Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:31]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1cccc(-c2ccccn2)c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(-c3ccccn3)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-pyridin-2-ylphenol (Chem. Pharm. Bull. 1985, 33, 1009): 1H-NMR (CDCl3) δ 8.71–8.68 (1H, m), 8.56 (1H, d, J=2.8 Hz), 8.22 (1H, d, J=7.4 Hz), 8.13 (1H, d, J=2.8 Hz), 8.02–7.99 (2H, m), 7.92–7.81 (2H, m), 7.79–7.76 (2H, m), 7.57 (1H, t, J=7.9 Hz), 7.44 (2H, d, J=8.2 Hz), 7.30–7.20 (2H, m), 5.43–5.33 (1H, m), 3.89 (3H, s), 1.60 (3H, d, J=6.9 Hz); MS (ESI) m/z 488 (M+H)+, 486 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21](OC)=[O:22])[N:18]=[C:17]3[N:25]([CH3:38])[C:26](=[O:37])[N:27]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])[C:16]=23)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[K+]>C(O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([CH2:21][OH:22])[N:18]=[C:17]3[N:25]([CH3:38])[C:26](=[O:37])[N:27]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])[C:16]=23)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c2c(n1)n(C)c(=O)n2Cc1ccccc1C#N
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: Cn1c(=O)n(Cc2ccccc2C#N)c2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)cc(CO)nc21
Reaction time: 8 h
Yield: 85.3 %

Procedure:
1.04 g (R)-7-(3-tert-butoxycarbonylaminopiperidin-1-yl)-1-(2-cyanobenzyl)-3-methyl-5-methoxycarbonyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine (2 mmol) was dissolved in 20 mL ethanol, to which 0.42 g potassium borohydride (8 mmol) was added in an ice bath. The stirring was continued at room temperature overnight. The reaction was monitored by TLC. After the reaction was finished, it was quenched by adding water. The reaction solution was extracted with dichloromethane for three times. The organic phase was combined, washed with saturated brine, dried with anhydrous sodium sulfate, and evaporated to dryness to afford 0.84 g crude product with a yield of 85.4%.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:20])[C:18]#[N:19])[CH:11]=[CH:10]2.O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:20])[C:18]#[N:19])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(C(C)C#N)ccc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C#N)c1ccc2cc(O)ccc2c1
Temperature: -10 °C
Reaction time: 7 h

Procedure:
15.6 g of boron tribromide, were dissolved in 100 ml of methylene chloride and cooled to -10° C. To this, 80 ml of methylene chloride solution of 6.0 g oa (6-methoxy-2-naphthyl)-propanonitrile were added dropwise over 2 hours, followed by stirring for 7 hours at room temperature. The resulting reaction mixture was poured into 500 ml of iced water and extracted with ether, followed by washing the ether phase twice with water and then distilling off the solvent. The resulting solid was recrystallized with chloroform-hexane mixture to obtain 4.5 g of oa (6-hydroxy-2-naphthyl)-propanonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][OH:16])[CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.[OH-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25]>CCOC(C)=O>[Cl:29][C:28]([Cl:31])([Cl:30])[CH2:27][O:26][C:24](=[O:25])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][OH:16])[CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccnc(OCCO)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccnc(OCCO)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a stirred solution of Intermediate 67c (139 mg, 0.50 mmol) in EtOAc (5 mL) and 1M NaOH solution (1.26 mL, 1.26 mmol) was added 2,2,2-trichloroethyl chloroformate (117 mg, 76 μL, 0.55 mmol) and the reaction was stirred at RT. After 1 h, a further 1.1 eq of 2,2,2-trichloroethyl chloroformate was added, stirred for an additional 1 h, then a further 2.2 eq. of 2,2,2-trichloroethyl chloroformate added. After stirring for an additional 2 h, the reaction was partitioned between H2O and EtOAc. The organic layer was separated, and the aqueous layer extracted with EtOAc. The combined organics were dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 0-50% EtOAc/cyclohexane, and triturated with Et2O to afford the title compound (74 mg, 33%). LCMS (Method 3) Rt 3.93 min, 451.1, 453 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]1[CH2:14][C:13](=[O:15])[NH:12][C:6]1=[N:7]2.[Br:16]Br>[N+](C)([O-])=O>[Cl:1][C:2]1[C:11]([Br:16])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]1[CH2:14][C:13](=[O:15])[NH:12][C:6]1=[N:7]2
Reactant: BrBr
Reactant: O=C1CN2Cc3c(Cl)cccc3N=C2N1
Solvent: C[N+](=O)[O-]
Product: O=C1CN2Cc3c(ccc(Br)c3Cl)N=C2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a solution of 1.30 g (8 mmole) of anhydrous ferric chloride in 30 ml of nitromethane was added 1.30 g (5 mmole) of solid 6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one and 0.80 g (5 mmole) of bromine. The system was stoppered, warmed to 50° in an oil bath overnight, cooled to room temperature and the solvent removed in vacuo. The resulting solid was suspended in water (50 ml), the mixture made basic (pH 10) with sodium bicarbonate and stirred at room temperature for 20 min. The solid was filtered under suction, washed with water, then isopropyl alcohol and dried yielding 1.9 g (78% yield) of a beige colored powder. Purification was effected by formation of the hydrochloride salt from acetonitrile; mp >275°.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([NH:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)([CH3:21])([CH3:20])[CH3:19]>C(O)C>[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([N:8]([CH2:25][CH2:24][C:23]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:27])[NH2:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)(C)NC(=O)CCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(N(N)CCC(=O)NC(C)(C)C)cc1
Reaction time: 14 h
Yield: 64.3 %

Procedure:
To a solution of tert-butyl amine (1.0 gm, 13.6 mmol) in dichloromethane (50 ml) was added 3-chloropropionyl chloride (2.06 g, 16.3 mmol) and NaOH (650 mg, 16.25 in 2.0 ml H2O) solution simultaneously at −20 deg C. for 1 h. The reaction mixture was allowed to stir for 1 h at RT. The organic layer was washed with 5% HCl followed by 5% aqueous sodium bicarbonate. The organic layer was dried and concentrated to get 2.23 g (yield: 99%) N-tert-butyl-3-chloropropanamide as white solid. To a solution of p-Tolylhydrazine hydrochloride (500 mg, 3.16 mmol) in ethanol (15 ml) was added triethylamine (1.31 ml, 9.4 mmol) and N-tert-butyl-3-chloropropanamide (510 mg, 3.12 mmol). The resulting reaction mixture was heated at 90 deg C. for 14 hrs. The reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to obtain the crude, which was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to obtain 500 mg (yield: 63.3%) of 3-(1-p-tolylhydrazinyl)-N-tert-butylpropanamide. The amide obtained (500 mg, 2.0 mmol) and N-methyl-4-piperidone hydrochloride (298 mg, 2.0 mmol) were dissolved in ethanolic HCl (20 ml) and stirred at RT for 15 minutes. The solvent was removed in vacuo. The reaction mixture obtained was dissolved in ethanol and heated at 90 deg C. for 14 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated. The crude obtained was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to obtain 10 mg (yield: 1.12%) of the desired product as TFA salt. 1H NMR (DMSO-D2O) TFA SALT 7.30-7.25 (d, 1H), 7.20 (s, 1H), 7.0-6.95 (d, 1H), 4.5 (m, 1H), 4.30-4.15 (m, 3H), 3.70-3.65 (m, 1H), 3.50-3.30 (m, 1H), 3.20-3.10 (m, 2H), 2.90 (s, 3H), 2.50-2.40 (d, 2H), 2.30 (s, 3H), 1.10 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([C:14]#[C:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C([O-])=O.[NH4+]>CO.[OH-].[Pd+2].[OH-]>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2C#Cc2ccc3ccccc3c2)CCN(C)C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc3c(c2)CCCC3)CCN(C)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a de-aerated solution of 2,8-dimethyl-5-naphthalen-2-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (50 mg, 0.14 mmol) in MeOH (5 mL), palladium hydroxide (25 mg, 50% w/w) and ammonium formate (45 mg, 0.71 mmol) were added. The reaction mixture was stirred at 80° C. for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mass was filtered through Celite and washed the residue with MeOH (10 mL). The filtrate was concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.26 (d, 1H), 7.22 (d, 1H), 7.02 (d, 1H), 6.9 (d, 1H), 6.63 (d, 1H), 6.58 (s, 1H), 4.6 (d, 1H), 4.4 (m, 1H), 4.2 (t, 2H), 3.62 (m, 1H), 3.02 (m, 1H), 2.9 (m, 4H), 3.0 (s, 3H), 2.7 (bs, 2H), 2.6 (bs, 2H), 2.4 (s, 3H), 1.8 (bs, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17](Cl)=[C:18]([F:23])[CH:19]=2)[N:14]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:13]=1)=[O:11])[CH3:8]>C(#N)C>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:18]([F:23])[CH:19]=2)[N:14]([C:25]([CH3:26])([CH3:28])[CH3:27])[CH:13]=1)=[O:11])[CH3:8]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCNCC3)c(F)cc2c1=O
Yield: 61.8 %

Procedure:
To a refluxed solution of 487 mg (5.65 mmoles) piperazine in 30 mL acetonitrile was gradually added 612 mg (1.87 mmole) of 1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-7-chloro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester over a 10 mn period. The solution was refluxed 30 minutes and evaporated to dryness. The residue was taken up in water and filtered to give 435 mg of 7-piperazinyl-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([O:8][C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][C:5]2([O:28][C@@H:27]3[C@@H:22]([CH2:23][CH2:24][C@@H:25]([C:29]([O:31][CH:32]4OC(C)C(OC5OC(C)C(O)C(OC(C)=O)C5O)C(OC(C)=O)C4O)=[O:30])[CH2:26]3)[C@:19]32[O:21][CH2:20]3)[O:4][CH2:3]1.[CH3:58][C@H:59]1[C@@H:64]([O:65][C:66](/[CH:68]=[CH:69]/[C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)=[O:67])[CH2:63][C@@:62]2([O:85][C@@H:84]3[C@@H:79]([CH2:80][CH2:81][C@H:82]([C:86]([O:88][C@@H:89]4[O:94][C@H:93]([CH3:95])[C@@H:92]([OH:96])[C@H:91]([O:97][C:98]([CH3:100])=[O:99])[C@H:90]4[O:101][C@@H:102]4[O:107][C@H:106]([CH3:108])[C@@H:105]([OH:109])[C@H:104]([O:110][C:111]([CH3:113])=[O:112])[C@H:103]4[OH:114])=[O:87])[CH2:83]3)[C@@:76]32[O:78][CH2:77]3)[O:61][CH2:60]1>>[CH3:58][C@H:59]1[C@@H:64]([O:65][C:66](/[CH:68]=[CH:69]/[C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)=[O:67])[CH2:63][C@@:62]2([O:85][C@@H:84]3[C@@H:79]([CH2:80][CH2:81][C@H:82]([C:86]([O:88][C@@H:89]4[O:94][C@H:93]([CH3:95])[C@@H:92]([OH:96])[C@H:91]([O:97][C:98]([CH3:100])=[O:99])[C@H:90]4[O:101][C@@H:102]4[O:107][C@H:106]([CH3:108])[C@@H:105]([OH:109])[C@H:104]([O:110][C:111]([CH3:113])=[O:112])[C@H:103]4[OH:114])=[O:87])[CH2:83]3)[C@@:76]32[O:78][CH2:77]3)[O:61][CH2:60]1.[CH3:1][CH:2]1[CH:7]([O:8][C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][C:5]2([O:28][CH:27]3[CH:22]([CH2:23][CH2:24][CH:25]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]3)[C:19]32[O:21][CH2:20]3)[O:4][CH2:3]1
Reactant: CC(=O)OC1C(O)C(C)OC(OC2C(C)OC(OC(=O)[C@@H]3CC[C@@H]4[C@H](C3)OC3(C[C@@H](OC(=O)/C=C/c5ccccc5)[C@@H](C)CO3)[C@@]43CO3)C(O)C2OC(C)=O)C1O
Agent: CC(=O)O[C@@H]1[C@@H](O)[C@H](O[C@H]2[C@H](OC(=O)[C@H]3CC[C@@H]4[C@H](C3)O[C@@]3(C[C@H](OC(=O)/C=C/c5ccccc5)[C@H](C)CO3)[C@]43CO3)O[C@H](C)[C@@H](O)[C@@H]2OC(C)=O)O[C@H](C)[C@H]1O
Product: COC(=O)C1CCC2C(C1)OC1(CC(OC(=O)/C=C/c3ccccc3)C(C)CO1)C21CO1

Procedure:
The complete structures of phyllanthostatin 1 and phyllanthoside were deduced by interpreting the 13C NMR (22.63 MHz, CDCl3), 1H NMR (400 MHz, CDCl3) and EI high resolution and FD mass spectra. Although the structure of phyllanthoside was not previously known, Kupchan and co-workers reported [Kupchan, S. M., supra] structural studies of two degradation products which proved very useful in the present study. Methanolysis of phyllanthoside gave an aglycone methyl ester, phyllanthocin (determined by X-ray crystallographic analysis) and a disaccharide, C12H22O9. Acid hydrolysis of the disaccharide yielded 6-deoxy-D-glucose and spectral evidence suggested that the disaccharide portion contained two acetate groups.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[O:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:19])[C:4]([OH:20])=[O:3])[C:18]=2[O:17][CH2:16]1
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CC(=O)C(=O)O)c1cccc2c1OCO2

Procedure:
14.4 g of the thus obtained 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxo-pentanoic acid ethyl ester is stirred with 150 ml of 1 M sodium hydroxide and 300 ml of methanol for 10 hours at room temperature. The methanol is then removed in a vacuum, and the remaining solution is extracted with diethyl ether. The aqueous phase is acidified with 1 M hydrochloric acid and extracted with diethyl ether. After drying and concentration by evaporation, 11.1 g of 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxo-pentanoic acid is obtained as a yellowish oil.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[C:14](OCC)(=[O:16])[CH3:15].O>C(O)C>[CH2:14]([O:16][C:4]1[N:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH3:15]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 5 N sodium hydroxide solution (2 mL) was added to a solution of methyl 5-chloropyrazine-2-carboxylate (150 mg) in ethanol (4 mL), and the mixture was stirred at room temperature for five hours. Ethyl acetate and water were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was made acidic with concentrated hydrochloric acid. Brine and ethyl acetate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated to obtain the title compound (135 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH:16]=[CH2:17])=[N:14][N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](/[CH:16]=[CH:17]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:14][N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: C=Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)OCC)c12
Reactant: Ic1ccccc1
Product: CCOC(=O)c1cc(Cl)nc2c1c(/C=C/c1ccccc1)nn2C1CCCCO1

Procedure:
Utilizing the procedure described in example 14.5 except substituting 4-[6-chloro-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester with 6-chloro-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester and substituting (3-iodo-benzyl)-dimethyl-amine for iodobenzene, 6-chloro-3-((E)-styryl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester was obtained (2.8 g, 65%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.Cl.[F:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.[F-].[K+].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:23][C@@H:24]1[CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[CH:9][N:10]=3)[N:7]=2)[CH2:25]1
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: F[C@@H]1CCN(c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)C1
Temperature: 170 °C
Reaction time: 4 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 100 mg, 0.339 mmol), (R)-(−)-3-fluoropyrrolidine hydrochloride (220 mg, 1.696 mmol) and KF (99 mg, 1.696 mmol) were suspended in NMP (1.5 mL). N-Ethyldiisopropylamine (296 μL, 1.696 mmol) was then added and the RM was stirred at 170° C. for 4 h. The mixture was diluted with EtOAc and extracted with 1 M HCl (3×). The aqueous layer was washed with TBME (2×) and then adjusted to pH 10 with 2 M NaOH. The solution was extracted with DCM (3×). The organic layer was washed with water (2×), dried over sodium, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) and triturated in DCM to afford the title compound as a yellow foam (tR 4.14 min (conditions 4), MH+=348.5, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.29 (m, 1H); 7.93 (m, 2H); 7.81 (d, 1H); 7.76 (m, 1H); 7.49 (dd, 1H); 7.43 (s, 1H); 6.81 (d, 1H); 5.46 (m, 1H); 4.38 (s, 2H); 3.62 (m, 4H); 2.20 (m, 2H)).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[Cl:9]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[C:7]([Cl:9])=[C:6]([CH3:8])[O:5][N:4]=1
Reactant: CNc1cc(C)on1
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CNc1noc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
Compound (15) (19.06 g) was dissolved in methylene chloride (150 ml) and a solution of chlorine (13.1 g) in carbon tetrachloride (139 ml) was added thereto dropwise. The mixture was stirred at room temperature for 10 minutes, then washed with a 50% potassium carbonate solution and water, dried and evaporated to give 3-methylamino-4-chloro-5-methylisoxazole (20) (21.07 g); mp. 43°-47° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([O:17][CH:18](C)C)=O)[N:9]=2)[CH:5]=[C:4]([O:21][CH:22]([CH3:24])[CH3:23])[N:3]=1.ClC1C=C(C2N=C[N:34](/C=C\C(OC(C)C)=O)[N:33]=2)C=C(OC)N=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]3[O:17][CH:18]=[N:33][N:34]=3)[N:9]=2)[CH:5]=[C:4]([O:21][CH:22]([CH3:24])[CH3:23])[N:3]=1
Reactant: COc1cc(-c2ncn(/C=C\C(=O)OC(C)C)n2)cc(Cl)n1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(Cl)nc(OC(C)C)c2)n1
Product: CC(C)Oc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(Cl)n1

Procedure:
(Z)-isopropyl 3-(3-(2-chloro-6-isopropoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylate, was synthesized by analogy to the synthesis of (Z)-isopropyl 3-(3-(2-chloro-6-methoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylate in Example 7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([O:13][CH3:14])[N:7]=1)[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[N:7]=[C:8]([O:13][CH3:14])[CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:11]=1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1nc(Cl)cc(OC)n1
Product: CCOC(=O)Cc1nc(OC)cc(N2CCOCC2)n1

Procedure:
1.5 g of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid ethyl ester and 20 ml of morpholine are mixed together in a microwave tube. After microwave irradiation for 1 h at 90° C., the reaction mixture is concentrated under reduced pressure and then diluted with 300 ml of ethyl acetate and 300 ml of water. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. 1.9 g of (4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetic acid ethyl ester are thus obtained in the form of a viscous oil which crystallizes and which is used as it is in the next step.
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[CH2:16]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H](Cc1ccccc1)NCc1ccccc1
Temperature: 15 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
L-Phenylalaninol (89.51 g, 0.592 moles) was dissolved in 375 mL of methanol under inert atmosphere, 35.52 g (0.592 moles) of glacial acetic acid and 50 mL of methanol was added followed by a solution of 62.83 g (0.592 moles) of benzaldehyde in 100 mL of methanol. The mixture was cooled to approximately 15° C. and a solution of 134.6 g (2.14 moles) of sodium cyanoborohydride in 700 mL of methanol was added in approximately 40 minutes, keeping the temperature between 15° C. and 25° C. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and partitioned between 1 L of 2M ammonium hydroxide solution and 2 L of ether. The ether layer was washed with 1 L of 1M ammonium hydroxide solution, twice with 500 mL water, 500 mL of brine and dried over magnesium sulfate for 1 hour. The ether layer was filtered, concentrated under reduced pressure and the crude solid product was recrystallized from 110 mL of ethyl acetate and 1.3 L of hexane to give 115 g (81% yield) of N-benzyl-L-phenylalaninol as a white solid.