Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.C[Si]([C:13]#[N:14])(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc(Br)cc1
Product: N#Cc1cc(Br)ccn1

Procedure:
The title compound was prepared from 4-bromo-pyridine-1-oxide (Rec. Trav. chime, 1951, 70, 581) and trimethylsilyl cyanide, using the procedure described in Chem. Pharm. Bull., 1985, 33, 565, and obtained as a solid (49% yield), m.p. 88°-93° C. Rf 0.53 (SS 11). Found: C,39.15; H,1.50; N,15.07. C6H3BrN2 requires C,39.37; H,1.65; N,15.30%.
Reaction SMILES: [Cl:1]C1C=CC(C#N)=C(N2CCOCC2)N=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[C:19](N2CCOCC2)[N:18]=1.P(Cl)(Cl)(Cl)=O.N1C=CC=CC=1>C(#N)C>[Cl:1][C:19]1[N:18]=[C:17]([Cl:16])[CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)c1ccc(Cl)nc1N1CCOCC1
Reactant: N#Cc1ccc(Cl)nc1N1CCOCC1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)c1ccc(Cl)nc1Cl
Yield: 91 %

Procedure:
Experimental procedure for synthesis of 6-chloro-2-morpholin-4-yl-nicotinonitrile (3) is the same as that described in synthesis of (D46). The reaction of 6-chloro-2-morpholin-4-yl-nicotinamide (2) (2.49 g) with phosphorus oxychloride (2.7 mL, 29 mmol) and pyridine (4.7 mL, 58 mmol) in acetonitrile (60 mL) gave a crude black oil upon workup. The black oil was fractionated by dry-pack column chromatography as follows: the oil was diluted with CH2Cl2 (300 mL) followed by the addition of silica gel (20 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (60 g, 230-400 mesh) and eluted with 10% EtOAc/hexanes. Pure fractions were combined and concentrated to give the title compound as a white solid (1.97 g, 91% isolated yield over 2 steps with respect to 1.85 g of compound 1). TLC eluted with 50% EtOAc/hexanes and rendered with UV lamp gave Rf=0.8; 1H NMR 400 MHz (CDCl3) δ 7.69 (d, J=8.2 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 3.85-3.77 (8H).
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:16]2[NH2+:15][C:14]3[C:9](=[CH:10][C:11]([Br:17])=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[C:5](Br)[CH:4]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[Br-:17].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:5]2[CH:4]=[C:3]([CH3:2])[C:16]3[C:7]([CH:6]=2)=[S+:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH:10]=2)[N:15]=3)[CH2:22][CH2:21]1
Reactant: Cc1cc(Br)cc2c1[NH2+]c1ccc(Br)cc1S2
Reactant: CN1CCNCC1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(N2CCN(C)CC2)cc2[s+]c3cc(N4CCN(C)CC4)ccc3nc12
Reaction time: 3 h

Procedure:
To a solution of 1-methyl-3,7-dibromophenothiazinium bromide (300 mg, 0.7 mmol) in chloroform (15 mL) kept under argon, 1-methylpiperazine (350 mg, 3.5 mmol) was added (30 min) with vigorous stirring. The mixture was stirred for 3 h and after that extracted once with aqueous HBr (10 mL, 1% v/v) and twice with water. The organic layer was dried (Na2SO4), concentrated and dried under vacuum. Compound was purified by flash chromatography (solvent system—dichloromethane-methanol).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:8]=2[C:9](=[O:11])[CH:10]=1)(OC)=[O:2].O.[BH4-].[Na+].CC(C)=O>CO>[OH:2][CH2:1][C:5]1[O:6][C:7]2[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:8]=2[C:9](=[O:11])[CH:10]=1
Reactant: COC(=O)c1cc(=O)c2ccc(S)cc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: O=c1cc(CO)oc2cc(S)ccc12
Reaction time: 2 h

Procedure:
The ester from Step 4 (3.0 g) in suspension in methanol (20 ml) and water (40 ml) at 0° was stirred vigorously during the portionwise addition of NaBH4 (1.8 g). The mixture was stirred for 2 hours at 5°. Acetone (1 ml) was added followed by acidification with 1N HCl and extraction with methanolchloroform (1:9, 3×50 ml). The combined extracts were dried (Na2SO4), reduced to dryness in vacuo and the residue was recrystallized from methanolethyl acetate to provide the title compound, m.p. 139°-140°.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([CH3:17])([CH2:14][CH:15]=[CH2:16])[CH2:12][OH:13].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.[OH-].[Na+].[NH2:32][C@H:33]([C:38]([OH:40])=[O:39])[C:34]([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1>[CH3:10][C:11]([CH3:17])([CH2:14][CH:15]=[CH2:16])[CH2:12][O:13][C:19]([NH:32][C@H:33]([C:38]([OH:40])=[O:39])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:21]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: C=CCC(C)(C)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 181.7 %

Procedure:
DIPEA (2.48 g, 19.2 mmol) was added dropwise to a 0° C. solution of 2,2-dimethylpent-4-en-1-ol (2.24 g, 19.6 mmol) and triphosgene (2.56 g, 8.64 mmol) in 60 mL dioxane. The resulting white suspension was stirred for 5 min at 0° C., then allowed to warm to 25° C. over 1 h. The suspension was cooled to 0° C. with an ice bath, followed by addition of 1 N NaOH (19.2 mL) and L-tert-butylglycine (2.52 g, 19.2 mmol). The reaction mixture was warmed to 25° C. and stirred for 72 h. The dioxane was removed in vacuo and the reaction mixture was basified to pH 12 with 1 N NaOH. The aqueous layer was extracted with dichloromethane (3×150 mL), then acidified to pH˜1 with 6 N HCl. The aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic layers were dried over MgSO4 and concentrated to give N-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine as a white powder (4.26 g, 827% yield). LRMS (ESI) m/z 272 [(M+H)+; calcd for C14H26NO4: 272].
Reaction SMILES: [NH2:1][NH2:2].C([Li])CCC.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O>C1COCC1>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[N:1][NH2:2])[NH2:22])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: NN
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2ccc(C(N)=NN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a stirring solution of hydrazine (3.32 mL, 3.32 mmol, 1 M in THF) in THF (5 mL) at −78° C. was added butyllithium (1.28 mL, 3.05 mmol, 2.5 M in hexanes). After 30 min, a solution of 4′-methyl-[1,1′-biphenyl]-4-carbonitrile (535 mg, 2.77 mmol) in THF (5 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto water (150 mL) and stirred vigorously for 1 h. The precipitate was isolated by filtration using water (2×20 mL) and isohexanes (3×20 mL) to wash the filter cake. The solid was dried under vacuum to yield 560 mg (90%) of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazonamide INT-39 as a fine yellow solid. LCMS-ESI (m/z) calculated for C14H15N3: 225; found 226 [M+H]+, tR=1.15 min (Method 10).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][C:29]=4[O:41][CH3:42])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:43])[N:15]=1)=[O:13])[CH3:2].O>CN(C)C=O.FC(F)(F)C(O)=O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:40]=[CH:39][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=4[O:41][CH3:42])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:43])[N:15]=1)=[O:13])[CH3:10]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(C(=O)OC(C)(C)C)cc3OC)nc1-2
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(C(=O)O)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl 4-({3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-8-yl}amino)-3-methoxybenzoate (500 mg, 0.857 mmol) in dimethylformamide (8 mL), trifluoro acetic acid (0.600 mL), were added. The mixture was stirred at room temperature overnight. Water was added and the mixture extracted with ethylacetate. The organic solvent evaporated to dryness. To give 450 mg of the title compound in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([N:14]1[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16][CH2:15]1)=[CH:9]2)([O-])=O>O.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([N:14]1[CH:20]3[CH2:19][CH2:18][N:17]([CH2:22][CH2:21]3)[CH2:16][CH2:15]1)=[CH:9]2
Reactant: O=[N+]([O-])c1cccc2cc(N3CCN4CCC3CC4)cnc12
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc2cc(N3CCN4CCC3CC4)cnc12
Temperature: 40 °C

Procedure:
0.8 g (2.7 mmol) of 4-(8-nitroquinolin-3-yl)-1,4-diazabicyclo[3.2.2]nonane, in suspension in a mixture of 8 ml of water and 4 ml of acetic acid, is introduced into a 25 ml three-necked round-bottomed flask and the suspension is heated at 40° C.; 0.43 g (7.7 mmol) of iron are then added, in two portions, and the mixture is heated at 50° C. for 1 h.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:27]COC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]1)=[O:4].[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2>>[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[N:46]([CH2:2][C:3]([N:5]4[CH2:11][CH2:10][CH2:9][N:8]([C:12]5[CH:17]=[CH:16][C:15]([C:18]([OH:27])([C:23]([F:25])([F:26])[F:24])[C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=5[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]4)=[O:4])[C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CBr)CC1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCCO4)C2=O)CC1

Procedure:
2-Bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-1,4-diazepan-1-yl)ethanone and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]\[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10].[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27]C.[O:29]1CCCC1>C(O)(=O)C>[O:29]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:10][CH2:9][CH:8]=[C:7]([CH3:11])[CH2:6][CH2:5][CH:4]=[C:3]([CH:2]=[O:1])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: C1CCOC1
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C/CC/C(C)=C/CO)CO
Reactant: CCCCCC
Solvent: CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C=O)=CCCC(C)=CCOC1CCCCO1
Temperature: 0 °C

Procedure:
In 300 ml of anhydrous tetrahydrofuran was suspended 58.6 g of (E)-4-methyl-6-(2'-tetrahydropyranyloxy)-4-hexen-1-yltriphenylphosphonium iodide [R. Tschesche and J. Reden, Ann. 853 (1974)]. To this suspension was added dropwise the equimolar amount of a n-butyllithium-hexane solution at -20° C in a stream of nitrogen. The mixture was stirred, and to this was further added 25.4 g of (E)-1,1-dimethoxy-6,10-dimethyl-5,9-undecadien-2-one (prepared in Referential example 1) in 50 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 hours, and, after addition of ice-water, extracted with n-hexane. The so obtained crude oil was suspended in 300 ml of 50% acetic acid, and stirred at room temperature for 2 hours. There was obtained 28.0 g of 7-formyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol tetrahydropyranyl ether from the n-hexane extract. The obtained product was dissolved in 200 ml of ethanol and, after addition of 1.5 g of sodium borohydride, stirred for 2 hours under ice-cooling. This was treated with dilute acetic acid and, after addition of water, extracted with n-hexane. The resultant was dissolved in 200 ml of methanol. To this was added 200 mg of p-toluenesulfonic acid, and the resulting solution was allowed to stand overnight and neutralized with an aqueous sodium hydrogencarbonate solution. After evaporation of the methanol, the residue was extracted with ether, and from the extract was obtained an oil. The so obtained oil was then chromatographed on silica gel to yield 18.2 g of a mixture of the (E,Z,E) and (E,E,E) isomers of 7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol.
Reaction SMILES: [CH3:1]CN=C=NCCCN(C)C.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][C:35](O)=[O:36])[C:29]2=[O:38])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C1COCC1.ClCCl>[CH3:1][C:35]([CH2:34][N:30]1[CH2:31][CH2:32][CH2:33][N:28]([CH:25]2[CH2:24][CH2:23][N:22]([C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])[CH2:27][CH2:26]2)[C:29]1=[O:38])=[O:36]
Reactant: O=C(O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
WSC (0.39 g) was added to a solution of [3-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-2-oxotetrahydropyrimidin-1(2H)-yl]acetic acid (0.70 g) obtained in Example 36a), a solution of methylamine in THF (1.85 mL) and HOBt (0.31 g) in THF/dichloromethane (1/1, 30 mL) and the mixture was stirred at room temperature overnight. The solvent were distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain the title compound (0.70 g, 97%) as a white powder.
Reaction SMILES: N[C:2]1[S:6][C:5]([C:7]([O-:9])=[O:8])=[C:4]([I:10])[C:3]=1[C:11]#[N:12].[I:13]CI.N(OCCC[CH2:22][CH3:23])=O>C(#N)C>[C:11]([C:3]1[C:4]([I:10])=[C:5]([C:7]([O:9][CH2:22][CH3:23])=[O:8])[S:6][C:2]=1[I:13])#[N:12]
Reactant: ICI
Reactant: N#Cc1c(N)sc(C(=O)[O-])c1I
Reactant: CCCCCON=O
Solvent: CC#N
Product: CCOC(=O)c1sc(I)c(C#N)c1I
Temperature: 38 °C
Yield: 83.5 %

Procedure:
To a solution of ethyl 4-cyano-5-[(2,4-dimethoxybenzyl)amino]-3-iodothiophene-2-carboxylate (4.50 g, 9.53 mmol) in dichloromethane (100 mL) at room temperature was added trifluoroacetic acid (22.5 mL, 292 mmol). The mixture was then stirred at room temperature for 10 minutes. The solvent was evaporated and the excess trifluoroacetic acid was removed by azeotroping with toluene. The crude material was diluted with ethyl acetate, then treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate five times and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield ethyl 5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 88%). LCMS: (FA) ES+, 323. 1H NMR (400 MHz, d6-DMSO) δ: 8.18 (s, 2H), 4.20-4.16 (m, 2H), 2.50-2.48 (m, 3H). To a suspension of 5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 8.85 mmol) in acetonitrile (46.2 mL) under argon was added diiodomethane (2.49 mL, 31.0 mmol). The mixture was heated to 38° C. for 30 minutes, then amyl nitrite (2.59 g, 22.1 mmol) was added dropwise over 5 minutes. The reaction was slowly allowed to cool to room temperature then the mixture was concentrated and column chromatography was performed to yield the title compound (3.20 g, 79%). LCMS: (FA) ES+, 434. 1H NMR (400 MHz, d6-DMSO) δ: 4.33-4.27 (m, 2H), 2.51-2.47 (m, 3H).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12]C[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](OC)=[NH:21])[CH:15]=2)([CH3:13])[CH:9](C)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:25]([NH:27][NH2:28])=O.[CH2:29](O)[CH3:30]>CO>[NH3:7].[CH2:1]([N:7]1[CH2:8][CH2:9][C:10]([CH3:13])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[CH:25][NH:27][N:28]=3)[CH:15]=2)[CH:29]([CH3:30])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CCC(C)(c2cccc(C(=N)OC)c2)C(C)C1
Reactant: CCO
Reactant: NNC=O
Solvent: CO
Product: CCCCCCN1CCC(C)(c2cccc(-c3nc[nH]n3)c2)C(C)C1
Product: N
Temperature: 100 °C
Yield: 63 %

Procedure:
To a solution of 1-hexyl-4-(3-(methoxycarbonimidoyl)phenyl)-3,4-dimethylpiperidine (Preparation 10, 200 mg, 0.35 mmol) in methanol (10 mL) was added a solution of formic acid hydrazide (30 mg, 0.5 mmol) in ethanol (20 mL). The resultant mixture was heated to reflux for 2 h and then concentrated in vacuo. The residual oil was heated at 100° C. for 20 minutes and then allowed to cool. The residue was purified by chromatography eluting with dichloromethane:methanol:0.88 ammonia (300:8:1) to give the title compound as a colourless oil (75 mg, 63%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:2]=[CH2:3].[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[N:10]=[C:9]([N:28]2[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]2)[N:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1nc(S(C)(=O)=O)nc(C(=O)OCC)c1OCc1ccccc1
Reactant: OCC1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOc1nc(N2CCC(CO)CC2)nc(C(=O)OCC)c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A solution of ethyl 6-(allyloxy)-5-(benzyloxy)-2-(methylsulfonyl)pyrimidine-4-carboxylate (1.911 g, 4.87 mmol) in THF (40 mL) was stirred with molecular sieves for 30 min. To this mixture was added piperidin-4-ylmethanol (1.683 g, 14.61 mmol) and the resulting mixture was stirred overnight at 70° C. The mixture was cooled to room temperature and diluted with ethyl acetate and washed with water followed by brine then dried (Na2SO4). Filtration followed by concentration gave a yellow oil that was purified by flash column chromatography (Biotage flash chromatography system; 0%-100%, 10 CV) to afford the title compound as a yellow oil (1.2043 g, 58% yield). 1H NMR (300 MHz, CDCl3) δ: 7.42-7.39 (2H, m), 7.35-7.27 (3H, m), 6.10-5.97 (1H, m), 5.42-5.34 (1H, m), 5.28-5.22 (1H, m), 4.91 (2H, s), 4.87-4.84 (2H, m), 4.72-4.63 (2H, m), 4.30 (2H, q, J=7.1 Hz), 3.50 (2H, t, J=5.8 Hz), 2.80 (2H, td, J=12.8, 1.8 Hz), 1.79-1.64 (3H, m), 1.28 (3H, t, J=7.1 Hz), 1.23-1.10 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7](CC1C=CC(OC)=CC=1)[CH:6]=[CH:5]2.C(OC([N:29]1[CH2:32][CH:31]([NH2:33])[CH2:30]1)=O)(C)(C)C.[ClH:34].C1C2C(=CC(NC3CCNCC3)=CC=2)C=CN=1>>[ClH:34].[NH:29]1[CH2:32][CH:31]([NH:33][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]3)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Agent: Cl
Agent: c1cc2cc(NC3CCNCC3)ccc2cn1
Product: O=c1[nH]ccc2cc(NC3CNC3)ccc12

Procedure:
6-(Azetidin-3-ylamino)-2H-isoquinolin-1-one hydrochloride was prepared by Buchwald Reaction starting from 6-Bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (13) and 3-Amino-azetidine-1-carboxylic acid tert-butyl ester. BOC deprotection was performed as described for Isoquinolin-6-yl-piperidin-4-yl-amine (48).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:13]([C:14]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=3[Cl:26])=[O:15])=[CH:12][NH:11][C:10]=12)(=[O:3])[CH3:2].[NH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:13]([C:14]([C:16]3[C:17]([Cl:26])=[CH:18][C:19]([C:20]([NH:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])=[O:22])=[CH:23][C:24]=3[Cl:25])=[O:15])=[CH:12][NH:11][C:10]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C(=O)O)cc3Cl)c[nH]c12
Reactant: NCCOCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C(=O)NCCOCCO)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichlorobenzoic acid (0.1 g, 0.25 mmol) was taken in a reaction vial. To it 2-(2-aminoethoxy)ethanol (0.029 g, 2.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.073 g, 3.8 mmol), 1-hydroxybenzotriazole (0.051 g, 3.8 mmol) and dimethylformamide (2 mL) were added. The whole reaction mixture was stirred at room temperature for overnight. Water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude mass which was purified by flash column chromatography to get 4-{[7-(acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-[2-(2-hydroxyethoxy)ethyl]benzamide (0.035 g, 29%).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:31])[C@H:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=CC=1)([O-])=O.[CH3:32][NH2:33]>C(Cl)Cl.C(O)C>[CH3:32][NH:33][C:11](=[O:31])[C@H:12]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (5.0 g, 11.9 mmol) in DCM at 0° C. was slowly added a solution of 8M methylamine (1.5 ml, 11.9 mmol) in ethanol. The reaction immediately turned bright yellow and was stirred for 0.5 h. The reaction was diluted with DCM (50 ml), washed with 10% sodium carbonate (1×50 ml), brine (2×50 ml) and dried over anhydrous magnesium sulphate. Filtration and evaporation gave a white residue which was crystallised from ethyl acetate/hexane to give N-benzyloxycarbonyl-L-phenylalanine methylamide (3.0 g, 81%) as a white crystalline solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: Cc1ccccc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cc1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methylbenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.