Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]/[O:6][CH3:7].S(Cl)([Cl:25])(=O)=O>ClCCl.O>[CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(Cl)cc1
Yield: 68.1 %

Procedure:
A solution of (E)-N-methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (500 mg) in dichloromethane was cooled to 0° C., and sulfuryl chloride (285 mg) was dropwise added thereto. The resultant mixture was stirred at the same temperature for 2 hours, diluted with water and extracted with diethyl ether. The solvent was dried and removed, and the residue was subjected to HPLC with a mixture of hexane and ethyl acetate to give 382 mg of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[Br:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[Br:28][CH2:29][C:30]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:31]
Reactant: O=C(Cl)CBr
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Solvent: ClCCl
Product: O=C(CBr)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (500 mg, 1.2 mmol) was dissolved in DCM (15 ml), and TEA (180 mg, 1.8 mmol) and 2-bromoacetyl chloride (243 mg, 1.55 mmol) were added. The mixture was stirred at RT for 2 hours, then was diluted with DCM (50 ml) and washed with HCl 1N (2×). The organic phase was dried over Na2SO4 and evaporated under vacuum, obtaining a crude (550 mg) containing the title compound (MS/ESI+ 541.17 [MH]+) which was employed in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[C:19](Cl)([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20])[CH:8]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 20 h
Yield: 56.9 %

Procedure:
A solution of 10 g (58 mmol) 5-chloro-2-nitroaniline in 250 ml dry tetrahydrofuran was added 8.5 ml (62 mmol) dry triethylamine. A solution of 7.0 ml (62.7 mmol) ethoxalylchloride in 50 ml dry tetrahydrofuran was added dropwise. Stirring was continued at 25° C. for 20 h. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with ethanol to give 9.0 g (57%) 4-chloro-2-ethoxalylamino-1-nitrobenzene. M.p. 105.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[N:7]2.[N+:18]([O-])([OH:20])=[O:19]>OS(O)(=O)=O.[OH-].[Na+]>[Br:1][C:2]1[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)=[N:7]2
Reactant: Brc1cccc2nc(N3CCNCC3)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2nc(N3CCNCC3)ccc2c1Br
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a -10° C. solution of 10 (300 mg, 1.03 mmol) in H2SO4 (10 ml) was added dropwise HNO3 (0.25 ml). The mixture was stirred 15 min. at -10° -0° C., poured onto ice, and diluted with 1M NaOH until basic. The mixture was then extracted with CH2Cl2 (3×), and the combined organic layers were dried (MgSO4). Concentration yielded 2a (240 mg, 70%) as a yellowish solid which was utilized in the next step without further purification. (m.p.>230° C., dec. ). 1H NMR d (ppm): 1.79 s (NH), 3.00 dd (CH2), 3.80 dd (CH2), 7.07 d (CH arom), 7.57 d (CH arom), 7.81 d (CH arom), 8.37 d (CH arom).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:24]/[N:25]5[CH2:29][CH2:28][NH:27][C:26]5=[O:30])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN1CCNC1=O
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\N1CCNC1=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield as a light yellow solid in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and 1-aminoimidazolidin-2-one. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.42 (s, 1H), 8.89 (d, 1H), 8.35 (d, 1H), 8.02 (m, 2H), 7.84 (d, 1H), 7.53 (dd, 1H), 7.36 (s, 1H), 6.22 (s, 2H), 3.75 (t, 2H), 3.41 (t, 2H), 2.42 (s, 3H). LCMS (method B): [MH]+=388, tR=1.89 min.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][N:17]=1.Cl>C1COCC1>[F:15][C:16]1[N:17]=[CH:18][C:19]([CH:20]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[OH:21])=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(F)nc1
Reactant: CSc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CSc1ccc(C(O)c2ccc(F)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Magnesium turnings (0.214 g, 8.79 mmol) in a minimal amount of THF were treated with 1,2-dibromoethane (50 μL, cat.) and the mixture was allowed to stand until effervescence was observed (1 min) A solution of 4-bromothioanisole (Aldrich) (1.705 g, 8.39 mmol) in THF (20 mL) was added dropwise and the mixture stirred for 2 h, occasionally heating to gentle reflux with a heat gun, to give a cloudy pale yellow solution. The resulting Grignard solution was added dropwise over 10 min to a solution of 6-fluoronicotinaldehyde (Frontier Scientific) (1.000 g, 7.99 mmol) in THF (10 mL) cooled in a dry ice/acetone bath. The mixture was stirred at −78° C. for 30 min, and then quenched by dropwise addition of 2 N aqueous HCl (9.0 mL, 2 equiv.). The cooling bath was removed and the mixture was allowed to warm to ambient temperature. The mixture was extracted into EtOAc from water, dried (MgSO4) and concentrated to give (6-fluoropyridin-3-yl)(4-(methylthio)phenyl)methanol (1.856 g, 7.44 mmol, 93% yield) as a colorless oil. 1H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H); 7.87 (t, J=8.22 Hz, 1H); 7.32 (d, J=8.02 Hz, 2H); 7.22 (d, J=7.82 Hz, 2H); 7.11 (d, J=8.41 Hz, 1H); 6.11 (br. s., 1H); 5.78 (s, 1H); 2.44 (s, 3H). m/z (ESI, +ve) 250.0 (M+H)+.
Reaction SMILES: C(C1C[C:9](C#N)([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:12]=2)CCC1=O)(OC)=O.[H-].[Na+].C(C(C1C=CC(OC(F)F)=C(OCC2CC2)C=1)(CCC(OC)=O)CCC(OC)=[O:37])#N>COCCOC>[CH:23]1([CH2:22][O:21][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=2[O:17][CH:18]([F:20])[F:19])[CH:9]=[O:37])[CH2:25][CH2:24]1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC(F)F)c(OCC3CC3)c2)CCC1=O
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 60 °C

Procedure:
2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one To a suspension of sodium hydride (80% dispersion in mineral oil, 11.6 g, 388 mmol) in dry 1,2-dimethoxyethane (700 mL) under an argon atmosphere was added a solution of crude dimethyl 4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pimelate (41 g) in dry 1,2-dimethoxyethane (700 mL). The resulting mixture was heated at 60° C. for 1 h, cooled to room temperature, quenched with dilute aqueous hydrochloric acid and concentrated The residue was diluted with water, was acidified to pH 3 and was extracted twice with methylene chloride. The organic extract was washed with acidic water, was dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with methylene chloride, followed by trituration with cold ether provided a solid (17.7 g, 43% from 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde): m.p. 115°-116° C.
Reaction SMILES: [Cl:1][CH:2]=[CH:3]Cl.N#N.[Li]CCCC.[CH3:12][C:13](=[O:34])[C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C@@H:21]([CH2:22][C:23](=[O:33])[CH2:24][CH2:25]2)[CH2:20][CH2:19]3)[CH2:16][CH2:15]1>C1COCC1>[Cl:1][C:2]#[C:3][C@@:23]1([OH:33])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:31]2([CH3:32])[C@H:17]3[CH2:16][CH2:15][C@@H:14]2[C:13](=[O:34])[CH3:12])[CH2:22]1
Reactant: ClC=CCl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@](O)(C#CCl)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
An attempt was also made to prepare the organometallic reagent with 1,2-dichloroethylene. A 100 mL three-neck flask equipped with a N2 gas bubbler, a thermometer, and a dropping funnel was charged with 1,2-dichloroethylene (cis, Aldrich, 0.16 mL, 2 mmol, mw=97, d=1.28). Dry THF (7 mL) was added, and the solution was cooled to -10° C., n-BuLi (2.5M in THF, 1.6 mL, 4 mmol) was added dropwise over a period of 10 min. The mixture was stirred at -30° C. for 20 min and then at 0°-5° C. for 10 more min. The resulting reagent was then recooled to -30° C. and was treated dropwise with a solution of 5β-pregnan-3,20-dione, 20-ketal (360 mg, 1 mmol) in THF (15 mL). The cooling bath was removed and the mixture was stirred at room temp. for 30 min. (100% conversion as detected by TLC). The cooling bath was removed and the resulting solution was quenched with sat. NH4Cl solution (1 mL). The solvent was removed and the residue was dissolved in acetone (30 mL). After adding 2N HCl (5 mL) the solution was stirred at ambient temperature for 1.5 h. The mixture was neutralized with dil. NaOH solution (pH 5-6). The precipitated solid (429 mg) was collected by filtration, washed with water, and dried. The crude product was then purified by column chromatography over silica gel (toluene acetone 95:5) to yield 3β-chloroethynyl-3α-hydroxy-5β-pregnan-20-one (130 mg); TLC-Rf 0.33 (toluene:acetone 95:5), NMR (CDCl3) δ 0.59 (s, 3H, Me), 0.97 (s, 3H, Me), 2.11 (s, 3H, Me), 2.55 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>C1COCC1>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCCOCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNCCOCCO
Temperature: 0 °C
Yield: 23.3 %

Procedure:
2-(2-aminoethoxy)ethanol (11 g, 104.62 mmol, 1.00 equiv) was dissolved in THF (300 mL) and cooled to 0° C. To the stirring solution was added dropwise tert-butyl 2-bromoacetate (20 g, 102.54 mmol, 1.00 equiv) and then triethylamine (15.5 g, 153.18 mmol, 1.50 equiv) dropwise The solution was then stirred for 16 h at room temperature. The solvent was removed and the residue then dissolved in DCM and washed twice with brine, then dried over anhydrous sodium sulfate and solvent removed. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) as eluent. This resulted in 5.25 g (16%) of the product as a yellow oil. MS (ES, m/z) 220 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([CH2:21][NH:22][CH3:23])=[C:10]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][NH2:25]>>[C:1]([O:5][C:6]([C:8]1[C:9]([CH2:21][NH:22][CH3:23])=[C:10]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:25][CH3:24])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1c(C(=O)OC(C)(C)C)cccc1C1CCC(=O)CC1
Reactant: CN
Product: CNCc1c(C(=O)OC(C)(C)C)cccc1[C@H]1CC[C@H](NC)CC1

Procedure:
from 4-(3-tert.butoxycarbonyl-methylaminomethylphenyl)-cyclohexanone and methylamine. Colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH3:22])[NH:6][C:5]2=[O:23].[N:24]([O-])=O.[Na+]>Cl.O>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:7]1[NH:6][C:5](=[O:23])[C:4]2[CH:3]=[C:2]3[NH:1][N:24]=[N:12][C:11]3=[CH:10][C:9]=2[N:8]=1)[CH2:21][CH3:22]
Reactant: CCCOc1ccccc1-c1nc2cc(N)c(N)cc2c(=O)[nH]1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCOc1ccccc1-c1nc2cc3nn[nH]c3cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
6,7-diamino-2-(2-propoxyphenyl)-4(3H)-quinazolinone (0.15 g, 0.51 mmol) was suspended in 1N HCl (5 mL) and cooled in an ice-methanol bath. A solution of sodium nitrite (0.035 g) in water (1 mL) was added in one portion. The reaction was stirred in an ice bath for 30 minutes, then warmed to room temperature for 90 minutes. The precipitated solid was collected by filtration, washed with water, and dried to afford the title compound as a brown solid (0.42 mmol, 83%): mp dec>260° C.; LRMS [MH+] 308.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:10]/[S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])[CH:5]=[CH:4][N:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:10][S:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: C/C(=N\S(=O)C(C)(C)C)c1ccnc(Br)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](NS(=O)C(C)(C)C)c1ccnc(Br)c1
Reaction time: 2.5 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(2-bromo-pyridin-4-yl)-eth-(E)-ylidene]-amide (9.3 g, 31 mmol) in THF (280 mL) was added a 1 M solution of L-Selectride in THF (61.3 ml, 61.3 mmol) dropwise. After 2.5 hours, the chilled mixture was quenched with saturated aqueous NH4Cl (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×400 mL). The combined organic layers were washed with brine, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 50-90% EtOAc in hexanes to afford 2-methyl-propane-2-sulfinic acid [(S)-1-(2-bromo-pyridin-4-yl)-ethyl]-amide as a light yellow oil which contained 5% of the opposite diastereomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[N:18][C:17]=2[CH:34]=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([CH:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[N:18][C:17]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (120 mg, 0.26 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (0.5 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (150 mg). 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (70 mg, 0.15 mmol) was dissolved in IPA (10 ml), added DiPEA (0.25 ml, 1.2 mmol) and stirred at rt for 30 mins 2-Chloro-5-ethyl piperidine was added to the above reaction mixture and heated the reaction mixture to 90° C. for overnight. After completion of the reaction, work-up (EtOAc/H2O) followed by purification on combiflash using the gradient mixture of ethyl acetate and petether (1:1) as eluent afforded the titled compound (20 mg) as an off-white solid. M.P.: 188-192° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.03 (s, 1H), 8.20 (s, 2H), 7.88 (s, 1H), 7.68 (t, J 8.2, 1H), 7.65-7.58 (m, 3H), 7.54-7.49 ((m, 1H), 4.80-4.70 (m, 2H), 3.33-3.23 (m, 1H), 3.22 (t, J 14, 2H), 2.48 (q, J 7.6, 2H), 2.30-2.22 (m, 2H), 2.07-1.95 (m, 2H), 1.20 (t, J 7.6, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:19][C:20]1[S:21][CH:22]=[C:23]([CH3:28])[C:24]=1[C:25]([NH2:27])=[O:26]>C(N(CC)CC)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:19][C:20]3[S:21][CH:22]=[C:23]([CH3:28])[C:24]=3[C:25]([NH2:27])=[O:26])=[O:18])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1csc(N)c1C(N)=O
Reactant: O=C(O)Cc1ccc(OCCn2ccnc2)cc1
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)Cc2ccc(OCCn3ccnc3)cc2)c1C(N)=O

Procedure:
This compound was prepared from 2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetic acid and 2-amino-4-methylthiophene-3-carboxamide using protocol B except that triethylamine was also added. The crude product was purified via silica gel column chromatography. Method[1], MS(ESI) 385.1, Retention time=1.254 min.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@H:27]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([CH3:39])[CH2:28]1)(C(C)(C)C)(C)C.CCCCCCC>C1COCC1>[OH:26][CH:27]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([CH3:39])[CH2:28]1
Reactant: C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF, 28 mL) was added to a solution of (2R,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-1-carboxylate (3.87 g, 12.27 mmol) in THF (10 mL). The reaction mixture was stirred at ambient temperature for about 3 hours. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel flash chromatography eluting with 40% EtOAc:heptane yielded (2R)-tert-butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate (2.3 g, 11.4 mmol) as a colorless oil. 1H NMR (d6 DMSO, 400 MHz) 4.41 (1H, br), 4.00 (1H, br), 3.48 (2H, br), 2.3-2.0 (2H, m), 1.72 (1H, m), 1.46 (9H, s) and 1.22 (3H, d).
Reaction SMILES: ClC1C(C(OO)=[O:9])=CC=CC=1.[CH2:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[CH2:14]>C(Cl)Cl.CCOCC>[CH2:12]([CH:13]1[O:9][CH2:14]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCc1ccccc1
Reactant: O=C(OO)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(CC2CO2)cc1
Reaction time: 5 h
Yield: 74.5 %

Procedure:
A solution of m chloroperbenzoic acid (mCPBA; 17 g, 0.1 mol) in 120 mL of methylene chloride was added (at ambient temperature) dropwise to a solution of allyl benzene (10 g, 85 mmol) in 200 mL of methylene chloride. After the reaction mixture was stirred for 5 h with a mechanical stirrer, 5 additional qrams of m CPBA were added and the reaction mixture stirred for another 2 h. The reaction mixture was then diluted with 200 mL of ether, washed with 2×100 mL of aqueous sodium bisulfite solution, 1×100 mL of aqueous sodium bicarbonate solution and 1×100 mL of brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by bulb-to-bulb distillation (60° C., 0.1 mm) to give 8.5 g (77% yield) of 1-benzyl ethylene oxide as a clear colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10]Cl)=[O:7])=[CH:4][C:3]=1[Br:20].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O-:39])=[O:38].[Na+]>>[NH2:1][C:2]1[C:13]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][O:39][C:37](=[O:38])[CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][C:23]2[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:28])=[O:7])=[CH:4][C:3]=1[Br:20]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: Nc1c(Br)cc(C(=O)OCCCl)cc1CN1CCCC1
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CN1CCCC1

Procedure:
This compound was prepared from 2-(4-amino-3-bromo-5-pyrrolidinomethyl-benzoyloxy)-ethylchloride and sodium 2-[(2,6-dichlorophenyl)-amino]phenylacetate analogous to Example 8.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[O:21]=[C:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=2)[NH:23]1>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=4)[NH:23][C:22]3=[O:21])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(NC=O)cc43)c(C)c2C1=O
Yield: 80.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (55 mg, 80.6%) as an orange solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([NH:17][C:18](=[O:20])[CH3:19])[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-]>C1COCC1.O.[Zn]>[NH2:14][C:12]1[CH:11]=[C:10]([NH:17][C:18](=[O:20])[CH3:19])[CH:9]=[C:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:13]=1
Reactant: CC(=O)Nc1cc(-c2ncccc2F)cc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(N)cc(-c2ncccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of N-(3-(3-fluoropyridin-2-yl)-5-nitrophenyl)acetamide (5 g, 18.18 mmol) in THF (50 ml), Zn (11.8 g, 181.18 mmol) was added followed by slow addition of solution of NH4Cl (9.7 g, 181.18 mmol) in 20 ml water. The mixture was stirred at RT for 1 h. The mixture was filtered through celite and bed washed with ethyl acetate. The mixture was diluted with ethyl acetate and washed with water and brine solution, dried over sodium sulphate and distilled to give the product in 90% yield (4.2 g). LC-MS (ESI): Calculated mass: 245; Observed mass: 246.1 [M+H]+ (rt: 0.21 min).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:17][C:18]([NH2:20])=[S:19]>>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:17]=1
Reactant: NC(N)=S
Reactant: CCCCON=C(C(=O)CBr)C(=O)OCC
Product: CCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 40.5 %

Procedure:
93 g (0.32 mole) of ethyl 4-bromo-2-n-butoxyimino-acetoacetate and 24 g (0.32 mole) of thiourea undergo a condensation reaction analogously to Example 4, stage 3, to give 35.2 g of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetate of melting point 129.5°-131°.