Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#N.[C:7](O)(=O)C.C([O-])(=O)C.[NH4+].O.[C:17]1(C)[CH:22]=CC=[CH:19][CH:18]=1>>[C:4]([C:3]1[CH:1]=[CH:19][CH:18]=[CH:17][CH:22]=1)(=[O:6])[CH3:7]
Reactant: Cc1ccccc1
Reactant: N#CCC(=O)O
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)c1ccccc1

Procedure:
A mixture of 6-fluoro-2-methyl-4-(4'-methylsulfinylphenyl indanone) (30.2 gm.), cyanoacetic acid (10.5 gm.), acetic acid (6.6 g.) and ammonium acetate (1.7 gm.) in dry toluene (20 ml.) is refluxed with stirring for 24 hours while the water is removed continuously in a Dean-Stark separator. The toluene is concentrated, the residue dissolved in 200 ml. of 4 N potassium hydroxide solution (100 ml. ethanol, 100 ml. water) and refluxed for 12 hours. The aqueous solution is evaporated to remove the ethanol, filtered and then acidified with concentrated HCl solution. The preceipitated 6-fluoro-2- 4-(p-methylsulfinylphenyl)-indenyl-1-acetic acid is collected and dried at 70° C in the vacuum oven.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C.O=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.[C-:26]#[N:27].[Na+]>O.C(OCC)C>[CH2:3]([N:2]([CH3:1])[C:15]1([C:26]#[N:27])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [C-]#N
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)C1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Methylbenzylamine (1.42 ml, 11 mmol) and acetic acid (0.63 ml, 11 mmol) in 2 ml of water were added to a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.5 g, 8.77 mmol) in diethylether (1.5 ml). After five minutes, a solution of sodium cyanide (451 mg, 9.21 mmol) in 1 ml of water was added, and the mixture was heated at 60° C. for 15 hours. After cooling the reaction mixture was extracted with ethyl acetate (×2), washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residues were purified by column chromatography on silica eluting with ethyl acetate in petroleum ether (5/95) to give tert-butyl 3-[benzyl(methyl)amino]-3-cyanoazetidine-1-carboxylate as a pale yellow oil, (2.52 g, 96%); 1H NMR Spectrum: (CDCl3) 1.46 (s, 9H), 2.18 (s, 3H), 3.42 (s, 2H), 4.00 (d, 2H), 4.17 (d, 2H), 7.26-7.35 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]([OH:13])=[S:12])[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.P(Cl)(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:13][C:11]([C:9]1[CH:8]=[CH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[C:3]=2[CH:10]=1)=[S:12])[CH3:20]
Reactant: Cc1csc2ccc(C(O)=S)cc12
Reactant: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=S)c1ccc2scc(C)c2c1

Procedure:
A mixture of 3-methylthiobenzo[b]thiophene-5-carboxylic acid (5.62 g) and phosphorous oxychloride (2 ml) in ethanol (200 ml) was heated under reflux for 18 hours and then evaporated. The residue was dissolved in ether and the solution was washed with sodium bicarbonate solution, water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised from ethanol to give 3-methylthiobenzo[b]thiophene-5-carboxylic acid ethyl ester (5.84g), m.p. 67°-69°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].[C:16](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>CCOC(C)=O>[CH3:16][O:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CN1Cc2c(O)ccc([N+](=O)[O-])c2C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 4-Hydroxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 205C, 50.0 mg, 0.240 mmol), potassium carbonate (49.8 mg, 0.360 mmol) in DMF (2 mL, 20 mmol) was treated with methyl iodide (22.4 μL, 0.360 mmol) and allowed to stir at room temperature overnight. The reaction was poured into EtOAc and washed with water and brine and the crude material was purified using an ISCO Combiflash unit (MeOH in DCM: 0-1%) to obtain the title product as a solid. (27 mg, 50% yield). 1H NMR (400 MHz, CD3OD) δ=3.17 (s, 3 H), 4.02 (s, 3 H), 4.44 (s, 2 H), 7.27 (d, J=8.8 Hz, 1 H), 7.94 (d, J=8.8 Hz, 1 H). MS (ES+): m/z 223.19 (100) [MH+]; HPLC: tR=0.76 min (UPLC, analytical).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1O.COC1C=C(SC)C(F)=CC=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:43][CH2:44][CH2:45][OH:46].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([O:46][CH2:45][CH2:44][Cl:43])=[CH:5][C:6]=1[F:10]
Reactant: OCCCl
Reactant: COc1cc(F)c(F)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COc1cc(SC)c(F)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1OCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 2-methoxy-4,5-difluoro-phenol (Intermediate 55) and 2-methoxy-4-methylthio-5-fluoro-phenol (Intermediate 56) (0.66 g), triphenylphosphine (2.16 g), 2-chloroethanol (0.55 ml) in tetrahydrofuran (15 ml) was slowly added diethyl azodicarboxylate (1.3 ml). The reaction was stirred at room temperature for 2 hours. Tetrahydrofuran was removed under vacuum. Chromatography (10% ethyl acetate-hexanes) afforded 0.31 g of 1,2-difluoro-4-(2-chloroethoxy)-5-methoxy-benzene (Intermediate 57) as a white solid: mp 51-52° C.; MS EI m/e 222 (M+), and 0.1 g of 1-fluoro-2-methylthio-4-(2-chloroethoxy)-5-methoxy-benzene (Intermediate 62) as a white solid: mp 58-60° C.; MS EI m/e 250 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[N:4]1([CH2:3][CH2:2][NH:1][S:11]([CH3:10])(=[O:13])=[O:12])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-aminoethyl)morpholine (0.5 g) in dichloromethane (5 ml) at 0° C. was added methane sulphonyl chloride (0.33 ml) and triethylamine (0.59 ml) The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diliuted with dichloromethane, the combined organics washed with brine, dried (MgSO4) and the solvents removed in vacuo to give a crude residue which was purified by flash chromatography to yield N-(2-morpholin-4-yl-ethyl)-methanesulfonamide (596 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8]2([CH3:16])[CH3:15].[CH3:17]I>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH3:17])[C:8]2([CH3:16])[CH3:15]
Reactant: COc1ccc2c(c1)C(C)(C)NC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(C)(C)N(C)C2=O
Reaction time: 0.5 h

Procedure:
With cooling with ice, 96 mg of 60% sodium hydride was added to 8.0 mL of a DMF solution of 382 mg of 5-methoxy-3,3-dimethylisoindolin-1-one, and stirred for 30 minutes with cooling with ice. 0.19 mL of methyl iodide was added to it, and stirred at room temperature for 7 hours. The solvent was evaporated away under reduced pressure, water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water and aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 381 mg of the entitled compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([N:30](S(C)(=O)=O)[S:31]([CH3:34])(=[O:33])=[O:32])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1N(S(C)(=O)=O)S(C)(=O)=O
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1NS(C)(=O)=O

Procedure:
The title compounds were prepared in one pot as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and N-(6-chloro-2-methylpyridin-3-yl)-N(methylsulfonyl)methanesulfonamide (143 mg, 0.48 mmol) as starting materials. Mono and bis methylsulfonyl compounds were separated by column chromatography.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[O:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:11][O:10][C:9]1[CH:8]=[C:7]([CH:15]=[CH:14][C:12]=1[O:13][CH2:3][C:2]#[CH:1])[CH:6]=[O:5]
Reactant: C#CCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccc(C=O)cc1OC
Yield: 96.8 %

Procedure:
Propargyl bromide (293 mL, 80% w/v, 1.97 mol) was added to a suspension of vanillin (250 g, 1.64 mol) and potassium carbonate (681 g, 4.93 mol) in MeCN (2.0 L). The suspension was heated to reflux for 6 h and the solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted with EtOAc, washed with water, brine and dried. The solvent was removed under reduced pressure to give 3-methoxy-4-propargyloxybenzaldehyde (302 g, 97%) as yellow crystalline solid; mp 95° C.; δH (400 MHz, CDCl3) 2.56 (t, J=2.5 Hz, 1H, C≡CH), 3.95 (s, 3H, OCH3), 4.86 (d, J=2.5 Hz, 2H, OCH2); 7.14 (d, J5,6=6.8 Hz, 1H, H5), 7.44 (d, J2,6=1.4 Hz, 1H, H2), 7.47 (dd, J5,6=6.8, J2,6=1.4 Hz, 1H, H6), 9.87 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.0, 56.6, 77.2, 77.4, 109.4, 112.5, 126.3, 130.9, 150.0, 152.1, 190.9; HRMS (ESI) Calculated for C11H10O3 [M+H]+, 191.0703 found 191.0706; νmax 1006, 1130, 1259, 1586, 1677, 2119, 2845, 2932, 3266 cm−1.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH3:6][O:7][C:8](=[O:12])[CH2:9][C:10]#[N:11].[OH-].[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8](=[O:12])[C:9]([C:10]#[N:11])=[CH:1][CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CC#N
Reactant: CC(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=CC(C)C
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of isobutyraldehyde (30.0 g, 416 mmol), methyl-cyano-acetate (20.6 g, 208 mmol), ammonium hydroxide (3.2 g, 41.6 mmol) and acetic acid (5.0 g, 83.2 mmol) in 500 mL of toluene is warmed to reflux under a Dean-Stark trap for 12 hours. The mixture is cooled to room temperature and extracted with saturated NaHSO3 (3×100 mL), saturated NaHCO3 (3×100 mL), and 100 mL of brine. The organic layer is dried over Na2SO4, and the solvent is evaporated. The remaining oil is distilled under high vacuum (0.5 mm Hg, B.P.=115-120° C.) to give 28.8 g of 2-cyano-4-methyl-2-pentenoic acid methyl ester 61 as an oil (90% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[N:18][OH:19])=[CH:12][CH:11]=2)[CH:3]=1.[C:21]([C:23]1[C:24]([NH2:30])=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=1)#[CH:22].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]4[C:24]([NH2:30])=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=4)[O:19][N:18]=3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(COc2cc(F)ccn2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(COc4cc(F)ccn4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(4-fluoro-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Manufacturing Example 59-1-5 and 3-ethynyl-pyridin-2,6-diamine (57.7 mg, 0.433 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (237 μL, 1.7 mmol). This mixture was stirred for 4 hours at room temperature. This mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (113 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].N1C=CC=CC=1.[Br:29][CH2:30][C:31](Br)=[O:32]>O1CCOCC1>[Br:29][CH2:30][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[O:32]
Reactant: CCOC(=O)Cc1ccc(N)c(C(=O)c2ccccc2Cl)c1
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(NC(=O)CBr)c(C(=O)c2ccccc2Cl)c1
Reaction time: 24 h

Procedure:
20.9 g (0.66 mol) of ethyl 4-amino-3-(2-chlorobenzoyl)-phenylacetate are dissolved in 170 ml of anhydrous dioxane. First 5.2 ml of absolute pyridine are added and then 13.3 g (0.066 mol) of bromoacetylbromide are added dropwise at room temperature and the mixture is stirred for 24 hours. The suspension is filtered through Kieselgur. The Kieselgur is washed with ether, and the combined filtrates are concentrated in vacuo. The resulting residue is induced to crystallise by addition of ethanol.
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18]C2NC3C=CC=CC=3N=2)[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3].[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[S:41])=[C:35]([N+:42]([O-:44])=[O:43])[CH:34]=1.[OH-].[Na+]>C(Cl)Cl>[CH2:28]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][C:35]=2[N+:42]([O-:44])=[O:43])=[S:41])[CH2:13][CH2:14]1)[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CN(CCCN1CCN(CCCNc2nc3ccccc3[nH]2)CC1)CC(C)C
Reactant: Cc1ccc(N=C=S)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(NC(=S)NCCCN2CCN(CCCN(CC(C)C)CC(C)C)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of N4-(3-{4-[3-(diisobutylamino)propyl]piperizano}propyl)-amine (intermediate of example 16) (103 mg, 0.33 mmol) and 4-methyl-2-nitrophenyl isothiocyanate (128 mg, 0.66 mmol) in CH2Cl2 (10 mL) has been stirred for 4 h at room temperature. NaOH 1M is added until alkaline pH. Organic layer was washed with NaOH 0.5M and dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH: 90/10).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 95.7 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acrylic acid ethyl ester (0.50 g, 1.0 mmol) in ethyl acetate(15 mL) in a Parr bottle was added platinum dioxide on carbon (0.25 g, 5% on carbon). The mixture was shaken under a positive pressure of hydrogen at 30 psi for 15 minutes at ambient temperature. The mixture was filtered through a pad of celite and concentrated to give the title compound (0.47 g).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH3:15][O:16][C:17](=[O:50])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C:28](=[O:29])[CH2:27][C@@H:26]([OH:30])[C@@H:25]1[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH:36]([O:40]CC1C=CC(OC)=CC=1)[CH2:35][CH2:34]2.ClC(Cl)C.C([O-])(O)=O.[Na+]>ClCCl.O>[CH3:15][O:16][C:17](=[O:50])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C:28](=[O:29])[CH2:27][C@@H:26]([OH:30])[C@@H:25]1[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[CH2:35][CH2:34]2
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2OCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2=O
Reaction time: 1 h
Yield: 64.3 %

Procedure:
DDQ (10 mg, 0.041 mmol) was added to a mixture of 15-5 (11 mg, 0.021 mmol) in dichloromethane (0.5 mL)/water (25 μL). After 1 h, dichloroethane (0.5 mL) was added and the reaction was stirred overnight. Saturated NaHCO3 solution was added and the resulting mixture was extracted with dichloromethane (3×20 mL). The combined dichloromethane solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (60% ethyl acetate/hexanes) gave 15-8 (5 mg, 59%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:21]([O-])=O)[CH:18]=3)[CH2:13]2)[C:11](=[O:24])[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pd]>[NH2:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C:12]1([C:11](=[O:24])[NH:10][C:9](=[O:25])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:20]2
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)CC1(C2)C(=O)NC(=O)N1Cc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of (±)-3-benzyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione from Step C (80 mg, 0.24 mmol) in EtOAc (1.5 mL) and MeOH (1.5 mL) was added 10% Pd/C (5 mg) and the reaction mixture was stirred vigorously under hydrogen (ca. 1 atm). After 18 h, the catalyst was filtered off and the filtrate was concentrated to yield the title compound. MS: m/z=308 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:31][CH2:32][C:33]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)=[O:34]
Reactant: O=C(Cl)CCl
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (500 mg, 1.20 mmol) in tetrahydrofuran (10 mL) were added chloroacetyl chloride (168 μL, 1.45 mmol) and triethylamine (253 μL, 1.81 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol to give the title compound (418 mg, 71%) as a pale-yellow powder.
Reaction SMILES: [F:1][CH:2]([F:8])[CH:3]([OH:7])[C:4]([NH2:6])=[O:5].[C:9]([Si:13]([CH3:16])([CH3:15])Cl)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Si:13]([O:7][CH:3]([CH:2]([F:8])[F:1])[C:4]([NH2:6])=[O:5])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:16])[CH3:15]
Reactant: NC(=O)C(O)C(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC(C(N)=O)C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,3-difluoro-2-hydroxypropanamide (700 mg, 5.6 mmol) in DMF (5.6 mL) was added tert-butyldimethylchlorosilane (1.10 g, 7.28 mmol) and triethylamine (1.17 mL, 8.40 mmol). The mixture was stirred at room temperature for 3 h, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to provide Intermediate 10 that was used without further purification. MS: m/z=240.3 (M+H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=O)[N:13]=[CH:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.ClC1N=C2C(NC=N2)=C[N:36]=1.N>C1COCC1>[NH2:36][C:14]1[N:13]=[CH:12][N:11]([CH2:10][C:9]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[C:19]2[C:15]=1[N:16]=[C:17]([CH:20]([CH3:22])[CH3:21])[N:18]=2
Reactant: Clc1ncc2[nH]cnc2n1
Reactant: COc1ccc(Cn2cnc(=O)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(N)c3nc(C(C)C)nc2-3)cc1OC1CCCC1

Procedure:
3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-hypoxanthine (5.74 g, 15 mmole) and phosphorus oxychloride (60 ml) were heated to 65° C. for 30 minutes. The reaction mixture was evaporated to dryness in vacuo and the residue evaporated twice with toluene. The crude chloropurine (15 mmole) was dissolved in THF (80ml ) and 32% aqueous ammonia solution (36.2 ml) and heated together with liquid ammonia (50 g) in a 450 ml pressure reactor to 60° C. (340 psi) for 4 hours. The solvents were evaporated in vacuo and the residue suspended in a mixture of diethyl ether and 1 M NaOH solution. The solid was collected and crystallized from ethyl acetate to give the title compound, 3.92 g (68.5 %) mp 190-193° C.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH:10]=[O:11])[CH2:5][CH2:4]1.OS([O-])=O.[Na+].[C-:17]#[N:18].[K+]>O>[OH:11][CH:10]([CH2:9][CH:6]1[CH2:7][CH2:8][N:3]([O:2][CH3:1])[CH2:4][CH2:5]1)[C:17]#[N:18]
Reactant: CON1CCC(CC=O)CC1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CON1CCC(CC(O)C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (1-methoxy-piperidin-4-yl)-acetaldehyde (10 g, 63 mmol) and NaHSO3 (8.6 g, 83 mmol) in 210 ml of water was stirred at room temperature for 30 min. Then, a solution of KCN (6.2 g, 95 mmol) in 50 ml of water was added to the mixture. After the addition, the mixture was stirred at room temperature for another 10 h. The resulting mixture was extracted with CH2Cl2 five times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel. Yield: 2.1 g of 2-hydroxy-3-(1-methoxy-piperidin-4-yl)-propionitrile as a solid.