Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([O:8][CH2:9][CH2:10][CH3:11])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:19]>N1C=CC=CC=1.O>[NH2:1][C:2]([O:8][CH2:9][CH2:10][CH3:11])=[C:3]([C:4]#[N:5])[C:6](=[S:19])[NH2:7]
Reactant: CCCOC(N)=C(C#N)C#N
Reactant: S
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCOC(N)=C(C#N)C(N)=S

Procedure:
A stirred mixture of 141 g of 3-amino-2-cyano-3-propoxypropenenitrile and 94.4 g of triethylamine in 250 ml of pyridine was heated at 80° for 4 hours while hydrogen sulfide gas was continually passed through the mixture. Thin-layer chromatography indicated reaction to be complete. The reaction mixture was diluted to 2 liters with water and the pale yellow precipitate was collected by filtration. The precipitate was recrystallized from ethanol to give 114 g of 3-amino-2-cyano-3-propoxypropenethioamide, m.p. 174°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[OH:26].[Cl-].[NH4+]>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: C#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2cc(Cl)ccc2Cl)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 54.3 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.21 g of 2,5-dichlorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.19 g of 4-(2,5-dichlorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (25)), m.p.: 87.7° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:39][CH2:40][C:41]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:42]=2[C:43]([O:45]CC)=[O:44])=[O:38])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:39][CH2:40][C:41]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:42]=2[C:43]([OH:45])=[O:44])=[O:38])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCN(CCCCNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCN1CCN(c2nc(C(=O)NCc3ccc(F)cc3C(=O)O)c(OCc3ccccc3)c3ncccc23)CC1
Reaction time: 24 h

Procedure:
Ethyl 2-((8-(benzyloxy)-5-(4-(4-(tert-butoxycarbonylamino)butyl)piperazin-1-yl)-1,6-naphthyridine-7-carboxamido)methyl)-5-fluorobenzoate (Example 4.3; 1.4 mmol) was dissolved in THF (4.5 ml) and water (4.5 ml). Solid LiOH hydrate (1.6 mmol) was added at room temperature. The reaction mixture was stirred for 24 h, after which 2N HCl was added until pH=6-7 was reached. The mixture was extracted twice with EtOAc and the combined organic fractions dried with magnesium sulfate. The crude material containing the title compound (0.27 gr) was used as such in the next step.
Reaction SMILES: [N:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][O:3][C:2]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Br[CH2:19][CH:20]([CH3:23])[CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:22][CH2:21][CH:20]([CH3:23])[CH2:19][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:2]2[O:3][CH2:4][C:5]3([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[N:1]=2)=[CH:16][CH:15]=1
Reactant: CC(CCl)CBr
Reactant: Oc1ccc(C2=NC3(CCCCC3)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CCl)COc1ccc(C2=NC3(CCCCC3)CO2)cc1
Yield: 100 %

Procedure:
To a solution of 4-(3-oxa-1-azaspiro[4.5]dec-1-en-2-yl)phenol ax8 (0.5 g, 2.16 mmol, 1 eq) in acetone (30 ml) is added 1-bromo-3-chloro-2-methylpropane (0.25 ml, 2.16 mmol, 1 eq) and potassium carbonate (0.6 g, 4.32 mmol, 2 eq). The mixture is stirred at reflux for 13 days. The mixture is concentrated, taken up in dichloromethane and washed twice with a saturated aqueous solution of ammonium chloride. The organic layer is dried over magnesium sulfate and the solvent is removed under reduced pressure to afford 0.7 g of 2-[4-(3-chloro-2-methylpropoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-ene ax64 as a colorless oil. This crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]C(Br)(Br)Br>>[Br:33][CH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2ccccc2nc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1nc2ccccc2cc1CBr
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A solution under argon of 2-chloro-3-quinolylmethanol (obtained according to 4.a, 15.5 g 80 mmol) and triphenylphosphine (32 g, 120 mmol) is treated with small portions of tetrabromomethane (40 g, 120 mmol) while keeping the temperature of the reaction medium below 30° C. After agitation under argon for 2 hours at ambient temperature, the reaction medium is concentrated under reduced pressure, and the residue is purified by column chromatography (SiO2, ethyl acetate/heptane: 1/1) in order to produce 13.5 g (66%) of a white solid, m.p. 125° C.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([CH2:16][CH2:17][C:18]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>COCCOC>[C:10]1([CH2:16][CH2:17][CH2:18][NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccccc1NC(=O)CCc1ccccc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: COC(=O)c1ccccc1NCCCc1ccccc1
Temperature: 0 °C

Procedure:
3.4 ml of boron trifluoride etherate are added to a solution of 5.6 g of methyl 2-(3-phenylpropanoylamino)benzoate in 35 ml of anhydrous 1,2-dimethoxyethane. After cooling to 0° C., 3.4 g of sodium borohydride are added in portions, while stirring and cooling, and then the mixture is stirred at 60° C. for 45 hours and, after cooling, is poured onto ice-water. Extraction with ethyl acetate, evaporation off of the solvent and column chromatography of the residue as described under (a) provides methyl 2-(3-phenylpropylamino)benzoate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:18](O)=[O:19]>>[CH2:11]([O:10][C:6]1[C:7]([CH3:9])=[N:8][C:3]([CH2:2][NH:1][CH:18]=[O:19])=[CH:4][CH:5]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=CO
Reactant: Cc1nc(CN)ccc1OCc1ccccc1
Product: Cc1nc(CNC=O)ccc1OCc1ccccc1

Procedure:
A solution of 6-aminomethyl-3-benzyloxy-2-methylpyridine (6.31 g) in 8.7 ml of formic acid is heated at 90° for 15 hours. The reaction mixture is cooled, made basic with ice-cold ammonium hydroxide solution and extracted with chloroform. (3×25 ml). The chloroform extract is dried over sodium sulfate and evaporated. Recrystallization from ether yields 3-benzyloxy-6-formylaminomethyl-2-methylpyridine, m.p. 67°-68°.
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:18]=1[Cl:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: NCc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2cccc(Cl)c2Cl)c(=O)c1=O
Yield: 89.2 %

Procedure:
Tetrahydrofuran (12 mL), 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5.0 mmol, Example 1), and 2,3-dichlorobenzylamine (0.88 g, 5.0 mmol) were stirred together at room temperature for 64 hours. After removal of solvent, trituation of the residue with diethyl ether and drying gave 1.46 g of a white solid. Four recrystallizations of this crude product from acetonitrile provided 0.927 g of the title compound as a white solid: mp 237°-243° C. (dec). MS (m/z) 327 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:14](=[O:23])[CH2:13][S:12]2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:35][N+:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[S:38][C:37]=1SC>>[C:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:14](=[O:23])[C:13](=[C:37]3[N:36]([CH3:35])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[S:38]3)[S:12]2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(N=C2SCC(=O)N2Cc2cccnc2)c1
Reactant: CSc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)c1cccc(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2cccnc2)c1

Procedure:
The title compound was prepared from intermediate 2-(3-acetylphenylimino)-3-pyridin-3-ylmethylthiazolidin-4-one and 3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate as described in Example 45. 1H-NMR (CDCl3): δ 8.87 (1H, d), 8.56 (1H, dd), 7.93 (1H, m), 7.74 (1H, m), 7.60 (1H, m), 7.53 (1H, d), 7.46 (1H, m), 7.27–7.38 (2H, m), 7.17–7.23 (2H, m), 7.05 (1H, d), 5.18 (2H, s), 3.74 (3H, s), 2.62 (3H, s); MS(ESI): 473 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[NH3:21].CO>C(Cl)Cl>[NH2:21][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2Cl)c1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Yield: 100 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(bromomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (728 mg, 1.941 mmol) and NH3 in MeOH (27.7 ml, 194 mmol, 7.0 N) in CH2Cl2 (20 ml) to give the title compound as a white solid (602 mg, 100%) which was used for the next step without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37-7.43 (1H, m) 7.34 (1H, s) 7.12-7.21 (2H, m) 6.99 (1H, br. s.) 3.98 (2H, br. s.) 1.65-1.89 (2H, m). LCMS: m/z 311 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[C:18](OCC)=[O:19])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(OC)cnc2n1Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc2c(c1)cc(CO)n2Cc1ccc(Cl)cc1

Procedure:
To Ethyl 1-(4-chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate from step 4 (170 mg, 0.493 mmol) in THF (4 mL), was added LiAlH4 (21 mg, 0.542 mmol) and heated to reflux for 30 min. After cooling, the reaction mixture was poured into water, extracted with EtOAc (4×25 mL), the organic phase dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 40% EtOAc in hexanes to yield the title alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][CH:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[C:10]2[N:11]([CH:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([N:8]2[C:15](=[O:17])[C:14]3[CH:13]=[CH:12][N:11]([CH:18]([CH3:20])[CH3:19])[C:10]=3[CH:9]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)ccc1C(Nc1cccc(Cl)c1F)c1c(C(=O)O)ccn1C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1C1c2c(ccn2C(C)C)C(=O)N1c1cccc(Cl)c1F
Temperature: 80 °C

Procedure:
A mixture of 2-[(3-chloro-2-fluoro-phenylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid (Step A2) (2.257 mmol), HATU (2.482 mmol) and NMM (6.77 mmol) in DMF (30 mL) was heated at 80° C. for 18 h. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 5.31 min (HPLC 1); ESI-MS: tR=1.29 min, [M+H]+ 417/419 (LC-MS 1); TLC: Rf=0.13 (1:3 EtOAc/heptanes).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([C:11]2[N:7]([CH3:6])[N:8]=[N:9][CH:10]=2)[OH:25])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cn1ccnn1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nncc1C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of n-BuLi (11.6 mL, 1.6 M, 18.6 mmol) in hexane was added dropwise to a solution of 73.1 (1.29 g, 15.5 mmol) in THF (75 mL) at −40° C. After stirring at −40° C. for 2 hours, 4-(benzyloxy)benzaldehyde was added at −40° C., and the reaction was warmed to room temperature. The reaction was quenched saturated NH4Cl (aq) after 3 hours of stirring and then extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue 73.2 was used in the next reaction without further purification. MS ESI (pos.) m/e 296.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:10]([O:9][C:3]1[C:2]([Br:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ncc(Cl)cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Clc1cnc(OCc2ccccc2)c(Br)c1

Procedure:
3-Bromo-5-chloro-2-pyridinol (7.0 g, 33.6 mmol) was stirred in toluene (160 ml) and silver carbonate (10.23 g, 36.9 mmol) added, followed by benzyl bromide (6.32 g, 4.39 ml, 36.9 mmol). The mixture was heated to reflux for 1 hour. After cooling, the mixture was filtered, washed with water (×2), dried (MgSO4) and evaporated. The residue was triturated with isohexane and the pale yellow solid filtered and dried. (8.36 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[C:25]3=[N:26][C:27]([C:30]([O:32]C)=[O:31])=[CH:28][CH:29]=[C:24]3[N:23]=[C:22]2[CH3:34])=[C:18]([Cl:37])[CH:17]=1)C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[C:25]3=[N:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=[C:24]3[N:23]=[C:22]2[CH3:34])=[C:18]([Cl:37])[CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc3Cl)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2ccc(C(=O)O)nc2n1Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Methyl 3-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (391 mg) was dissolved in 1,4-dioxane (4 ml). 1N Aqueous sodium hydroxide solution (3.7 ml) was added and the mixture was stirred at room temperature for 2 days and at 80° C. for 2 hr. To the reaction mixture was added 1N hydrochloric acid to adjust the pH to 4. Water (40 ml) was added and the precipitated crystals were collected by filtration to give 3-(4-(N-(tert-butoxycarbonyl)-amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (261 mg) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[N:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH3-][C:24]#N.[Na+].CC(O)=O>CO.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:24])[CH2:15][C:14]=2[N:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C(Cn1cnc2c1CCNC2)OCc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCc2c(ncn2CC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of (4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester (176 mg) in MeOH was added formaldehyde (36.5% in water, 0.052 mL) followed by NaBH3CN (29 mg) and AcOH (0.5 mL). The reaction mixture was stirred at RT overnight. DCM was added and the mixture was washed with sat. NaHCO3. The aq. layer was extracted with DCM, the combined org. layers were dried (MgSO4), filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 10 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in % B: 25 for 3CV, 25 to 50 over 2CV, 50 for 5CV, 50 to 100 over 3CV, 100 for 2CV) to afford (5-methyl-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester (39 mg, yellow oil). LC-MS (B): tR=0.46 min; [M+H]+: 286.16.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10]>CO.[OH-].[Pd+2].[OH-].[C]>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(CN1CCCCC1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCCCC1=O
Reaction time: 4 h
Yield: 106 %

Procedure:
Under a nitrogen atmosphere, to a solution of benzyl (2-oxopiperidin-1-yl)acetate (6.0 g, 24 mmol) in methanol (60 ml) was added 20% palladium hydroxide-carbon (400 mg) at room temperature, and the mixture was stirred for 4 hr under a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (4.0 g, yield over weight).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N+]([O-])=O)\[CH3:10])=[CH:4][CH:3]=1.[N+:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[C-:15]>CC(O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:10])=[CH:15][NH:14][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: C/C(=C\c1ccc(Cl)cc1)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
2.6 mmol TBD/g polystyrene (21.4 g, 55.7 mmol) was added to a suspension of (E)-1-chloro-4-(2-nitroprop-1-enyl)benzene (10 g, 50.6 mmol) and ethyl 2-isocyanoacetate (6.01 g, 53.1 mmol) in i-PrOH (40 mL) and dry THF (40 mL). The reaction mixture was stirred at room temperature overnight. The suspension was filtered, washed with i-PrOH/THF (1/1, v/v, 40 mL). The combined filtrate was evaporated under reduced pressure to furnish 11.0 g (82%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CS(O)(=O)=O.C1C(=O)N([Br:42])C(=O)C1>C(#N)C>[Br:42][CH2:21][C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(CBr)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a warm (90° C.) and stirred solution of ketone 57 (5 g, 0.016 mol) in a mixture of 4:1 toluene and acetonitrile (125 ml) was added methane sulfonic acid (2.64 ml, 0.041 mole) and stirred for 1 hour. The reaction mixture was cooled to 68° C., NBS (3.19 g, 0.018 mol) was added at once and stirred the contents at 65° C. for 4 hour followed by stirring at RT for 18 hour. The solid from the reaction mixture was collected by filtration and dissolved in dichloromethane (100 ml). dichloromethane layer was washed with 10% aq. sodium carbonate and subjected to usual workup and concentration to obtain alpha bromo-ketone 58 (3.0 g, 48%) as an off-white solid.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[CH3:11][C:12]1[C:24]2[N:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[CH:17][C:16]=2[C:15]([NH:25][CH2:26][CH2:27][NH2:28])=[N:14][N:13]=1.C([BH3-])#N.[OH-].[Na+]>CO.[Zn]>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:28][CH2:27][CH2:26][NH:25][C:15]1[C:16]3[CH:17]=[C:18]4[N:23]([C:24]=3[C:12]([CH3:11])=[N:13][N:14]=1)[CH:22]=[CH:21][CH:20]=[CH:19]4)[CH2:3]2
Reactant: O=C1CN2CCC1CC2
Reactant: Cc1nnc(NCCN)c2cc3ccccn3c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nnc(NCCNC2CN3CCC2CC3)c2cc3ccccn3c12
Reaction time: 0.12 h

Procedure:
To a solution of 3-quinuclidinone hydrochloride (600 mg, 3.7 mmol) in methanol (15 mL) was added a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine (900 mg, 3.7 mmol) in methanol (11 mL) over a one minute period at room temperature. After stirring for 5 to 10 minutes, a solution of zinc modified cyanoborohydride (8.7 mL of 0.50M cyanoborohydride in methanol, 4.4 mmol) was added [Kim, et al., J. Org. Chem. 50, 1927 (1985)]. A yellow precipitate formed. After stirring for 4 days at room temperature, 50% sodium hydroxide (1 mL) was added and the solvent was evaporated. The residue was mixed with 4:1 chloroform:methanol (at 20 mL) and filtered through a plug of basic alumina. The filtrate was evaporated and the residue was purified by flash chromatography (alumina, 4:1 chloroform:methanol to 100% methanol) to give the title compound as the free base which was converted to the fumaric acid salt (fumaric acid/ethanol), mp 205°-208° C.