Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16]C)[CH:12]=2)[C:7]1=O)[C:3](O)=[O:4].[CH3:19][NH:20][NH2:21].B(Br)(Br)Br>CC(O)C>[OH:16][C:11]1[CH:10]=[CH:9][C:8]2[C:7]3[C:6](=[CH:2][C:3](=[O:4])[N:20]([CH3:19])[N:21]=3)[CH2:15][CH2:14][C:13]=2[CH:12]=1
Reactant: CNN
Reactant: COc1ccc2c(c1)CCC(C(O)C(=O)O)C2=O
Agent: BrB(Br)Br
Solvent: CC(C)O
Product: Cn1nc2c(cc1=O)CCc1cc(O)ccc1-2
Reaction time: 3 h
Yield: 27 %

Procedure:
A solution of the product from step 1 (700 mg, 2.8 mmol) and N-methylhydrazine (0.3 mL) in 2-propanol (10 mL) was heated to reflux 18 h. The solvent was removed under vacuum and the solid was triturated with methanol (2 mL), collected and then suspended in methylene chloride (2 mL) at 0° C. BBr3 (10 mL of 1M solution in DCM, 10 mmol) was slowly added dropwise and the ice bath removed. After 3 h at ambient temperature, saturated NH4Cl solution (10 mL) was added. The DCM was removed under vacuum and the resulting slurry was carefully neutralized with saturated NaHCO3 solution and washed with water. The solids were collected to afford 8-hydroxy-2-methyl-5,6-dihydro-2H-benzo[h]cinnolin-3-one (175 mg, 27%) as a white solid; m p>300° C. MS m/z 229 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(O)C1(NC(=O)OC(C)(C)C)CCC1
Yield: 93 %

Procedure:
A 70.21 g (257 mmol) portion of ethyl 1-tert-butoxycarbonylamino-β-oxocyclobutanepropanoate was dissolved in 500.0 ml of ethanol. Thereto was added 4.86 g (514 mmol) of sodium borohydride in small portions under ice cooling. After 2 hours of stirring at the same temperature, water was added and the solvent was evaporated. The resulting residue was extracted with chloroform, washed with saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent, 65.25 g (93%) of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[S:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]1.[BH3-]C#N.[Na+].CC(O)=O>CO>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:26][C:23]1[CH:24]=[CH:25][S:21][CH:22]=1
Reactant: O=Cc1ccsc1
Reactant: COc1ccc(NCc2c(Cl)cncc2Cl)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(N(Cc2ccsc2)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate B1 (200 mg, 0.64 mmoles) was dissolved in MeOH (10 mL). Molecular sieves (4A, 200 mg) were added, and then thiophen-3-carbaldehyde (0.056 mL, 0.64 mmoles) was added. The mixture was stirred at room temperature for 2 hours, then NaBH3CN (121 mg, 1.9 mmoles) was added. AcOH was added dropwise to pH=5. After 48 hours, molecular sieves were removed by filtration, and water was added (20 mL). The mixture was extracted with AcOEt (3×50 mL), and the organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The crude material was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 7/3) to yield the title compound in amount of 173 mg.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:23][CH2:22][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][NH:12][C:11]2=[O:21])[CH2:9][CH2:8]1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:27]1([O:33][CH2:2][C:3]2[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=2)[CH2:6][N:7]2[CH2:23][CH2:22][C:10]3([N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:13][NH:12][C:11]3=[O:21])[CH2:9][CH2:8]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1NCN(c2ccccc2)C12CCN(Cc1cccc(CCl)c1)CC2
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1cccc(COc3ccccc3)c1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-(3-chloromethyl-benzyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4one, prepared as in Example 8 above, (203 mg, 0.500 mmol), phenol (56.8 mg, 0.603 mmol), KI (83.1 mg, 0.500 mmol) and K2CO3 (174 mg, 1.26 mmol) in DMF was stirred at room temperature for 1 day. The reaction mixture was diluted with H2O and a white solid precipitated. The solid was collected by filtration, washed with H2O and dried under house vacuum. The crude product was initially purified by flash chromatography (5% MeOH in CHCl3) and by tapered prep TLC (5% MeOH in CHCl3) to yield the title product as a white amorphous solid.
Reaction SMILES: N#N.[Br:3][C:4]1[N:5]=[C:6]([CH2:9][OH:10])[S:7][CH:8]=1.CCN(CC)CC.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][S:18]([O:10][CH2:9][C:6]1[S:7][CH:8]=[C:4]([Br:3])[N:5]=1)(=[O:20])=[O:19]
Reactant: OCc1nc(Br)cs1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1nc(Br)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-bromo-thiazol-2-yl)-methanol (695 mg, 3.58 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.67 mL, 4.74 mmol) followed by DMAP (44 mg, 0.36 mmol) and Ms-Cl (0.36 mL, 4.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromothiazol-2-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (257 mg, 3.91 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-bromothiazole as a yellow oil. LC-MS-conditions 01: tR=0.83 min.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(N(CC)CC)C.[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[C:12]1([S:22]([NH:3][CH2:2][CH2:1][NH2:4])(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NCCNS(=O)(=O)c1cccc2ccccc12
Reaction time: 1 h
Yield: 3.5 %

Procedure:
To a solution of ethylenediamine (1.06 g, 17.6 mmol) in dimethylformamide (10 ml), triethylamine (1.79 g, 17.7 mmol) was added, followed by stirring. With stirring at room temperature, a solution of 1-naphtalenesulfonyl chloride (4.00 g, 17.6 mmol) in dimethylformamide (15 ml) was dropwise added thereto, and the reaction was carried out in an ice bath for 1 hour. Insoluble materials were removed by filtration, and the filtrate was concentrated. To the residue, chloroform and water were added, and insoluble materials were filtered off. Furthermore, the aqueous layer was separated, washed with ethyl acetate twice and adjusted to pH 11 with potassium carbonate, followed by extraction with ethyl acetate three times. The extracts were collected, washed with water twice, dried over anhydrous sodium sulfate and concentrated. The residue was allowed to stand in a refrigerator overnight, and the precipitate was collected and recrystallized from ethyl acetate to give Compound (10) (153 mg). Yield, 4%.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCN1CCCCC1
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCCN3CCCCC3)cccc2c1Nc1ccccc1C
Yield: 26.9 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were dissolved in dry dimethylformamide (100 ml) at 80° , then 1-(3-chloropropyl)piperidine hydrochloride (4.0 g, 20 mmol) added and stirred for I hour. The mixture was poured into water, extracted with ether, and the extracts dried and evaporated. Chromatography (silica gel, 3-5% methanolic ammonia in dichloromethane) and recrystallisation from ether/petroleum ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-piperidinopropoxy)quinoline (1.2 g, 27%), m.p. 76°-78°.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1ccccn1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2ccccn2)CCN1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.3 %

Procedure:
To a solution of (R)-2-methyl piperazine (6.6 g, 0.066 mol) in xylene (100 mL) at 140° C. under nitrogen was added 2-chloro pyridine (4 g, 0.035 mol) slowly over a period of 1 h. The heating was continued for additional 12 h and cooled to RT. The solvent was removed under reduced pressure and the resulting residue was purified by chromatography using chloroform methanol (8/2) as eluent to afford the title product as a liquid (2.5 g, 40%). TLC-Chloroform/MeOH (8/2); Rf=0.2. HPLC purity: 97%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccccc1F
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccccc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.24 g (1.5 mmol) of 2-fluorobenzamide and 0.19 g (1.6 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-fluorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.28 g (1.5 mmol) of 2,3-dichloro-4-cyano aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.41 g (Yield 73%) of the title compound as a solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[C:26]([C:24]1[N:25]=[C:21]([C:19]([NH:18][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:14][O:15][S:44]([CH3:43])(=[O:46])=[O:45])[CH2:16][O:17][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:12][C:7]=2[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[O:20])[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:23]=1)#[N:27]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CO)CO)cc1C1=CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(COS(C)(=O)=O)COS(C)(=O)=O)cc1C1=CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide (0.600 g, 1.21 mmol, as prepared in the previous step) in CH2Cl2 (25 mL) was cooled to 0° C. and was treated with Et3N (421 μL, 3.02 mmol) and methanesulfonyl chloride (190 μL, 2.42 mmol). The mixture was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane afforded the title compound (0.551 g, 70%) as a white solid. Mass spectrum (APCI, m/z): Calcd. for C28H40N4O8S2Si, 653.2 (M+H). found 652.8.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:18]1([CH:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=O)[CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:18]1([CH:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=[C:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)=C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Sodium hydride (60%, 202 mg, 5.06 mmol) was suspended in anhydrous THF (15 mL) and cooled in an ice bath. Ethyl 2-(diethoxyphosphoryl)propanoate (1.2 g, 5.06 mmol) was added dropwise under nitrogen and the mixture was stirred in an ice bath for 1 h. 1-(Diphenylmethyl)azetidin-3-one (1 g, 4.21 mmol) was added in portions as a solid and the mixture was stirred at room temperature for 1 h, then left to stir at room temperature overnight. Water (50 mL) was added and the mixture was extracted with DCM (3×50 mL). Brine was added, and the aqueous and organic layers were separated. The organic layer was dried over sodium sulfate and concentrated. The resulting crude yellow oil was purified by FCC, eluting with 0-50% EtOAc, to afford a clear oil which crystallised upon standing. The solids were sonicated with heptane and the remaining solid was collected by filtration. The filtrate was concentrated and sonicated with heptane to afford a second crop of solid. The filtrate was concentrated and the residue was sonicated with heptane to afford a further crop of solid material. The resultant solids were collected and combined to afford the title compound (892 mg, 66%) as a white solid. δH (250 MHz, CDCl3) 7.56-7.39 (m, 4H), 7.38-7.15 (m, 6H), 4.63-4.45 (m, 1H), 4.24-4.01 (m, 4H), 3.96-3.76 (m, 2H), 1.72-1.58 (m, 3H), 1.27-1.14 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:27][C:22]1[CH:21]=[C:20]([CH:10]([NH:11][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: Cc1ccc(C(N[C@@H](C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(N[C@@H](C)c2ccccc2)c2cccc(N)c2)cc1C
Yield: 94.6 %

Procedure:
In a similar manner to that described in Example (1b), a solution of isomer A of N-[(3-nitrophenyl)-(3,4-dimethylphenyl)methyl]-N-[(S)-1-phenylethyl]amine (1.10 g) [prepared as described in step (a) above] in methanol (20 ml), nickel chloride hexahydrate (1.45 g) and sodium borohydride (469 mg) were reacted, to afford isomer A of the title compound (954 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1)=[O:4].C(N(CC)CC)C.[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.3 %

Procedure:
Into a solution of 1 (10 g, 55 mmol) in anhydrous CHCl3 (100 mL) was added triethylamine (19 mL, 138 mmol) and triphenylmethyl chloride (14.5 g, 52 mmol). The mixture was stirred at RT for 3 d before concentrating and redissolving in EtOAc. The solution was washed sequentially with 10% aq. citric acid, water, and brine before drying over MgSO4 and concentrating under reduced pressure to give 2 (20 g, 100%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:4][CH2:3]1.Cl.C(O[C:22](=N)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])C.Cl.[OH-].[Na+]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22]1[NH:13][C:12]2[CH:14]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[N:15]=1)[CH3:28]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added as a solid. The reaction was stirred at 40-50° C. (internal temperature) until the reaction was complete. The reaction was monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time was 1-2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of Celite filtering material. The Celite filtering material was washed with absolute EtOH (2×250 mL), and the filtrate was concentrated under reduced pressure providing a thick brown/orange oil. The resulting oil was taken up in 850 mL of a 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and a precipitate formed. The resulting mixture was stirred for 1 hour and then filtered. The solid was washed with H2O (2×400 mL) and dried at 50° C. in a vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([F:32])[CH:25]=2)[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[CH:13]=1)=O>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:10]([C:12]2[CH:22]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([F:32])[CH:25]=3)[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=2)=[O:9])=[N:3]1
Reactant: COC(=O)c1cc(Oc2ccc(C#N)c(F)c2)c2c(c1)OC(C)(C)C2
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)c(F)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (478 mg, 4.92 mmol) and 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (183a) (168 mg, 0.49 mmol) to give a white solid (176 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1 H) 7.56 (dd, J=8.59, 7.33 Hz, 1 H) 7.16-7.32 (m, 1 H) 7.07 (d, J=3.03 Hz, 2 H) 6.68-6.83 (m, 3 H) 3.71 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C22H19FN4O3 m/z 407.00 (M+H+).
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[O:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[N:26][O:27][CH3:28])[C:23]([NH2:25])=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[O:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1/[C:22](=[N:26]\[O:27][CH3:28])/[C:23]([NH2:25])=[O:24])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CO/N=C(/C(N)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Toluene (26 ml) and conc. hydrochloric acid (1.1 ml) were added to 2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (E/Z=6/94) (3.48 g, 0.013 mol), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water (80 ml) was added. The mixture was extracted with ether (80 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (3.25 g, Yield: 93.4%).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[N:8]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=3)[CH2:9][C:10](=O)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C(=O)(O)[O-].[Na+].O>COCCOCCOC>[CH:1]1[C:6]2[C:7]3[N:8]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=3)[CH2:9][C:10](=[S:21])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: S=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Temperature: 100 °C
Yield: 767.4 %

Procedure:
A mixture of 15 g indolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 3.09 g phosphorus pentasulfide and 11.46 g sodium bicarbonate in 300 ml diglyme was heated at 100° C. for two hours. The resulting mixture was cooled and poured into 3 L water to precipitate a solid. The solid was collected, triturated successively with cyclohexane, ether and hexane and dried (P2O5) to give 14.1 g solid. Recrystallization of 4.0 g from n-propanol gave 3.0 g solid, m.p. 259°-261° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[NH:5][CH2:6][CH3:7].C(O[CH:17]=[C:18]([C:24]([O:26]CC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>>[F:11][C:10]1[CH:9]=[C:8]2[C:4](=[C:3]([O:12][CH3:13])[C:2]=1[F:1])[N:5]([CH2:6][CH3:7])[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]2=[O:26]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCNc1ccc(F)c(F)c1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(CC)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 32 %

Procedure:
A mixture of 4.0 g (0.021 mole) of the 3,4-difluoro-N-ethyl-2-methoxyaniline (XIII) [prepared as described in Step (C3) above] and 5.54 g (0.026 mole) of diethyl ethoxymethylenemalonate was heated at 150°-160° C. for 9 hours. The mixture was then allowed to cool to room temperature, and 42 ml of acetic anhydride and 18 ml of concentrated sulfuric acid were then added, in that order. The reaction mixture was poured into ice-water to precipitate crystals, which were collected by filtration to give 2.09 g of ethyl 6,7-difluoro-1-ethyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (X, R9' =ethyl) as a colorless powder.