Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=O)=[O:7].[N:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([NH:31][CH2:30][CH2:29][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:14])=[O:7]
Reactant: NCCN1CCCCC1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)O)ccn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)NCCN2CCCCC2)ccn1
Yield: 13.2 %

Procedure:
To solution of 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid (80.0 mg, 0.24 mmol), 2-piperidine-1-yl-ethylamine (46.2 mg, 0.05 ml, 0.36 mmol), EDC (69.0 mg, 0.36 mmol) and HOBt (48.7 mg, 0.36 mmol) in DMF 4 ml was added DIPEA (46.5 mg, 0.06 ml, 0.36 mmol), and stirred. Reaction mixture was then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by preparative-TLC (n-Hexane:EtoAC:MeOH=6:3:1) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-(2-piperidine-1-yl-ethyl)-isonicotinamide as a yellow solid (14.3 mg, 13.3% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([N:11]=[N+]=[N-])[N:3]=1.Cl>CO.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1
Reactant: [N-]=[N+]=Nc1nc(N)nc2nc[nH]c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1nc(N)c2[nH]cnc2n1
Yield: 46.9 %

Procedure:
9-(R) -2-phosphonomethoxypropyl) -2-amino-6-azidopurine (0.30 g, prepared according to Example 27) in 50% aqueous methanol (200 ml) containing hydrochloric acid (0.5 ml) was hydrogenated over 10% Pd/C (0.5 g) overnight at room temperature. The mixture was filtered, washed with water, filtrate alkalized with ammonia and evaporated in vacuo. The residue was deionized on a column of Dowex 50×8 (50 ml) (cf. Example 25) and the ammonia eluate evaporated to dryness. The residue in water (pH adjusted to 9) was applied on a column of Dowex 1×2 (acetate) which was first washed with water to remove salts and the product was then eluted with 1 M acetic acid. The fractions containing product were pooled, evaporated to dryness and codistilled with water (3×20 ml). The residue was crystallized from water (ethanol added to turbidity) to afford 9-(R)-2-phosphonomethoxypropyl)-2,6-diaminopurine (120 mg) identical with the preparation according to Example 19.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][CH2:28][OH:29])C>CS(C)=O>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][CH2:28][OH:29])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CCCO
Solvent: CS(C)=O
Product: O=c1cc(CCO)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 5-hydroxy-pent-2-ynoic acid ethyl ester employing the procedure described in Example 105. [αa]D25 +6.40 (c 0.5, DMSO).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[NH:3][C:2]1=[O:10].C(=O)([O-])[O-].[K+].[K+].[P:17](Cl)([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[S:18]>CC(C)=O>[CH2:20]([O:19][P:17]([O:10][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=1)([O:22][CH2:23][CH3:24])=[S:18])[CH3:21]
Reactant: O=c1[nH]c2c(s1)CCCC2
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
A mixture of 6.2 g of 2,3,4,5,6,7-hexahydrobenzothiazoline-2-one, 8.4 g of potassium carbonate and 300 ml of acetone was refluxed for 1 hour and after the addition of 11.4 g of O,O-diethyl chlorothiophosphate thereto, the mixture was refluxed for another hour. The mixture was stirred at room temperature for 24 hours and was filtered to remove mineral salts. The filtrate was concentrated to dryness by distillation under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 7.3 g of 2-(diethoxythiophosphoryloxy)-4,5,6,7-tetrahydrobenzothiazole having a refractive index of nD22 = 1.532.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:21][C@@H:22]5[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]5)=[O:20])[CH:17]=4)[NH:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:21][C@@H:22]5[CH2:27][CH2:26][CH2:25][N:24]([CH2:34][C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=6)[CH2:23]5)=[O:20])[CH:17]=4)[NH:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1ccccn1
Reactant: O=C(N[C@@H]1CCCNC1)c1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(N[C@@H]1CCCN(Cc2ccccn2)C1)c1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (1 mL) and acetic acid (2 drops) was added to (R)-3-(2,3-dihydrobenzofuran-5-yl)-N-(piperidin-3-yl)-1H-indazole-5-carboxamide (12 mg) and picolinaldehyde (7 mg). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (28 mg) was added in one portion. The reaction was stirred overnight. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:21][C:22]1[C:23]([NH2:29])=[N:24][CH:25]=[N:26][C:27]=1Cl.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:29][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:22]=1[Br:21]
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Nc1ncnc(Cl)c1Br
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Yield: 52.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (300 mg, 1.12 mmol) was treated 5-bromo-6-chloropyrimidin-4-amine (373 mg, 1.79 mmol), cesium fluoride (340 mg, 2.24 mmol), N,N-diisopropylethylamine (0.974 mL, 5.59 mol) according to Preparation 13. The residue was purified using SP1® Purification System (0% to 10%, dichloromethane-methanol) to give 0.26 g (60% yield) of the title compound as a solid. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClC1C(CO)=CC(F)=C(Cl)N=1>>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Agent: OCc1cc(F)c(Cl)nc1Cl
Product: OCc1cccnc1Cl
Yield: 43.9 %

Procedure:
Compound 12A (0.20 g, 44%) was prepared from 2-chloro-nicotinic acid (0.5 g, 3.17 mmol) using a procedure similar to the synthesis of 1A. HPLC Rt=0.77 min.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(Cl)cc4)cc3CC[C@@H]12
Yield: 75.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-chlorophenylboronic acid (122 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), followed by recrystallization from ethyl acetate, to give 166 mg (75%) of the title compound as a white solid. mp 192°. FDMS: m/e=339. α[D]589 =+76.14 (c=1.00, chloroform).
Reaction SMILES: [NH2:1][C:2]1([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[ClH:17]>[C].[Pd].CO>[ClH:17].[ClH:17].[NH2:1][C:2]1([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1
Reactant: CC1(N)CN(Cc2ccccc2)CC12CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(N)CNCC12CC2
Reaction time: 13 h
Yield: 80 %

Procedure:
Methanol (91 mL) was added to (−)-7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (16.2 g) for dissolution. To the solution, 5% palladium carbon (5.33 g, water content: 50%) and concentrated hydrochloric acid (15.8 mL) were added. A reaction vessel was purged with hydrogen gas, and the mixture placed in the reaction vessel was stirred for 13 hours. The catalyst was removed through filtration and washing with ethanol. All the organic layers were combined and concentrated under reduced pressure. Ethanol and isopropyl alcohol were added to the residue, and the mixture was concentrated under reduced pressure several times under azeotropic conditions. After azeotropy, isopropyl alcohol was added to the residue, and the mixture was stirred at room temperature so as to precipitate crystals. The crystals were collected through filtration and dried under reduced pressure, to thereby yield first crystals of the title compound (9.75 g, yield: 80%). Through elemental analysis, the obtained first crystals were found to be a dihydrochloride salt. To another residue obtained through concentration of the filtrate, methanol and isopropyl alcohol were added, and the mixture was cooled so as to precipitate crystals. The crystals were collected through filtration and dried under reduced pressure, to thereby yield second crystals of the title compound (1.41 g, yield: 120).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[F:8].B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(Br)c1
Agent: B
Solvent: C1CCOC1
Product: CNCc1ccc(F)c(Br)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of 1,1-dimethylethyl [(3-bromo-4-fluorophenyl)methyl]carbamate (0.755 g, 2.48 mmol) in THF (1 mL) was added BH3.THF (12.5 mL, 1.0 M in THF). The mixture was heated with a microwave at 80° C. for 30 min twice. The reaction was then quenched with HCl (10 mL, 1 N) slowly, after which the mixture was stirred for 2 h at room temperature, basified with NaHCO3 to pH ˜9, and extracted with EtOAc (50+20 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, concentrated to afford the title compound 0.52 g (96%). LC-MS m/z 218 (M+H)+.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][CH:35](O)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccc(Cl)cc1Cl)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1ccc(Cl)cc1Cl)O2

Procedure:
2-(2,4-Dichlorophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 625 mg of 2-(2,4-dichlorophenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.65 (d, 1H, J 2.2 Hz), 7.57 (d, 1H, J 8.4 Hz), 7.49 (dd, 1H, J 8.4, 2.2 Hz), 6.67-6.51 (m, 3H), 5.21 (dd, 1H, J 10.3, 2.1 Hz), 2.91 (m, 1H), 2.69 (m, 1H), 2.16 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N:18]([O-])=O.[Na+]>O.[Zn]>[CH2:15]([O:14][C:12]([CH2:11][CH2:10][CH2:9][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([NH2:18])=[CH:5][CH:4]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CCCN(C)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [Zn]
Solvent: O
Product: CCOC(=O)CCCN(C)c1ccc(N)cc1
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
Ethyl 4-(N-methylanilino)butyrate (J.C.S. Perkin I, 1972, 1803) (22 g) was dissolved by addition of conc. hydrochloric acid (60 ml) under ice-cooling. To the solution was added a solution of sodium nitrite (8 g) in water (10 ml) dropwise at 0° to 4° C. with vigorous stirring. The mixture was stirred at the same temperature for 30 minutes. Then zinc powder (30 g) was added at below 10° C. The resulting mixture was further stirred for 30 minutes at 15° C. The zinc was filtered off. The filtrate was made alkaline with sodium bicarbonate and then was extracted with ether. The ether layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel and developed with ethyl acetate/hexane (1:1) to obtain N-ethoxycarbonylpropyl-N-methyl-p-phenylenediamine (9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][C:3]=1[NH:17][C:18](=[O:33])[C@H:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C@@H:20]([CH3:25])[C:21]([F:24])([F:23])[F:22].S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:17][C:18](=[O:33])[C@H:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C@@H:20]([CH3:25])[C:21]([F:24])([F:23])[F:22]
Reactant: CCCC(CC(=O)OC)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCC(CC(=O)O)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
1.50 g (2.97 mmol) of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)hexanoate (diastereomer mixture) were dissolved in 5 ml of acetic acid, 5 ml of 30% strength sulphuric acid were added and the mixture was heated at reflux (bath temperature about 140° C.). After 1.5 h, a further 2.5 ml of acetic acid were added, and the reaction mixture was stirred under reflux for another 2.5 h. After cooling, the mixture was allowed to stand at RT overnight, then added to water and extracted three times with ethyl acetate. The combined organic phases were washed with 5% strength sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure, and the residue was dried under high vacuum. This gave 1.44 g of the target product (98.8% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Nc1c(F)cccc1C(=O)O
Agent: Br
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a suspension of 2-amino-3-fluorobenzoic acid (5 g, 32.2 mmol) in chloroform (200 mL) was added dropwise bromine (1.1 equiv.) in chloroform (125 mL) solution. The mixture was stirred at room temperature for 16 hrs. The resulting white solid was collected by filtration and washed thoroughly with methylene chloride until the filtrate was colorless. The solid was air-dried to give 9.6 g of white powder as HBr salt of 2-amino-5-bromo-3-fluorobenzoic acid (95% yield). ES/MS m/z 234/236 (MH+).
Reaction SMILES: [OH:1][CH:2]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][C:4](=[O:16])[N:3]1[CH3:17].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[OH:1][CH:2]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:6]=2[CH2:5][C:4](=[O:16])[N:3]1[CH3:17]
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(O)N(C)C(=O)C3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC(=O)N(C)C1O

Procedure:
The title compound is prepared from a mixture of 1,2-dihydro-1-hydroxy-2,8-dimethyl-4H-pyrido[4,3-b]indol-3(5H)-one, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:25])[CH:6]=[C:7]([CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]([Cl:37])=[CH:34][CH2:35]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH2:4][C:5]([CH3:6])([O:25][CH2:35][CH:34]=[C:33]([Cl:37])[Cl:32])[CH:24]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)[CH3:2]
Reactant: CCc1cc(O)cc(C)c1OCCCOc1ccc(C(F)(F)F)cn1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1=C(OCCCOc2ccc(C(F)(F)F)cn2)C=CC(C)(OCC=C(Cl)Cl)C1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 0.7 g of 3-ethyl-5-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]phenol and 0.27 g of potassium carbonate, to which a solution of 0.34 g of 1,1,3-trichloropropene dissolved in 5 ml of N,N-dimethylformamide was added dropwise, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined diethyl ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude produce was subjected to silica gel chromatography, which afforded 0.6 g of 3-ethyl-1-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (65% yield), nD23.0 1.5188.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[CH2:9][CH:10]([OH:12])[CH3:11])[CH:2]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][CH:10]([CH2:9]/[CH:8]=[CH:7]/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH3:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)C/C=C/c1cccnc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)C/C=C/c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
To a stirred solution of (4E)-5-(3-pyridyl)-4-penten-2-ol (5.00 g, 30.67 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride (8.77 g, 46.01 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-hexane (3:7, v/v). Selected fractions were combined and concentrated by rotary evaporation to give a viscous, brown oil (5.83 g, 60.1%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15](CC2C=CC(OC)=CC=2)[C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:37][C:38]([NH2:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:37][C:38]([NH2:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2ccc(N3CCOCC3)nc2)c2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)nc2)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3 %

Procedure:
3.0 mg of 4-benzylamino-6-[4-methoxybenzyl-(6-morpholinopyridin-3-yl)amino]pyridine-3-carboxyamide was dissolved in 0.5 mL of methylene chloride, to which 0.5 mg of trifluoroacetic acid was added, stirred at room temperature for 4 hours, and further heated at reflux at 70° C. for 8 hours. After cooling, the solvent was evaporated, saturated sodium bicarbonate in water was added to the residue, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) and silica gel thin layer chromatography (chloroform:ammonium-saturated methanol=10:1) to obtain 1.2 mg (4 steps, yield 3%) of the title compound as a light brown solid.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][N:6]=[C:7]([NH2:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1.N1C=CC=CC=1.O>C(Cl)Cl>[CH3:16][C:11]1[CH:10]=[C:9]([CH2:8][C:7]2[NH:17][S:1](=[O:2])[O:5][N:6]=2)[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CC(N)=NO)cc1C
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(CC2=NOS(=O)N2)cc1C
Reaction time: 3 h
Yield: 32 %

Procedure:
Thionyl chloride (17.7 mL, 0.24 mol) in methylene chloride (40 mL) was added dropwise to a solution of N'-hydroxy-2-(3,4-dimethylphenyl)ethanimidamide (10.8 g, 0.06 mol), methylene chloride (130 mL) and pyridine (9.8 mL, 0.12 mol) at 5° C. After 3 hours, the mixture was poured into water and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Recrystallization from ethyl ether afforded the desired product (4.3 g, 32%) as an off-white solid, m.p. 127°-130° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=[O:10])=[CH:5][CH:4]=1.[C:20]([CH2:22][C:23]([NH2:25])=[S:24])#[N:21]>N1CCCCC1.C(O)C>[CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:10])[NH:25][C:23](=[S:24])[C:22]([C:20]#[N:21])=[C:11]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: N#CCC(N)=S
Reactant: CN(C)c1ccc(C(=O)C(=O)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc(C2(O)NC(=S)C(C#N)=C2c2ccccc2)cc1

Procedure:
A mixture of 10.1 g. p-dimethylaminobenzil, 3.2 g. cyanothioacetamide, 10 drops of piperidine and 100 ml. ethanol is stirred for 12 hours at ambient temperature. The precipitated product is filtered off with suction, washed with chloroform and recrystallised from ethanol. There are obtained 6.0 g. of the desired product in the form of yellow crystals; m.p. 184°-185° C. (decomp.).