Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].[CH2:17]([Mg]Br)[CH3:18]>O1CCCC1>[OH:2][CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:17][CH3:18]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Solvent: C1CCOC1
Product: CCC(O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
(R)-tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (1.53 g, 6.67 mmol) was purged with nitrogen, and then was diluted with tetrahydrofuran (20 mL) and cooled to 0° C. in a ice-water bath. Ethylmagnesium bromide (3.34 mL, 10.01 mmol) was added slowly over 10 minutes. The reaction was stirred for 1 h in the ice water bath. After stirring 1 h, the reaction was slowly quenched with 30 mL sat. ammonium chloride. This was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed 1× brine, then dried over sodium sulfate, filtered and concentrated to afford crude (4R)-tert-butyl 4-(1-hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate as a colorless oil (1.65 g) which was carried on directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C=O.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]3[CH2:22][N:14]([C:15]([O:16][CH2:17][CH3:18])=[O:19])[CH2:13][CH2:12][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)NCCc1coc2c(OC)cccc12
Agent: C=O
Solvent: O
Product: CCOC(=O)N1CCc2c(oc3c(OC)cccc23)C1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of ethyl 2-(7-methoxy-1-benzofuran-3-yl)ethylcarbamate (from step 4) (0.649 g, 2.5 mmol), paraformaldehyde (0.150 g, 5.0 mmol) and 4-toluene sulphonic acid (0.0475 g, 0.125 mmol) was subjected to Dean-Stark for 2-3 hrs. After cooling to RT, water was added and organic layer was separated dried over anhy. sodium sulphate and concentrated. On purification on silica gel, it yielded ethyl 8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (96%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:45])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:42]C)(OC)[CH2:38][Br:39])[CH:32]=1)(C)(C)C>C1(C)C=CC=CC=1>[Br:39][CH2:38][C:37]([C:33]1[CH:32]=[C:31]([C:30]2[CH2:29][C:28](=[O:45])[NH:21][C:9]3[CH:10]=[C:11]([C:17]([F:18])([F:19])[F:20])[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]=3[N:7]=2)[CH:36]=[CH:35][CH:34]=1)=[O:42]
Reactant: COC(CBr)(OC)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
A solution of (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J6) (0.32 g) and 3-oxo-3-[3-(2-bromo-1,1-dimethoxy-ethyl)-phenyl]-propionic acid tert-butyl ester (0.43 g) (Example K28) in toluene (3 mL) was heated to 100° C. for 2 h. The solvent was evaporated in vacuum and the crude product was purified by chromatography on silica gel using AcOEt/Hexan(1:3) as eluent. A solution of the purified material (0.57 g) in CH2Cl2/TFA (1:1, 7 mL) was stirred at 20° C. for 15 min and then evaporated. The residual oil was dissolved in AcOEt and the solution was washed with IN HCl and with brine, dried and evaporated to give crude 4-(3-bromoacetyl-phenyl)-7-dimethylamino-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (0.22 g) as light-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:22])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1nc2c(cc1NC(=O)Oc1ccccc1)CCCC2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4c(nc3OC)CCCC4)CC2)c1
Yield: 54 %

Procedure:
Phenyl N-(2-methoxy-5,6,7,8-tetrahydroquinoline-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1.C(O)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[CH3:1][C:2]1([CH3:30])[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2(C)C)OCO4)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)c2cc3c(cc2C(=O)N1CCC1CCNCC1)OCO3
Reaction time: 1.25 h
Yield: 71 %

Procedure:
To a reaction vessel, 2 g (0.0048 mol) compound XIV, 10 ml ethanol and 50 ml 10% solution of hydrogen chloride in ethyl acetate were added, the reaction was kept at room temperature for 1-1.5 h, filtrated, the filter cake was washed with ethyl acetate, dried, and 1.2 g compound II-4 was obtained, with yield of 71%. 1H NMR (D2O): δ 1.27 (s, 6H), 1.45 (m, 2H), 1.56 (q, 2H, J=6.9 Hz), 1.69 (br s, 1H), 2.00 (d, 2H, J=13.9 Hz), 3.00 (t, 2H, J=12.6 Hz), 3.37 (t, 2H, J=7.6 Hz), 3.45 (d, 2H, J=12.3 Hz), 5.96 (s, 2H), 6.79 (s, 1H), 6.86 (s, 1H); MS (ESI): m/z 317 [M-Cl]+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[C:28](=O)[C:29](=[O:35])[C:30]=3[O:31]C(C)C)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[NH3:37]>>[NH2:37][C:28]1[C:29](=[O:35])[C:30](=[O:31])[C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:16][CH:17]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: N
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(N)c(=O)c2=O)cc1
Reaction time: 16 h

Procedure:
3-[4'-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione (0.44 g; preparable as in Example 2) was stirred in saturated ethanolic ammonia solution (10 ml) at ambient temperature for 3 hours and then kept at ambient temperature for approximately 16 hours. The solvent was evaporated and the resulting residue was triturated with diethyl ether to give an off-white solid which was dried in vacuo to give 3-amino-4-[4'-(2-ethyl-5,7-dimethyl -3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]cyclobut-3-ene-1,2-dione (0.25g; m.p. 217° C.), an active compound of the present invention.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:20][CH2:21][CH:22]([OH:24])[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]([O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:20]([CH2:21][CH:22]([OH:24])[CH3:23])[C:5]=32)=[CH:10][CH:9]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(O)CN
Reactant: CC(C)COc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)COc1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A solution of 2.3 g of (RS)-2-(2-oxoethyl)-6-isobutoxy-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.93 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:4). 1.52 g (57%) of (RS)-1-(7-isobutoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])(=[O:25])=[O:24].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:30]([C:29]4[CH:28]=[C:27]([NH:26][S:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)(=[O:24])=[O:25])[CH:35]=[CH:34][CH:33]=4)=[O:31])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2nc(N3CCNCC3)oc2c1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccn2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1cccc(NS(=O)(=O)c2ccccn2)c1)N1CCN(c2nc3ccc(Cl)cc3o2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Compound 10 is prepared using synthesis method 2: intermediate 3b (0.16 g, 0.67 mmol) is placed in 21 mL of acetonitrile in the presence of 0.18 g (0.67 mmol) of intermediate 5a and 103 μL of Et3N. 0.21 g (0.67 mmol) of TBTU is then added and the mixture is then stirred for 5 h at ambient temperature. After evaporation under reduced pressure the residue is taken up by water and extracted using AcOEt. After the organic phases are dried and after reduction to dryness the residue obtained is purified by flash chromatography (CH2Cl2-MeOH, gradient 99-1 to 95-5 over 65 min). 0.23 g of solid is obtained (yield: 68%).
Reaction SMILES: [OH:1][C:2]1([CH2:16][C:17](O)=O)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:20][C:21]([F:41])([F:40])[C:22]1[C:30]2[N:29]=[C:28]([CH2:31][CH2:32][CH2:33][NH:34][CH3:35])[NH:27][C:26]=2[CH:25]=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=1>>[F:41][C:21]([F:20])([F:40])[C:22]1[C:30]2[N:29]=[C:28]([CH2:31][CH2:32][CH2:33][N:34]([CH3:35])[CH2:17][CH2:16][C:2]3([OH:1])[CH2:7][CH:6]4[CH2:8][CH2:9][CH:3]3[CH:4]=[C:5]4[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:27][C:26]=2[CH:25]=[C:24]([C:36]([F:37])([F:38])[F:39])[CH:23]=1
Reactant: CNCCCc1nc2c(C(F)(F)F)cc(C(F)(F)F)cc2[nH]1
Reactant: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Product: CN(CCCc1nc2c(C(F)(F)F)cc(C(F)(F)F)cc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1

Procedure:
Prepared according to procedures P2.2 to P2.3 in Example 21 using rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid and [3-(4,6-bis-trifluoromethyl-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:18]#[N:19])[C:10]([CH3:17])=[C:11]([C:14]([CH3:16])=[CH2:15])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][N:28]([CH3:34])[C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>CSC>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:18]#[N:19])[C:10]([CH3:17])=[C:11]([C:14]([CH3:16])=[CH2:15])[C:12]=3[N:31]3[CH2:32][CH2:33][C@H:29]([N:28]([CH3:34])[CH3:27])[CH2:30]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: C=C(C)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Reactant: CN(C)[C@H]1CCNC1
Solvent: CSC
Solvent: CCN(CC)CC
Product: C=C(C)c1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
2-Cyclopropyl-7-fluoro-6-isopropenyl-5-methyl-1,3-benzoxazole-4-carbonitrile (I-315) (34 mg, 0.13 mmol) was dissolved in dimethyl sulfide (2 ml), then triethylamine (38 μl, 0.27 mmol) and (3S)-3-(dimethylamino)pyrrolidine (36 μl, 0.28 mmol) were added, followed by stirring under nitrogen atmosphere at 90° C. for 4 hours. After cooled, this was concentrated under reduced pressure, diluted with chloroform and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (21 mg, 25%) as a brown crystal.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
To a stirred solution of 6-hydroxy-3-oxo-2,3-dihydrobenzofuran of Example 6(a) (32 kg, 213 moles) in DMF (192 L) was added potassium carbonate (31.0 kg, 224 moles). After stirring for 5 min. at room temperature, benzyl bromide (145.2 kg, 264 moles) was added and the resulting mixture was stirred for 2 hours at room temperature. The mixture was poured into water (651 L), stirred for 30 minutes and the product collected by centrifugation. The crude solid was washed with water (580 L), 80% ethanol (100 L) and dried under vacuum to afford the desired product (49.1 kg; 95%) which was used without any further purification.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:21])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])(=O)C>O.N>[SH:4][CH2:5][CH:6]([CH3:21])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:16])[NH2:17])=[O:8]
Reactant: CC(=O)SCC(C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: N
Solvent: O
Product: CC(CS)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
Nα -(3-Acetylthio-2-methylpropanoyl)-L-arginine (1 g.) is dissolved in a mixture of water (5 ml.) and concentrated ammonia (5 ml.). After one hour at room temperature the solution is concentrated to 3 ml. in vacuo (no heat) and ion exchange resin AG-50 W is added until the pH of approximately 4. The suspension is applied to a column of the same resin and the Nα -(3-mercapto-2-methylpropanoyl)-L-arginine is eluted with pyridine-acetate buffer pH 6.5. The solvent is removed in vacuo and the residue is freeze dried, yield 0.86 g., m.p. 100°.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>CCO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[N:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc2c(c1)C(=NOCc1ccccc1)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A mixture of (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (150 mg, 0.35 mmol), NH2OCH2Ph (94 mg, 0.76 mmol) and pyridine (61 μl, 0.700 mmol) in EtOH (10 ml) was heated to reflux. After 2 h, the solution was cooled down to RT and evaporated under vacuum. The crude residue was triturated with Et2O/H2O 90/10 to give (E)-3-{1′-benzyl-4-benzyloxyimino-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide (55 mg) as a 70/30 mixture of the two isomers (hydrochloride salts).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](F)=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:14]([NH2:16])[CH3:15]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([NH:16][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Fc1ncccc1-c1sccc1Br
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNc1ncccc1-c1sccc1Br
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A mixture of 3-bromo-2-(2-fluoropyridin-3-yl)thiophene (0.47 g) and ethylamine (0.4 g) in dioxane (2 mL) in a sealed tube was heated at 100° C. for 2 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated to give 3-bromo-2-(2-ethylaminopyridin-3-yl)thiophene (0.45 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH2:15]Br>>[CH2:3]([N:2]([CH3:1])[CH2:15][C:14]1[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:12]([O:11][CH3:10])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: CNCc1ccccc1
Product: COc1cc(CN(C)Cc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A solution of N-methyl-benzyl amine was alkylated with 3-methoxy-4-nitro-benzyl bromide as described above for compound 338. 1H NMR (400 MHz, CDCl3): δ7.83 (d, J=8.6 Hz, 1H), 7.35 (s, 4H), 7.26 (s, 1H), 7.17 (s, 1H), 7.01 (d, J=7.04 Hz, 1H), 3.97 (s, 3H), 3.55 (s, 4H), 2.22 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:8]2[C:6]3[N:7]=[C:2]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccc(F)cc4)ncnc23)CC1
Solvent: C1COCCO1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccc(F)cc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-(4-fluorobenzylamino)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 210°-212° C.) and piperazine in dioxane at 80° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[NH:26][N:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncccc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1ccc(COc2ccc(-c3n[nH]c4cccnc34)cc2)cc1

Procedure:
A mixture of [4-(benzyloxy)phenyl](3-fluoropyridin-2-yl)methanone (3.0 g) and hydrazine hydrate (5.0 mL) in EtOH (90 mL) was refluxed for 4 days. The mixture was concentrated under reduced pressure. The residue was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (0.83 g).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:14][CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: OCCc1ccc2ccccc2c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCc1ccc2ccccc2c1Br
Yield: 101.6 %

Procedure:
A solution of 1-bromo-2-(2-hydroxy-ethyl)-naphthalene (46.5 g, 0.185 mol) in methylene chloride (370 mL) was placed under a nitrogen atmosphere, cooled in an ice bath, and stirred. Triethylamine (32.3 mL, 0.232 mol) was added followed by acetyl chloride (15.8 mL, 0.222 mol) dropwise over 5 minutes. The reaction mixture was removed from the ice bath and stirred at room temperature for 15 minutes. The reaction mixture was washed with water (300 mL), 1N hydrochloric acid (200 mL) and water (250 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to afford the title compound as an oil (55.1 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([CH:33]=2)[C:31]#[N:32])O1>>[C:31]([C:30]1[CH:33]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:6][N:7]=2)[CH:27]=[N:28][CH:29]=1)#[N:32]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)nc1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cncc(C#N)c2)nc1
Yield: 47 %

Procedure:
Prepared in a similar manner to Example 23 from 2-(6-bromopyridin-3-yl)-N-isobutyl-2-methylpropanamide (example 40a) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile. Yield: 47%. 1H NMR (400 MHz, dMSO): δ 0.72-0.74 (d, 6H), 1.51 (s, 6H), 1.66-1.69 (m, 1H), 2.82-2.86 (m, 2H), 7.62-7.64 (m, 1H), 7.82-7.85 (m, 1H), 8.10-8.12 (d, 1H), 8.65-8.66 (d, 1H), 8.89-8.90 (t,1H), 9.05-9.06 (d, 1H), 9.50-9.51 (d, 1H); MS+H (323).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].F[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26]>CCO>[CH2:12]([C:4]1[S:3][C:2]([NH:1][C:15]2[C:16]([N+:25]([O-:27])=[O:26])=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]([F:22])([F:24])[F:23])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1)[CH3:13]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1F
Reactant: CCOC(=O)c1cc(CC)sc1N
Solvent: CCO
Product: CCOC(=O)c1cc(CC)sc1Nc1c([N+](=O)[O-])cccc1C(F)(F)F

Procedure:
Ethyl 2-amino-5-ethylthiophene-3-carboxylate and 2-fluoro-3-trifluoromethylnitrobenzene, m.p. 72°-73° C. (EtOH).
Reaction SMILES: CO.Cl.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:24]=[C:23]2[C:14]([N:15]3[C:20]([CH2:21][O:22]2)=[N:19][NH:18][C:17](=[O:25])[C@H:16]3[CH3:26])=[CH:13][C:12]=1[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C=O.[BH3-][C:36]#N.[Na+]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:24]=[C:23]2[C:14]([N:15]3[C:20]([CH2:21][O:22]2)=[N:19][NH:18][C:17](=[O:25])[C@H:16]3[CH3:26])=[CH:13][C:12]=1[CH:27]1[CH2:32][CH2:31][N:30]([CH3:36])[CH2:29][CH2:28]1
Reactant: [BH3-]C#N
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4CCNCC4)cc3N21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4CCN(C)CC4)cc3N21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of MeOH (10 mL) and acetic acid (1 mL) was added (R)-7-(2-fluoro-phenyl)-4-methyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (0.300, 0.761 mmol) and paraformaldehyde (0.228 g, 7.61 mmol) and the reaction mixture was stirred at rt for 4 h. Then NaCNBH3 (0.096 g, 1.52 mmol) was added and the reaction mixture was stirred for 30 min. The solvent was removed in vacuo and the residue was purified by prep-TLC (eluting with 10% MeOH in DCM) to give (R)-7-(2-fluoro-phenyl)-4-methyl-6-(1-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.160 g, 51%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.50-7.41 (m, 1H), 7.32-7.26 (m, 2H), 7.25-7.19 (m, 1H), 7.09 (s, 1H), 6.86 (s, 1H), 5.02-4.93 (m, 1H), 4.70-4.59 (m, 2H), 3.63-3.46 (m, 2H), 3.04-2.89 (m, 2H), 2.84 (s, 3H), 2.76 (m, 1H), 2.28-2.01 (m, 3H), 1.96-1.83 (m, 1H), 1.52 (d, J=6.4 Hz, 3H). LCMS (Table 1, Method 4) Rt=1.617 min; MS m/z: 409 [M+H]+.