OCC1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To 24.7 g of N-chloroacetyl-N-methyl-2-hydroxy-3-phenyl-3-(2-nitrophenoxy)-propylamine dissolved in 300 ml of anhydrous DMF there was added 3.5 g of 50% NaH in mineral oil. The reaction mixture was heated at 50° C. for 3 hours under stirring and then allowed to stand for 16 hours, then poured into 2 liters of water: a brown solid was separated and was filtered and purified by mixing with boiling 95% ETOH. There was obtained 18 g (Yield 80%) of 2-[α-(2-nitro-phenoxy)-benzyl]-4-methyl-morpholin-5-one, m.p. 192°-195° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[OH:16])(=[O:4])=[O:3].C(O)C.[N:20]([O-])=[O:21].[Na+]>O.[Cl-].[Zn+2].[Cl-]>[N:20]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]=1[OH:16])=[O:21]
Reactant: CS(=O)(=O)Nc1cccc2c(O)cccc12
Reactant: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc2c(O)c(N=O)ccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture comprising 119 g of 5-methanesulfonylamino-1-naphthol, 100 g of zinc chloride and 500 ml of ethanol was heated at 50° C., and then a solution of 35 g of sodium nitrite as dissolved in 70 ml of water was added dropwise thereto at 50° to 65° C. After being heated and stirred at 60° to 65° C. for 2 hours, the resulting solution was cooled with water to room temperature, and reddish brown crystals formed were taken out by filtration and washed with ethanol. The crystals were added to 200 ml of concentrated hydrochloric acid and stirred for 1 hour at room temperature, and then 200 ml of water was added thereto. Yellowish brown crystals (2-nitroso-5-methanesulfonylamino-1-naphthol) formed were taken out by filtration, washed with water and dried. Yield: 90 g.
Reaction SMILES: [OH-:1].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1.Cl.ClC1C=CC=C[C:15]=1[CH3:20].ClC1C=CC(C)=CC=1>O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:1])[CH2:20][CH2:15]1
Reactant: [OH-]
Reactant: Cc1ccccc1Cl
Reactant: c1ccc2scnc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccc(Cl)cc1
Product: O=C1CCSc2ccccc2N1
Temperature: 100 °C

Procedure:
100 parts by weight of 50% NaOH solution were initially introduced and heated to reflux. 66 parts by weight of benzothiazole were added in the course of 3 hours and the mixture was then stirred under reflux for 2 h. It was then cooled somewhat and acidified at 100° C. with 120 parts by weight of conc. HCl and a further 100 parts by weight of water were then added. 70 parts by weight of a chlorotoluene mixture comprising about 50% o-chlorotoluene and about 50% p-chlorotoluene were added and the separating water phase was separated off. The organic phase was heated to 100° C., 35 parts by weight of acrylic acid were added in the course of 1 hour and the mixture was heated to reflux until water no longer separated from the condensate. The organic phase of the condensate was fed back into the reaction mixture. The mixture was then cooled to about 25° C. and the solid was filtered off with suction. It was washed with 70 parts by weight of the chlorotoluene mixture.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[O:21]=[C:22]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[C:29]([F:39])[CH:28]=2)[CH2:25][C@H:24]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])[O:23]1>O1CCCC1>[O:1]1[C:5]([C:6]([N:36]2[CH2:37][CH2:38][CH:33]([C:30]3[CH:31]=[CH:32][C:27]([N:26]4[CH2:25][C@H:24]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])[O:23][C:22]4=[O:21])=[CH:28][C:29]=3[F:39])[CH2:34][CH2:35]2)=[O:8])=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)c1ccno1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)c4ccno4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of isoxazole-5-carboxylic acid (79 mg) and 1,1′-carbonyldiimidazole (80 mg) in dry tetrahydrofuran (2.0 mL) is stirred at ambient temperature for one hour, and a solution of (S)-(−)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg) in dry tetrahydrofuran (6.0 mL) is added. The mixture is then stirred at ambient temperature for 19 hours, concentrated under reduced pressure, diluted with methylene chloride (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromagraphed on silica gel (70-230 mesh, 10 g), eluting with methanol/methylene chloride (7.5/92.5). Pooling and concentration of those fractions with an Rf=0.67 by TLC (methanol/chloroform, 10/90) and recrystallization from chloroforr/diethyl ether gives the title compound, mp 290-292° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:5](/[N:7]=[C:8](/[N:10](C)C)\[CH3:9])=[O:6].NO.[OH-].[Na+]>O1CCOCC1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:10]=[C:8]([CH3:9])[N:7]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: C/C(=N\C(=O)c1ccc(C)c(Br)c1)N(C)C
Agent: NO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1noc(-c2ccc(C)c(Br)c2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
A solution of (E)-3-bromo-N-(1-(dimethylamino)ethylidene)-4-methylbenzamide (preparation 57b, 0.20 g, 0.71 mmol) in dioxane (1.20 mL) was added dropwise to a stirred solution of hydroxylamine (0.06 g, 0.85 mmol) and sodium hydroxide (0.03 g, 0.85 mmol) in acetic acid (2.50 mL) and the mixture was stirred at 100° C. After 0.5 hours, the mixture was concentrated in vacuo, 4% aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic solution was dried (MgSO4) and the solvent removed in vacuo to give the title compound (0.10 g, 56%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[C:15]([F:33])[CH:14]=3)[C:9]([CH2:11]O)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C(Cl)Cl.ClC(Cl)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][N:24]=4)=[O:21])=[C:15]([F:33])[CH:14]=3)[C:9]([CH3:11])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A suspension of Intermediate AJ (N-{4-[4-amino-6-(hydroxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea) (200 mg, 0.433 mmol) in CH2Cl2 (5 mL) was treated with thionyl chloride (129 mg, 1.08 mmol) and allowed to stir for 30 min at rt. The reaction mixture was diluted with dichloroethane (25 mL) and the volatiles removed under vacuum. The residue was suspended in dichloroethane (25 mL) and concentrated a second time. The residue was then placed under high vacuum for 1 h. All material was then suspended in THF (10 mL) and cooled to −78° C. L-Selectride (438 mg, 2.29 mmol) was added and the reaction moved to a rt water bath. After 1 h the reaction was quenched with MeOH (1 mL) and diluted with 1 N NaOH (4 mL). 2 ml, 30% H2O2 (2 mL) was added dropwise, and the reaction allowed to stir for 0.5 h. The mixture was diluted with EtOAc (50 mL) and washed well with sodium thiosulfate solution and brine. The organic layer was dried with sodium sulfate and the volatiles removed under vacuum to provide an amorphous solid. Trituration with CH2Cl2 provided the desired compound as a white solid (111 mg, 59%). 1H-NMR (DMSO-d6) δ 10.10-10.30 (m, 2H), 8.54 (d, 1 H, J=5 Hz), 8.28 (t, 1H, J=8 Hz), 8.02 (s, 1H), 7.81 (s, 1 H), 7.60 (s, 1 H), 7.36-7.40 (m, 1H), 7.28-7.32 (m, 1H), 7.14-7.18 (m, 1H), 2.10 (s, 3H); MS [M+H]+=446.0; LCMS RT=2.97 min.