Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH2:12])=[CH:7]2.ClC1C=CN=C2C=1N=CC(N=C(C1C=CC=CC=1)C1C=CC=CC=1)=C2.Cl.C(=O)(O)[O-:40].[Na+]>O1CCCC1>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:40])=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: Nc1cnc2c(Cl)ccnc2c1
Agent: Cl
Agent: Clc1ccnc2cc(N=C(c3ccccc3)c3ccccc3)cnc12
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cnc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
8-chloro-1,5-naphthyridin-3-amine. A round bottom flask under nitrogen was charged with 8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine (315 mg, 0.92 mmol), 2M aqueous HCl (1.42 mL, 2.84 mmol), and tetrahydrofuran (0.25M, 3.67 mL). This was stirred at RT for 30 minutes. Reaction basified with aq. sodium bicarbonate solution and product extracted with dichloromethane. This was dried over sodium sulfate and concentrated to afford orange solid; which was purified via ISCO silica gel chromatography, 40 g column, 30% (90/10/1 DCM:MeOH:NH4OH)/DCM over 40 minutes to afford 7-amino-1,5-naphthyridin-4-ol (140 mg, 95% yield) as yellow solid. MS[M+H]=180.2. Calc'd for C8H6ClN3=179.6. 2) 8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine. A round bottom flask under nitrogen atmosphere was charged with 8-chloro-1,5-naphthyridin-3-amine (160 mg, 0.89 mmol), DMF (2.2 mL, 0.89 mmol). This was cooled to 0° C. and SODIUM HYDRIDE (60% dispersion in oil) (107 mg, 4.45 mmol) added portionwise. This was quickly followed by addition of 1-bromo-2-methoxyethane (0.12 mL, 1.25 mmol) dropwise via syringe. Ice bath removed and reaction mixture heated to 85° C. and stirred at this temperature for 16 hours. Reaction diluted with 5 mL of 5% MeOH/Dichloromethane, loaded onto silica gel column and eluted with 2% MeOH/DCM to afford 8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine (70 mg, 33% yield) as a light yellow solid. MS[M+H]=238.2. Calc'd for C11H12ClN3O=237.7.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[O:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][C:43](O)=[O:44]>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:43](=[O:44])[CH2:42][CH:38]2[CH2:39][CH2:40][CH2:41][O:37]2)[CH2:7]1)#[N:2]
Reactant: O=C(O)CC1CCCO1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)CC2CCCO2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 77 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and tetrahydrofuran-2-ylacetic acid (Matrix Scitific, cat. No. 020454). LCMS (M+H)+: m/z=608.2.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS([Cl:37])(=O)=O>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(CO)n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(CCl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 4-(6-hydroxymethylpyridine-2-carbonyl)-piperazine-1-carboxylate (1.26 g) and diisopropylethylamine (1.0 g) were dissolved in 20 mL of methylene chloride, 0.1 mL of methanesulfonyl chloride was added dropwise into the above solution at ice temperature, and the mixture was stirred at room temperature overnight. After the solvent was removed under reduced pressure from the reaction mixture, the residue was purified by chromatography on silica gel (methylene chloride-ethanol=40:1) to give 1.07 g of t-butyl 4-(6-chloromethylpyridine-2-carbonyl)piperazine-1-carboxylate as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][C:35]=1[C:42]([F:45])([F:44])[F:43]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:38]([C:37]2[CH:40]=[CH:41][C:34]([S:33][CH3:32])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)[OH:39])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(C=O)cc1C(F)(F)F
Reactant: COc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cnc2c(c1)cc(C(O)c1ccc(SC)c(C(F)(F)F)c1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a −78° C. suspension of 1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridine (3.17 g, 11 mmol) in dry tetrahydrofuran (50 mL) was added n-butyllithium in n-hexane (1.6 M, 6.9 mL, 11 mmol) dropwise. The mixture was stirred at −78° C. for 30 min before adding 4-methylsulfanyl-3-trifluoromethyl-benzaldehyde (2.65 g, 12 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched by adding brine (20 mL). The mixture was extracted with ethyl acetate (300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) afforded (1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanol as colorless oil (5.08 g, 91%): LC/MS m/e calcd for C23H20F3N2O4S2 [M+H]+ 509.07, observed 509.0.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C@H:7]([CH2:12][OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Cl:1][CH2:2][C:3]([NH:6][C@H:7]([CH2:12][OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:4]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C[C@@H](CO)NC(=O)CCl
Reaction time: 2 h

Procedure:
A solution of chloroacetyl chloride, 25.64 g (0.227 mol), in 57 ml of acetone is added dropwise with stirring to a solution of L-leucinol, 26.63 g (0.227 mol), and sodium acetate, 37.24 g (0.454 mol), in a mixture of 340 ml of acetone and 170 ml of water at 0°-5° C. The mixture is stirred and allowed to reach room temperature over two hours, the solvent is evaporated in vacuo and the residue is suspended in 250 ml of chloroform and washed with water, 2×300 ml. The chloroform layer is separated, dried over sodium sulfate, evaporated in vacuo and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (S)-2-chloro-N-[1-(hydroxymethyl)-3-methylbutyl]acetamide, 28 g; [α]D25 -32.6° (c 0.52, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Yield: 98.6 %

Procedure:
To a solution of 4-chloro-3-nitroaniline (1.72 g, 10.0 mmol) in 60 mL of anhydrous DCM was added crystalline DMAP (1.22 g, 10.0 mmol). The reaction mixture was stirred until all solids dissolved, then 3-trifluoromethylbenzoyl chloride (2.71 g, 13.0 mmol) was added dropwise. The reaction mixture was left to stir at ambient temperature for 6 hrs. The completion of the reaction was monitored by TLC and LC/MS. Then it was transferred into a separatory funnel and washed with water (3×100 mL), saturated NaHCO3 (2×100 mL), brine (1×100 mL), dried over anhydrous Na2SO4 and filtered through a short pad of silica gel. Solvent was removed in vacuo to give the title product as a light-brown solid (3.4 g, 100% yield).
Reaction SMILES: [C:1]([C:5](=[CH:10]OC)[C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3].[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[C:1]([C:5](=[CH:10][NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[O:14][CH3:13])[C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C(=COC)C(=O)OC
Reactant: COc1ccccc1N
Product: CCC(=O)C(=CNc1ccccc1OC)C(=O)OC

Procedure:
A mixture of methyl 2-propanoyl-3-methoxyacrylate (70 g) and 2-methoxyaniline (45 ml) was heated on a steam bath for 30 minutes, then diluted with petroleum ether and left to crystallize. Filtration and washing with ether gave methyl 2-propanoyl-3-(2-methoxyphenylamino)acrylate (78.2 g) as a mixture of E/Z isomers.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:18][C:19]1[CH:20]=[C:21]([O:27][CH3:28])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:7]=1
Reactant: COc1ccc(N)cc1OC
Reactant: Clc1ncnc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2ncnc(Cl)n2)cc1OC
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (12.6 g, 84 mmol) was dissolved into DMF (100 mL) under N2 and cooled to 0° C. DIEA (11.7 g, 90 mmol) was added, followed by 4-aminoveratrole (13.35 g, 87 mmol). The reaction solution was stirred with gradual warming to RT. The reaction was quenched after 3.5 h with water, which causes a gray precipitate to form. This precipitate was recovered by vacuum filtration, washed with cold water, dried under high vacuum, then eluted through a 28×4.5 cm column of silica gel (0.1% NH4OH(aq) buffered 1%, 2%, 3%, 4%, and 5% MeOH/CH2Cl2 step gradient) giving (4-chloro-[1,3,5]triazin-2-yl)-(3,4-dimethoxy-phenyl)-amine as an off white solid.
Reaction SMILES: C[C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=[CH:4][C:3]=1[O:21]C.B(Br)(Br)Br.[CH2:27](Cl)Cl>>[CH2:9]([NH:8][C:7]1[CH:2]=[C:3]([OH:21])[CH:4]=[CH:5][C:6]=1[CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCNc1cccc(OC)c1C
Reactant: ClCCl
Agent: BrB(Br)Br
Product: CCCCCCCCCCCCNc1cc(O)ccc1C
Temperature: 0 °C
Yield: 70 %

Procedure:
As a general methyl group de-protection procedure, 4 methyl-3-dodecylamino-1-methoxy benzene 120 was suspended in dry CH2Cl2, cooled to 0° C. and 5 equivalents of a solution of BBr3 (1M CH2Cl2, Aldrich Chem. Co.) were added and the reaction maintained at 0° C. for 16 hours. The reaction was quenched at 0° C. by slow addition of MeOH and then careful addition of solid NaHCO3 (10 Equiv.) until foaming stops. The mixture was filtered, the filtrate was concentrated to an oil, and the product was isolated by normal phase chromatography eluting with methanol/CH2Cl2. The solvent was removed from the pure fractions to give 3-dodecylamino-1-hydroxy-4 methylbenzene 120 (R═H, R′═R′″═H, R″═Me) as a waxy solid in 70-80% yield (1HNMR (CDCl3) δ 6.91 (d, 1H), 6.17 (d, 1H), 6.14 (dd, 1H) 4.62 (bs, OH), 3.53 (bs, NH), 3.14 (t, 2H), 2.09 (s, 3H), 1.70 (p, 2H), 1.46 (m, 18H), 0.93 (t, 3H))
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])#[N:2].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].C(O)(=O)C.[Na]>ClCCl>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])#[N:2]
Reactant: CC(C)C=O
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCCN2
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCCN2CC(C)C

Procedure:
To the material isolated in Step A in 2 mL of dichloromethane was added 0.041 mL (0.90 mmol) of iso-butyraldehyde, followed by 0.026 mL (0.45 mmol) of acetic acid and 0.10 g (0.45 mmol) of sodium tracetoxyborohydride. After 16 h at ambient temperature the reaction was diluted with 30 mL of dichloromethane and washed twice with equal volumes of saturated aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative reversed phase BPLC afforded the tide compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:30])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccccn4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 19 h
Yield: 56.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) and commercially available picolinic acid (42 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (123 mg) was added, and the admixture was stirred at room temperature for 19 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 38 mg of the title compound (yield: 56%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O.CN([CH:18]=[O:19])C>>[CH:18]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:19]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccccc12

Procedure:
As shown by the above generalized scheme, the indole is treated with phosphorus oxychloride and DMF to produce the corresponding 3-formyl indole (XIV). The latter is treated with nitromethane and ammonium acetate to obtain the corresponding 3-(2'-nitroethenyl)indole (XV), which then is reduced to the desired tryptamine (XVI).
Reaction SMILES: [C:1]1([CH:13]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]2)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[C:1]1([C@H:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)[CH2:14]2)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1
Reactant: N[C@H]1CCC(c2n[nH]c3cnc4[nH]ccc4c23)C1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1ccc(N[C@H]2CC[C@H](c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Temperature: 120 °C
Yield: 4.9 %

Procedure:
A mixture of (1S)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine (0.20 g, 0.83 mmol, Preparation #30), 6-chloronicotinonitrile (0.12 g, 0.83 mmol), DIEA (0.22 mL, 1.2 mmol), and EtOH (3 mL) were heated for about 1 h at about 120° C. in a microwave (250 psi maximum pressure, 1 min ramp, 300 max watts). The reaction mixture was concentrated in vacuo and purified by RP-HPLC (Table 2, Method s) to give 6-((1S,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile (0.014 g, 5%): LC/MS (Table 2, Method a) Rt=1.75 min; m/z: 344 (M+H)+ and 6-((1S,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile (0.020 g, 7%): LC/MS (Table 2, Method a) Rt=1.81 min; m/z: 344 (M+H)+.
Reaction SMILES: CO.[OH:3][CH2:4][CH2:5][NH:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:8]=1[NH2:9].Cl.[C:24](=N)(OC)[CH3:25]>O>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:7]2[N:6]([CH2:5][CH2:4][OH:3])[C:24]([CH3:25])=[N:9][C:8]=2[CH:10]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCCO
Reactant: COC(C)=N
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCO
Yield: 42.6 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(2-hydroxyethyl)aminoanilin-5-yl)benzoxazole (see Working Example 88-1) (0.10 g, 0.4 mmol) was added methyl acetimidate hydrochloride (0.08 g, 0.7 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.05 g, 49% yield) as white crystals.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][O:33][CH3:34].Cl.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][O:33][N:32]([CH3:31])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[N:20]=[CH:19][N:18]=2)[CH:23]=1
Reactant: CNOC
Reactant: O=C(O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a stirred solution of 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoic acid (0.05 g, 0.12 mmol) in DMF (2 mL) were added MeNH-OMe.HCl (0.0084 g, 0.12 mmol), EDCI.HCl (0.0361 g, 0.18 mmol), HOBT (0.0084 g, 0.062 mmol) and DIPEA (0.023 g, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 h and was quenched with water. A white solid was isolated by filtration and dried under vacuum to give N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (0.025 g, 44.5%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1C(O)=O.C([N:22](CC)CC)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)(C)C>[CH3:1][C:2]1[C:3]2[N:4]([N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[NH2:22]
Reactant: CCN(CC)CC
Reactant: Cc1c(C(=O)O)ccn2nc(-c3ccccc3)nc12
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1c(N)ccn2nc(-c3ccccc3)nc12
Yield: 25.4 %

Procedure:
To a suspension of 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (710 mg, 2.81 mmol) and triethylamine (1.17 ml, 8.42 mmol) in tert-butanol (20 ml) is added diphenyl phosphorazidate (909 μl, 4.21 mmol) at 25° C. After the addition the white suspension is refluxed for 24 hours. The crude material is loaded on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 10-100% and then ethyl acetate/methanol 10% as eluent affording 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (160 mg, 25.4%) as a white solid. mp.: 213-5° C. MS: m/z=225.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21](O)[CH2:22]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:21]=[CH2:22])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CCCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 87 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.70 g, 1.969 mmol) was combined with potassium vinyl trifluoroborate (0.396 g, 2.95 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (1:1) (0.058 g, 0.079 mmol) and TEA (0.412 mL, 2.95 mmol) in n-propanol (10 mL) and heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was filtered through Celite™ and concentrated to dryness. The residue was dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified on silica gel (eluted with 0 to 10% CH3OH/DCM) to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (0.52 g, 1.718 mmol, 87% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (s, 1H), 7.45-7.55 (m, 2H), 7.40 (s, 1H), 7.25 (s, 1H), 6.75 (dd, 1H), 6.04 (d, 1H), 5.43 (d, 1H), 3.77 (s, 2H), 2.05 (br. s., 2H). LC-MS (ES+) m/z 303.32, 305.30 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[CH3:21][C:22]1[N:30]2[C:25]([C:26]([CH3:31])=[CH:27][CH:28]=[CH:29]2)=[C:24]([CH2:32][N+](C)(C)C)[CH:23]=1.[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:32][C:24]2[CH:23]=[C:22]([CH3:21])[N:30]3[C:25]=2[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cc1cccn2c(C)cc(C[N+](C)(C)C)c12
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cccc(C)c23)c2ccccc21
Yield: 26 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added (3,8-Dimethyl-indolizin-1-ylmethyl)-trimethyl-ammonium; iodide, CAS: (3,8-Dimethyl-indolizin-1-ylmethyl)-trimethyl-ammonium; iodide (93.4 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(3,8-Dimethyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (20 mg, 26%) as a colorless foam.
Reaction SMILES: NC1(C2N[C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18]C)C(=O)N(CCC)[C:9]=3[N:8]=2)CCCC1.C(C(C(Cl)=O)C(Cl)=[O:28])C>O1CCCC1.N1C=CC=CC=1>[CH2:17]([NH:12][C:13](=[O:16])[CH2:14][C:9]([NH2:8])=[O:28])[CH3:18]
Reactant: CCCn1c(=O)c2[nH]c(C3(N)CCCC3)nc2n(CCC)c1=O
Reactant: CCC(C(=O)Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCNC(=O)CC(N)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.5 g di 8-(1-aminocyclopentyl)-1,3-dipropylxanthine in 45 ml of anhydrous tetrahydrofurane, 1.4 ml of pyridine are added and, after cooling to 5° C., 2.26 ml of ethyl malonyl chloride are dropwise added. The mixture is stirred at room temperature for 2 hours, followed by concentration under vacuum, addition of 1N HCl and extraction with ethyl acetate. The organic phase is washed with water, dried and evaporated, thereby obtaining 6.5 g of raw product which is purified by column chromatography (SiO2). 2.6 g of mono malonamide mono ethyl ester are obtained, which is finally saponified by treatment with tetrahydrofurane (26 ml) and NaOH 1N (30 ml) at room temperature for 1 hour.