Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH:5]1[O:10][C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:7]=2[O:6]1)=[O:4].O.[NH2:29][NH2:30]>C(O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:7]2[O:6][CH:5]([C:3]([NH:29][NH2:30])=[O:4])[O:10][C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:8]=2[CH:23]=1
Reactant: COC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Temperature: 25 °C

Procedure:
A solution of 2.47 g 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxylic acid methyl ester in 9 ml ethanol was added to a solution of 0.61 ml hydrazine monohydrate in 9 ml ethanol. The reaction mixture was refluxed for 1 h. After cooling to room temperature, the solvent was removed in vacuo. The crude product was purified by preparative HPLC (C18 reverse phase column, elution with water/TFA gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a solid. Yield: 1.1 g.
Reaction SMILES: [N:1]1[N:2]=[C:3]([SH:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl[C:12]1[N:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=1>C(O)(=O)C>[N:1]1[N:2]=[C:3]([S:10][C:12]2[N:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Sc1nnc2ccccn12
Reactant: Nc1ccc(Cl)nn1
Solvent: CC(=O)O
Product: Nc1ccc(Sc2nnc3ccccn23)nn1
Temperature: 80 °C

Procedure:
A reaction mixture of [1,2,4]triazolo[4,3-a]pyridine-3-thiol (8.49 g, 55.0 mmol) and 6-chloropyridazin-3-amine (6.82 g, 50 mmol) in acetic acid (100 mL) was heated at 80° C. for 20 hrs. The reaction was stripped to dryness via rotary evaporation and the resulting material was suspended in H2O (100 mL). To this suspension, solid Na2CO3 was added in portions until pH 10 was achieved and then the mixture was sonicated. The resulting solid was collected by filtration and rinsed thoroughly with water followed by ethyl ether. The solid was dried in vacuum over P2O5 to provide the title compound, 6-([1,2,4]Triazolo[4,3-a]pyridin-3-ylsulfanyl)-pyridazin-3-ylamine, as a white power (11.0 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15-7.25 (m, 1 H) 7.53-7.58 (m, 1 H) 7.61 (ddd, J=9.22, 6.69, 1.26 Hz, 1 H) 7.84-7.90 (m, 1 H) 7.99 (dt, J=9.09, 1.01 Hz, 1 H) 8.51 (dt, J=7.01, 1.04 Hz, 1 H) 8.79 (br. s., 2 H). ESI-MS:m/z 553.2 (M+H)+.
Reaction SMILES: [C:1]1([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16](B(O)O)[CH:17]=3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:16]2[CH:15]=[CH:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[CH:12]=3)[CH:17]=2)=[CH:27][CH:26]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc2cc(-c3cccc4ccccc34)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3cc(-c4cccc5ccccc45)ccc3c2)cc1
Yield: 88.9 %

Procedure:
Under the atmosphere of argon, 3.2 g of 2-(naphthalen-1-yl)naphthalene-6-boronic acid and 2.8 g of 4-bromoiodobenzene were dissolved into 30 ml of toluene, and 0.23 g of tetrakis(triphenyl-phosphine)palladium was added to the obtained solution. After 28 ml of a 2 M aqueous solution of sodium carbonate was added, the resultant mixture was heated under the refluxing condition for 8.5 hours. After the obtained mixture was left standing for one night, the mixture was subjected to extraction with toluene. The extract was washed with a saturated aqueous solution of sodium chloride, and the solvent was removed using an evaporator. The residue was purified in accordance with the silica gel column chromatography (the developing solvent: toluene), and 3.6 g of 2-(4-bromophenyl)-6-(naphthalen-1-yl)naphthalene was obtained as a light yellow solid substance (the yield: 83%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[C:7]=1[S:14](Cl)(=[O:16])=[O:15].O>O1CCCC1>[Br:5][C:6]1[C:7]2[S:14](=[O:15])(=[O:16])[N:4]([CH:1]([CH3:3])[CH3:2])[C:12](=[NH:13])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)N
Reactant: N#Cc1cccc(Br)c1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1C(=N)c2cccc(Br)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
70 mg of isopropylamine is added at ambient temperature to a solution of 150 mg 2-bromo-6-cyano-benzenesulfonyl chloride in 5 ml of tetrahydrofuran. After stirring for 16 h at ambient temperature the mixture is poured into water and extracted with ethylacetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated. Chromatography of the residue with cyclohexane—ethyl acetate (2:1) affords 99 mg of 7-bromo-2-isopropyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-ylideneamine (P2.1).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[C:4]([C:7]1[CH:11]=[CH:10][N:9]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=1)(=[O:6])[CH3:5].[Cl:22]C(=C(Cl)C(Cl)=C(Cl)C(Cl)Cl)C=O>CO>[Cl:22][CH2:5][C:4]([C:7]1[CH:11]=[CH:10][N:9]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=1)=[O:6]
Reactant: CC(=O)c1ccn(S(=O)(=O)c2ccc(C)cc2)c1
Reactant: O=CC(Cl)=C(Cl)C(Cl)=C(Cl)C(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)CCl)c2)cc1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
In a 100 cm3 one neck flask fitted with a condenser and a calcium chloride guard, 4 g of 3-acetyl-1-tosyl pyrrole 2 (15 mmoles) was introduced together with 30 cm3 of methanol. Then 4.5 g of 2,3,4,5,6,6-hexachloro-2,4-hexadiene-1-one (15 mmoles) was set under reflux during 6 hours and maintained under stirring at ambient temperature during one night. The solvent was evaporated and the crude product (8.5 g) was dissolved in 15 cm3 of chloroform, filtered (the pentachlorophenol was not very soluble in this solvent) and separated on silica gel column (250 g; 60-200 82 m; eluting with 1-29-70 acetic acid-ethyl acetate-heptane; VR =650 cm3) to give 2.35 g of white crystals 3 (M=297.5, yield: 53%).
Reaction SMILES: [CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][CH:11]=[C:10]([CH3:15])[C:9]1(O)[C:8]1[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Cr](Cl)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][C:11](=[O:26])[C:10]([CH3:15])=[C:9]1[C:8]1[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CCCCC12CCCC=C(C)C1(O)c1ccc(OCOC)cc1C2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCC12CCCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 9a-butyl-2-(methoxymethoxy)-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-4b(7H)-ol (32 mg, 0.1 mmol) in dichloromethane (1 mL) was treated with pyridinium chlorochromate (PCC, 32 mg, 0.15 mmol). After stirring at room temperature for 5 hours, the mixture was treated with additional PCC (5 mg, 0.023 mmol). The mixture was concentrated and purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 10% EtOAc in hexane. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 9a-butyl-2-(methoxymethoxy)-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-6(7H)-one as an oil.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[Li]CCCC.[Br:25]Br>C1CCCCC1>[Br:25][C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]([OH:14])=[O:13]
Reactant: BrBr
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C(O)c1nc(-c2ccccc2)sc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-phenyl-1,3-thiazole-4-carboxylic acid (3.2 g) in abs. THF (190 mL) was added at 78° C. over 10 min n-BuLi (25 mL, 1.6M in hexanes). After addition, Br2 (1.3 mL) in cyclohexane (7.4 mL) was added over 10 min. The reaction mixture was allowed to warm up to RT and was stirred at this temperature for 3 h. The reaction mixture was then cooled to 0° C., carefully quenched with HCl (1M, 32 mL) and extracted with EtOAc (2×). The combined org. phases were washed with aq. sodium thiosulfate (20%), dried over MgSO4 and evaporated to dryness to give 4.5 g of the desired product. The crude was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:13](=[N:1]/[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc2ccc(O)cc12
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc2cccc(/N=C/c3ccccc3)c2c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of 8-amino-2-naphthol 1 (8.2 g, 52 mmol), benzaldehyde (16 mL, 156 mmol) and sodium sulfate (41.3 g, 291 mmol) in THF (100 mL) was stirred at reflux over night. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane/ethyl acetate/triethyl amine 75/23/2) to give 12.65 g of impure (E)-8-(benzylideneamino)naphthalen-2-ol (2) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=S)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19].O=O.[K+].O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:19][C:13]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: S=C=Nc1ccc(Br)cc1
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Clc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
4-Bromophenyl isothiocyanate (3.639 g, 17.00 mmol) was added to a solution of 2-amino-4-chlorophenol (2.441 g, 17.00 mmol) in acetonitrile (20 mL) and the reaction was stirred at room temperature for 2 h. The resulting brown solution was then added dropwise, via a dropping funnel, to a suspension of potassium superoxide (6.04 g, 85.0 mmol) in acetonitrile (20 mL) pre-cooled to 0° C. in an ice bath. After 20 minutes the initial exotherm had subsided and the reaction was allowed to warm to room temperature for 40 minutes. Water (120 mL) was added dropwise and the resulting off-white solid was collected by filtration, washed with additional water (60 mL) and dried overnight on a lyophilizer to afford N2-(4-bromophenyl)-5-chloro-1,3-benzoxazol-2-amine as an off-white solid (4.06 g, 74%); RP-HPLC Rt 17.229 min, 99% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 321 (M−H)− and 323 (M−H)−; 1H NMR (400 MHz, d6-DMSO) 7.17 (1H, dd, J 8.5 and 1.9 Hz), 7.53 (4H, m), 7.71 (2H, d, J 8.8 Hz), and 10.95 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][O:9]C(=O)C)=[C:4]([CH:15]=O)[CH:3]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCC1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:15]/[C:4]3[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=3[O:6][CH2:7][CH2:8][OH:9])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: CC(=O)OCCOc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1OCCO
Temperature: 70 °C
Yield: 43 %

Procedure:
Acetic acid 2-(4-chloro-2-formyl-phenoxy)-ethyl ester (1.5 g, 9.3 mmol) and 6-chlorooxindole (2.7 g, 11.2 mmol) were mixed in anhydrous methanol (20 mL) at room temperature. Then Pyrrolidine (0.8 g, 11.2 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h, then cooled to r.t and the precipitation was collected by filtration to obtain title compound as a yellow solid (1.4 g).
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=O)[CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=1>CO>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CCN1CCCC1)Nc1cccc(Br)c1
Solvent: CO
Solvent: C1CCOC1
Product: Brc1cccc(NCCCN2CCCC2)c1
Reaction time: 8 h

Procedure:
A 1M solution of BH3 in tetrahydrofuran (10 ml, 10 mmol) was added dropwise to N-(3-bromo-phenyl)-3-pyrrolidin-1-yl-propionamide (0.3 g, immol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride was added. The aqueous phase was extracted twice with ethyl acetate and the organics were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in methanol and loaded onto an SCX cartridge, which was washed with methanol and the product subsequently eluted with 2M ammonia in methanol. Removal of all solvents under rotary evaporation gave the desired product. Yield 0.23 g, 82%. LCMS method: 2, RT: 2.71 min; MI: 283-285 [M+1].
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[H-].[Na+].[Cl:54][CH2:55][CH2:56]Cl.O>CN(C)C=O>[Cl:54][CH2:55][CH2:56][N:2]([CH3:1])[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reactant: ClCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCCl)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reaction time: 0.33 h

Procedure:
314 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) was dissolved in 8 mL N,N-dimethylformamide, then 21 mg sodium hydride was added thereto and stirred for 20 minutes, and 0.35 mL 1,2-dichloroethane was added thereto and stirred at room temperature for 2 hours. Further, 0.35 mL 1,2-dichloroethane was added thereto and stirred at 60° C. for 24 hours. Water was added to the reaction solution which was then extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated, and then the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 325 mg of the title compound as a colorless amorphous.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][OH:16])[CH3:12].[H-].[Na+].O>CN(C=O)C>[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCN(CC)CCO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To the solution of 8.0 g (51 mMol) of 1-chloro-4-nitrobenzene and 6.0 g (6.8 mL; 51 mMol) of 2-diethylamino-ethanol in 50 mL of DMF at 0° C. is added 2.7 g of NaH portionwise over 2 h. After stirring another hour at rt, the reaction mixture is poured onto 300 mL of water and stirred. After filtering off some crystalline product, the aqeous layers are extracted with ethyl acetate. The combined organic layers are dried and evaporated to obtain diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine. Title compound: ES-MS: 239 [M+H]+; single peak at tR=5.1 min (System 2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 3.85 g (7.00 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-4-[(t-butyldiphenylsiloxy)methyl]-1,1'-biphenyl (Step D) in 25 mL of dry tetrahydrofuran under a nitrogen atmosphere was added by syringe 10.5 mL (0.530 mmol) of a 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran. The reaction mixture was stirred for two hours then diluted with 700 mL of diethyl ether. The mixture was washed with water (3×150 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), then dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give an oil which was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (55:45) to afford 2.02 g (92%) of the product as a white solid (mp 89°-93° C.). 1H NMR (200 MHz, CDCl3): δ1.40 (s, 9H), 2.50 (s, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 7.18-7.45 (m, 8H). FAB-MS: calculated for C19H23NO3 313; found 314 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.CC(C)([O-])C.[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.O>[CH2:27]([N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Oc2cccc3nc4c(c(c23)N(Cc2ccccc2)C1=O)CCCC4
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry dimethylformamide (60 ml) was added potassium t-butoxide (3.15 g), with stirring. After 15 mins, benzyl bromide (2.66 ml) was added, and the reaction mixture was stirred for two hrs. The reaction mixture was diluted with water (300 ml), extracted twice with 100 ml-portions of diethyl ether, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was adhered to silica and flash chromatographed (10-30% ethyl acetate/hexane). The mixed fractions were flash chromatographed (3% ethyl acetate/dichloromethane), and the appropriate fractions were combined, and concentrated. Trituration of the residue with (1/1-diethyl ether/pentane) gave 4.58 g (68%) of 1-benzyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:27][C:26]3([F:29])[F:28])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:27][C:26]3([F:29])[F:28])[C:17]([OH:19])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CC2(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CC2(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
216 mg (465 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoate (mixture of two racemic diastereomers) in 1 ml of dichloromethane and 537 μl (6.97 mmol) of TFA were reacted according to General Method 6A. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 88 mg (44% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1>C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N)cc2F)CC1
Yield: 92.6 %

Procedure:
A solution of 1-(2-fluoro-4-nitrophenyl)-4-methylpiperazine (5.00 g, 20.9 mmol) (from Step A above) and 10% palladium-on-carbon (0.20 g, 0.2 mmol) in ethyl acetate (100 mL) and ethanol (50 mL) was hydrogenated at 50 psi in a Parr shaker for 4 h. The mixture was filtered through Celite™. The Celite™ was washed with ethyl acetate (50 mL) and the solvent was evaporated to give 3-fluoro-4-(4-methyl-1-piperazinyl)benzenamine as a white solid (4.05 g, 93%, mp 89-91° C.).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:12])OC)[CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH2:18])[CH3:14]>CO>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH:18][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=1)=[NH:12])[CH3:14]
Reactant: CCOC(CN)OCC
Reactant: COC(=N)c1cccc(Br)c1
Agent: Cl
Solvent: CO
Product: CCOC(CNC(=N)c1cccc(Br)c1)OCC
Temperature: 25 °C

Procedure:
To a solution of methyl 3-bromobenzenecarboximidoate hydrochloride (Step 1 above) in MeOH (10 mL) at 0° C. was added [2,2-bis(ethyloxy)ethyl]amine (1.74 mL; 12 mmol) in one portion and the mixture was gradually warmed to room temperature (overnight). The mixture was concentrated in vacuo, partitioned between CH2Cl2/1M NaOH and the layers were separated. The aqueous layer was extracted with CH2Cl2 (×2), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo affording the title compound as a light brown oil which was used directly for Step 3 below. LC/MS (method A) tR 1.25 min, m/z 315, 317 (M+H, Br isotopes, 4%), 223, 225 (M+H−2EtOH, Br isotopes, 100%).
Reaction SMILES: C(O[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]3[N:20]=[CH:21][S:22][C:18]=3[CH:17]=2)[C:12]1=[O:25])C.CO.[NH3:29]>C(Cl)(Cl)Cl>[S:22]1[C:18]2[CH:17]=[C:16]([N:13]3[CH2:14][CH2:15][N:11]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][C:5]=4[C:4]([NH2:29])=[O:26])[C:12]3=[O:25])[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21]1
Reactant: N
Reactant: CCOC(=O)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Temperature: 40 °C
Yield: 28.57 %

Procedure:
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-isonicotinic acid ethyl ester (I-185a: 0.16 g, 0.4 mmol) in methanolic ammonia (20 mL) was taken in a reaction flask and the flask was heated to 40° C. overnight. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was cooled to room temperature and concentrated. The concentrate was partitioned between DCM and water. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (10% MeOH in CHCl3) afforded 40 mg of the product (28.57% yield).