Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.Cl.[C:22]12([NH2:28])[CH2:27][CH:25]([CH2:26]1)[CH2:24][CH2:23]2>O1CCOCC1.[Cl-].[Na+].O>[C:22]12([NH:28][C:2]3[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=3)[CH2:27][CH:25]([CH2:26]1)[CH2:24][CH2:23]2
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: NC12CCC(C1)C2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1ncc(C#N)c(NC23CCC(C2)C3)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (427 mg, 2.3 mmol) in 1,4-dioxane (10 mL) was added DIEA (890 mg, 6.9 mmol) and bicyclo[2.1.1]hexan-1-amine hydrochloride (320 mg, 2.4 mmol). The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was poured into a saturated brine solution and then extracted with ethyl acetate (20 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give the desired product (502 mg, 2.0 mmol, 89% yield). MS (ESI) m/z=247.2 [M+1]+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20](OC)[O:21]C)[N:16]([C:25]([NH:27][C:28]1[CH:33]=[C:32]([N:34]3[CH2:50][CH2:49][C:37]4([CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)[CH2:36][CH2:35]3)[C:31]([C:51]#[N:52])=[CH:30][N:29]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:51]([C:31]1[C:32]([N:34]2[CH2:35][CH2:36][C:37]3([CH2:41][NH:40][CH2:39][CH2:38]3)[CH2:49][CH2:50]2)=[CH:33][C:28]([NH:27][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:21])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:26])=[N:29][CH:30]=1)#[N:52]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(N2CCC3(CCN(C(=O)OC(C)(C)C)C3)CC2)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)cc1N1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 8-(2-(6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-1-carboxamido)-5-cyanopyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (intermediate 37D, 70 mg, 0.095 mmol) in THF (0.5 ml) and H2O (0.5 ml) was added conc. HCl (0.1 ml, 1.2 mmol). The reaction mixture was stirred at room temperature for 4 h, then conc. HCl (0.1 ml, 1.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (4×) and EtOAc (4×). The combined organic phases were then dried over Na2SO4, filtered and evaporated. The crude material was triturated with EtOAc and dried under high vacuum to give the title compound as an off-white powder. (UPLC-MS 3) tR 0.64 min; ESI-MS 476.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C=O)C>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([I:3])[CH:5]=2)[C:14]=1[C:15]#[N:16]
Reactant: OCc1cccc(I)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 3-iodobenzyl alcohol (1.85 g; 7.9 mmol) in anhydrous DMF (5 mL) over 30 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.0 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 2 hours. The reaction mixture is poured into ice water with vigorous stirring and refrigerated overnight. The resulting solid is filtered, washed with water, and dried under vacuum at 30° C. overnight to give 1.86 grams of 2-fluoro-6-(3-iodobenzyloxy)-benzonitrile.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)C2CCC(O)CC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2CCC(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled solution of 4-methoxybenzyl 4-hydroxycyclohexanoate (7.5 g, 28 mmole), 4-dimethylaminopyridine (0.73 g, 6 mmole) and N-benzyloxycarbonyl-L-valine (7.54 g, 30 mmole) in dichloromethane (90 ml) was added dicyclohexyl-carbodiimide (6.8 g, 33 mmole) and the mixture was stirred for 2 days at room temperature. The mixture was cooled and the urethane was filtered. The solution was evaporated and 250 ml ethyl acetate was added. The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 13 g=93%
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH2:13])=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].BrBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl.O>[N+:1]([C:4]1[C:5]2[S:12][C:11]([NH2:13])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=S)Nc1cccc([N+](=O)[O-])c1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Nc1nc2cccc([N+](=O)[O-])c2s1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To 0.60 g (3.0 mmol) of (3-nitrophenyl)thiourea in 25 mL of carbon tetrachloride was added 0.17 mL (3.4 mmol) of bromine in 10 mL of carbon tetrachloride dropwise over 1 h. The mixture was heated to reflux for 18 h, cooled to room temperature and the precipitate that formed was collected by filtration. The precipitate was slurried in glacial acetic acid and the solids were collected by filtration. The solids thus obtained were slurried in water and saturated potassium carbonate was added until the pH was about 9. The free base was collected by filtration to give 0.30 g (51%) of the title compound as a light orange solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:3](=O)[C:2]1=NN.C1N2CCN(CC2)C1.C([OH:27])CCCCC>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][C:2]1=[O:27]
Reactant: CCCCCCO
Reactant: NN=C1Nc2ccccc2C1=O
Agent: C1CN2CCN1CC2
Product: O=C1Cc2ccccc2N1
Temperature: 130 °C
Yield: 66.5 %

Procedure:
14.8 g of isatin (99 mmol, 98.2% purity) were initially charged into a 250 ml three-neck flask and 150 ml of 2-ethylhexanol were added. 6.0 g of hydrazine hydrate (117 mmol; 98% purity) were added with stirring. The reaction mixture was heated to 90° C. for 15 min to form the isatin hydrazone (yellow suspension). The water of reaction was azeotropically removed at 90° C./100 mbar using 1-hexanol. 2.4 g of DABCO (21 mmol, 98%) were then added and the suspension heated to 130° C. for 2.5 h. After the end of the reaction (GC analysis: hydrazone 0.3 area %), 100 ml of 1-hexanol were distilled off (80° C./50 mbar). The remaining solution was cooled to 5° C., the precipitated solid filtered off and dried in a vacuum drying cupboard at 70° C. Altogether, 8.0 g of dry 2-oxindole product (light brown) were obtained which corresponded to an overall yield of 66.5%. Purity: 99.9 area %.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45]C(=O)C)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[OH:45])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.7 %

Procedure:
3-Aminopyridine (0.151 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.065 g, 0.159 mmol, 30%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1[CH:29]=[CH:30][C:31]2N(O)N=[N:34][C:32]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.C(N)CCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([NH:34][CH2:32][CH2:31][CH2:30][CH3:29])=[O:26])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid (10 mg, 0.25 mmol) in THF (4 mL) is added HOBt (68 mg, 0.5 mmol). After 10 min EDCl (96 mg, 0.5 mmol) and triethylamine (0.104 mL, 0.75 mmol) are added and the solution is stirred for 30 min then a solution of n-butylamine in 2 mL THF is added and the mixture is stirred at RT for 6 h. The solvent is removed under reduced pressure to afford the title compound: (M−1)−=442.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:4]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([Cl:9])[S:6][C:7]=1[Cl:8]>>[Br:2][C:3]1[C:4]([S:10]([NH2:1])(=[O:12])=[O:11])=[C:5]([Cl:9])[S:6][C:7]=1[Cl:8]
Reactant: N
Reactant: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Br
Product: NS(=O)(=O)c1c(Cl)sc(Cl)c1Br
Reaction time: 15 h

Procedure:
90 ml of an aqueous solution of NH3 (32%) is added at RT to a solution of 8.88 g of 4-bromo-2,5-dichloro-thiophene-3-sulfonylchloride in 120 ml of EtAc. The mixture obtained is stirred for ca. 15 h and two phases obtained are separated. The organic layer is washed with 1 N HCl and H2O, and dried. Solvent of the organic solution obtained is evaporated. 4-Bromo-2,5-dichloro-thiophene-3-sulfonamide in the form of a white powder is obtained. m.p. 113-117° C., 13C-NMR: δ=108.287; 125.342; 130.404; 135.716.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:7]1(=[O:23])=[O:22].[CH3:24][NH:25][CH3:26].Cl>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:25]([CH3:26])[CH3:24])[S:7]1(=[O:23])=[O:22]
Reactant: CNC
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccccc1F
Agent: Cl
Product: CN(C)C/C=C/CN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.13 g, 0.33 mmol) was treated with dimethyl amine to give (2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbut-2-en-1-amine (90 mg) after treatment with HCl.
Reaction SMILES: ClC1C(CSCCN)=[N:4]C=CC=1.[S:13]([OH:17])([OH:16])(=[O:15])=[O:14].CS[C:20](=[NH:22])[NH2:21]>O>[S:13]([OH:17])([OH:16])(=[O:15])=[O:14].[NH2:21][C:20]([NH2:22])=[NH:4]
Reactant: NCCSCc1ncccc1Cl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)N

Procedure:
A solution of 3-chloro-2-((2-aminoethyl)thiomethyl)pyridine (22.4 g) and S-methylisothiourea sulphate (15.1 ) in water (100 ml) was heated under reflux for 3 hours. Concentration, acidification with sulphuric acid and dilution with ethanol afforded 2-[3-chloro-2-pyridyl)methylthio)ethyl]guanidine sulphate.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:13][C:14](=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[O:24][CH3:25])=[CH:7][C:6]=1[CH3:27].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CC[N:37](CC)CC.CC1OC(=O)C2C(C=1C1C=CC=CC=1OCCN1CCN(C)CC1)=C(C)C(OC)=CC=2OC.N>CS(C)=O.O>[CH3:11][C:10]1[CH:9]=[C:8]([C:12]2[NH:37][C:14](=[O:13])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[O:24][CH3:25])[CH:7]=[C:6]([CH3:27])[C:5]=1[O:4][CH2:3][CH2:2][N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]1
Reactant: CN1CCNCC1
Reactant: COc1cc(OC)c2c(=O)oc(-c3cc(C)c(OCCCl)c(C)c3)cc2c1
Reactant: CCN(CC)CC
Agent: COc1cc(OC)c2c(=O)oc(C)c(-c3ccccc3OCCN3CCN(C)CC3)c2c1C
Agent: N
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCN(C)CC4)c(C)c3)cc2c1
Temperature: 110 °C

Procedure:
The compound 3-[4-(2-chloro-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-isochromen-1-one (298 mg, 0.767 mmol) was dissolved in DMSO (5 mL) and N-methyl piperazine (388 mg, 3.83 mmol) and Et3N (392 mg, 3.83 mmol) were added. The reaction mixture was heated at 110° C. for 16 h before being cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The solvent was evaporated in vacuo to leave a residue which was purified by column chromatography. The yield was 60 mg (17%). The compound 3-[3,5-dimethyl-4-(2-(4-methyl piperazin-1-yl-ethoxy)-phenyl]-6,8-dimethoxy-isochromen-1-one (60 mg, 0.13 mmol) and NH3 (2.0 M solution in ethanol, 20 mL) were mixed in a steel bomb and heated at 130° C. for 16 h. The solvent was removed and the crude compound was purified by column chromatography. The compound was then converted to the hydrochloride salt of 3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (40 mg, 62%), an off-white solid. Selected data: MS (ES) m/z: 452.1; MP 195-198° C. (HCl salt).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[N:6]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:13][O:12][C:7]1[N:6]=[C:5]2[N:4]([CH3:14])[C:3]([CH2:2][O:1][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:11][C:10]2=[CH:9][CH:8]=1
Reactant: COc1ccc2nc(CO)n(C)c2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.25 g of 2-hydroxymethyl-5-methoxy-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 69), 0.66 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.35 ml of tributylphosphine, 0.36 g of 1,1'-(azodicarbonyl)dipiperidine and 15 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.70 g of the title compound, melting at 80-85° C. (softening).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1.O>O1CCCC1.C(OCC)(=O)C>[CH3:9][C:8](=[CH:24][C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: O=Cc1cccnc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1cccnc1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Sixty percent sodium hydride (in oil) (224 mg, 5.6 mmol) was suspended in tetrahydrofuran (5 mL). To this, triethyl 2-phosphonopropionate (1.2 mL, 5.6 mmol) was added under a nitrogen atmosphere with cooling in an ice bath and the mixture was stirred at the same temperature for 30 minutes. To this, 3-pyridinecarboxaldehyde (300 mg, 2.8 mmol) was added and the mixture was stirred at the same temperature for 1.5 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 2/1) to give ethyl 2-methyl-3-(pyridin-3-yl)acrylate (480 mg, yield: 90%).
Reaction SMILES: CS(Cl)(=O)=O.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][OH:16])([O-:8])=[O:7].C(N([CH2:22][CH3:23])CC)C.[O:24]1[CH2:29][CH2:28]OCC1>>[CH3:15][C:10]1[CH:9]=[CH:22][C:23]([O:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N+:6]([O-:8])=[O:7])=[C:28]([CH:11]=1)[CH:29]=[O:24]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: C1COCCO1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Product: Cc1ccc(OCc2ccccc2[N+](=O)[O-])c(C=O)c1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
Methanesulphonyl chloride (5.4 ml) was added dropwise to a stirred solution of 2-nitrobenzenemethanol (10.0 g) and triethylamine (10.1 ml) in 1,4-dioxane (10 ml) at 15°-25° C. After 30 min the mixture was filtered, washed with 1,4-dioxane (50 ml) and the filtrate added to a stirred mixture of 5-methylsalicylaldehyde (9.1 g) and potassium carbonate (9.9 g) in N,N-dimethylacetamide (50 ml). The mixture was stirred at 20° C. for 24 h, water (160 ml) was added and, after a further 1 h, the mixture was filtered. The filtrate was washed with water:1,4-dioxane (1:1; 50 ml) and water (150 ml) and dried at 40° C. in vacuo to give the title compound as a cream coloured solid (15.7 g) m.p. 124° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[Br:31])[CH2:19][CH2:20][CH2:21]O)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.C1(P(=[CH:60][C:61]([O:63][CH3:64])=[O:62])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]([CH2:19][CH2:20]/[CH:21]=[CH:60]/[C:61]([O:63][CH3:64])=[O:62])[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[Br:31])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(CCCO)Cc1cc(F)ccc1Br
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/CCN(Cc1cc(F)ccc1Br)C(=O)OC(C)(C)C
Temperature: -65 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (1.8 eq) was added to a stirred solution of dimethylsulfoxide (3.8 eq) in methylene chloride (0.25 M) at −78° C. maintaining the temperature<−65° C. After 20 min, a solution of N-(tert-butoxycarbonyl)-N-((2-bromo-5-fluorophenyl)methyl)-N-(3-hydroxypropyl)amine (1 eq) was added and the resulting mixture stirred 30 minutes. Hunig's base (4 eq) was added and the reaction allowed to warm to RT. The mixture was then cooled to 15° C. and methyl (triphenylphosphoranylidene)acetate was added. The resulting mixture was stirred 12 h and purified by flash chromatography on silica gel (10-20% ethyl acetate/hexane) to give methyl (2E)-5-(N-(tert-butoxycarbonyl)-N-((2-bromo-5-fluorophenyl)methyl) amino)pent-2-enoate as a clear oil. EI-MS m/z 474, 476 (M−H+HOAc)−
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:27][CH2:28][CH3:29])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:28]([O:27][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:30])[CH3:29]
Reactant: CCOC(=O)C(=Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Yield: 97.6 %

Procedure:
Compound (c) (1.47 g; 3.38 mmole) was hydrogenated for 3 hours at atmospheric pressure in ethyl acetate (50 ml) using Pd/C (0.74 g, 5%) as a catalyst. The reaction mixture was filtered through celite, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 1.44 g (yield 98%) of the desired product.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]2[NH:19][C:18](=[O:20])[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1>[O:20]=[C:18]1[C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[NH:12][CH2:11][CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:19]1[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1N[C@H](c2ccccc2)CCNC12CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CN1C(=O)C2(CCCC2)NCC[C@H]1c1ccccc1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.147 g, 6.14 mmol) in THF (10 mL) was added (9S)-9-phenyl-6,10-diazaspiro[4.6]undecan-11-one (0.300 g, 1.23 mmol) at ambient temperature. The reaction was warmed to 60° C. for 2 h, then cooled to ambient temperature. Benzyl bromoacetate (0.309 g, 1.35 mmol) was added dropwise to the reaction. After 1 h, the mixture was quenched with a saturated aqueous ammonium chloride solution. The mixture was concentrated in vacuo then partitioned between H2O and CH2Cl2. The aqueous phase was then extracted several times with CH2Cl2. The combined organic extracts were washed with saturated brine, then dried over MgSO4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc:hexane-0:100 to 100:0, to yield the title compound. MS: m/z=393 (M+1).