Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3][S:2]1.Cl.[CH3:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][NH2:15].P(C#N)(OCC)(OCC)=O>CN(C)C=O.O1CCCC1.C(N(CC)CC)C>[S:1]1[CH2:5][CH:4]([C:6]([NH:15][CH2:14][CH2:13][C:12]([O:11][CH3:10])=[O:16])=[O:8])[CH2:3][S:2]1
Reactant: COC(=O)CCN
Reactant: O=C(O)C1CSSC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)C1CSSC1
Yield: 9.4 %

Procedure:
The reaction was carried out as described in Example 97, but using 5 ml of a solution of 3.3 mmol of 1,2-dithiolane-4-carboxylic acid (prepared as described in Example 96) in anhydrous dimethylformamide, 5 ml of anhydrous tetrahydrofuran, 1.01 ml of triethylamine, 502 mg of β-alanine methyl ester hydrochloride and 0.55 ml of diethyl cyanophosphate. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate solution by evaporation under reduced pressure, and the residue was recrystallized from a 2:1 by volume mixture of ethyl acetate and hexane, to obtain 73 mg of the title compound as pale yellow crystals having an Rf value of 0.41 (silica gel thin layer chromatography; using a 2:1 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCOC(C)=O>CS(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1ccc2ncc(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cnc3ccc(C)cc3n2)c(OC)c1
Yield: 97.2 %

Procedure:
2-Chloro-7-methylquinoxaline (0.51 g, 2.86 mmol), prepared according to J. Chem. Soc. 1948 1310-1313, and (2,4-dimethoxyphenyl)methanamine (1.29 mL, 8.57 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mL EtOAc and extracted three times with 100 mL brine. The crude product was purified by flash chromatography on a 90 g silica gel cartridge with 20 to 80% EtOAc in hexane, 50 min, at 40 mL/min to afford N-(2,4-dimethoxybenzyl)-7-methylquinoxalin-2-amine (860 mg, 2.78 mmol, 97% yield).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[CH2:7]1[CH2:17][CH2:16][N:15]2[C:10](=[N:11][CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O:20][CH3:21])=[O:19]>CN(C=O)C.CC(=O)OCC.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd]>[CH2:9]([C:10]1[N:15]([CH2:16][CH2:17][C:7]2[CH:16]=[CH:17][CH:7]=[CH:8][CH:9]=2)[C:1](=[O:4])[C:13]2[C:12](=[C:12]([C:25]3[CH:26]=[CH:27][C:22]([C:18]([O:20][CH3:21])=[O:19])=[CH:23][CH:24]=3)[CH:13]=[CH:14][CH:14]=2)[N:11]=1)[CH3:8]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [CH2-]c1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc2c(-c3ccc(C(=O)OC)cc3)cccc2c(=O)n1CCc1ccccc1
Yield: 1038.4 %

Procedure:
The white crystal (3.7 g, 11.83 mmol) from step 1 mixed with Herrmann's palladacycle (0.166 g, 0.18 mmol), [(t-Bu)PH]BF4(0.206 g, 0.71 mmol), cesium carbonate (3.87 g, 11.82 mmol), and DBU (0.18 mL, 1.20 mmol) in DMF (30 mL) under Ar was added with 4-(carbomethoxy)phenylboronic acid (2.17 g, 11.82 mmol). The reaction mixture was irradiated with microwave 120 W to reflux for 20 min. After irradiation, the resulting mixture was evaporated to get oil residue. The residue suspended in EA (50 mL) was washed with water (3×50 mL). The EA layer dried over MgSO4 was evaporated to give title compound as beige solid (2.57 g, 52.7%). Rf=0.11 (EA/Hexane=1:4); 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.2 Hz, 3H), 2.62 (q, J=7.2 Hz, 2H), 2.97 (dd, J=7.6 Hz, 2H), 4.23 (dd, J=7.6 Hz, 2H), 7.18-7.27 (m, 5H), 7.45 (t, J=7.6 Hz, 1H), 7.69-7.71 (m, 2H), 7.74 (dd, J=7.6 and 1.2 Hz, 1H), 8.03-8.05 (m, 2H), 8.28 (dd, J=8.0 and 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 10.7, 28.0, 34.7, 45.3, 52.1, 121.2, 126.2, 126.9 (2C), 127.2, 128.7, 128.83, 128.85, 128.9, 130.2, 130.7, 134.8, 137.5, 138.0, 143.2, 144.3, 156.4, 162.3, 167.2;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccc(Cl)cc2)s1

Procedure:
prepared by reaction of 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(N(CC)CC)C.Cl[C:15]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1>CO>[Cl:1][C:18]1[CH:17]=[N:16][C:15]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[C:20]([CH:19]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: OC1CNC1
Reactant: COC(=O)c1cccnc1Cl
Reactant: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)cnc1N1CC(O)C1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
To a solution of azetidin-3-ol hydrochloride (637 mg, 5.82 mmol, commercially available from Matrix Scientific #011272) and trietylamine (1.69 ml, 12.11 mmol) in methanol (10 ml), methyl 2-chloropyridine-3-carboxylate (1 g, 4.84 mmol) was added and the mixture stirred at 150° C. under microwave irradiation 10 min (2 cycles of 5 min each). The residue obtained after solvent evaporation was purified by SPE-Si cartridge (10 g) eluting with a mixture cyclohexane/ethylacetate from 90/10 to 60/40. Collected fractions after solvent evaporation afforded the title compound (D62) (D004/099/1) (800 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:3]=1N.B(F)(F)[F:13].F.N([O-])=O.[Na+]>O>[F:13][C:3]1[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: FB(F)F
Reactant: Cc1cccc(C(C)C)c1N
Agent: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C(C)C)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
44.7 g (0.3 mole) of 2-methyl-6-isopropylaniline are added dropwise to 200 ml of 40% strength tetrafluoboric acid at 5° C., followed by a solution of 20.7 g of sodium nitrite in 20 ml of water. The mixture is stirred for 1 hour at 10° C. The precipitated diazonium tetrafluoborate is filtered off under suction and suspended in succession in 50 ml of ice water, 50 ml of cold ethanol and 50 ml of diethyl ether. The suspension is added dropwise to a flask preheated at 150° C. When the evolution of gas has ended, the product is obtained by distillation over a Claisen still (bath temperature 100° C., pressure 4 mbar, distillation temperature 41°-42° C.). 28 g (61%) of 2-fluoro-3-isopropyltoluene are obtained.
Reaction SMILES: S(=O)(=O)(O)O.O[C:7]1([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C-]#[N:21].[K+].[ClH:23].FC(F)(F)[C:26]([OH:28])=O>CO.C(OCC)C>[ClH:23].[O:19]=[C:16]1[NH:17][CH:18]=[C:13]([C:7]2([NH:21][CH:26]=[O:28])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:14]=[CH:15]1
Reactant: O=c1ccc(C2(O)CCCCC2)c[nH]1
Reactant: [C-]#N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: O=CNC1(c2ccc(=O)[nH]c2)CCCCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Concentrated sulfuric acid (150 ml) was added dropwise over 45 minutes to a suspension of 5-(1-hydroxycyclohexyl)-2(1H)-pyridinone (37.0 g) and potassium cyanide (370 g) in 770 ml of trifluoroacetic acid at 0° C. The resulting suspension was stirred at room temperature for 17 hours and then cooled to 0° C., and diethyl ether was added slowly. The solvent was decanted, and the solids were washed with diethyl ether. The product was then dissolved in methanol and neutralized with poly-4-vinylpyridine. The polymer was removed by filtration, and the filtrate was concentrated to yield a white foam, which was dissolved in methanol and acidified with ethereal HCl. The solvent was removed in vacuo to afford a foam (43.2 g) which was used in subsequent reactions without further purification.
Reaction SMILES: C([C:3]1[N:41]=[C:6]2[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33](C6C=CC=CN=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1)#C.[NH3:42].[CH2:43](O)[CH3:44]>C1COCC1>[C:11]1([C:9]2[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33]([C:44]6[CH:43]=[CH:8][CH:9]=[CH:10][N:5]=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)=[N:42][C:6]3[N:5]([N:4]=[C:3]([NH2:41])[N:7]=3)[CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCO
Reactant: C#Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 140 °C

Procedure:
To 500 mg 2-bromo-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described under example 53) in 3 ml THF and 5 ml ethanol are added 8 ml of a ammonia solution (25% in water). The reaction mixture is heated to 140° C. for 22 hours. The solvent is evaporated and the solid residue is stirred in diethyl ether/ethanol (9:1). The product is filtrated, dried and further purified by RP HPLC (water, 10 mM NH4COOH, pH 3.7/ACN) to yield the desired compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1.CS(C)=O>C(#N)C>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCc1cccnc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step F (2 mmol), and 3-aminomethylpyridine (4.2 mmol), in dimethylsulfoxide (7 mmol) and acetonitrile (15 mL) was stirred at 80° C. for 18 hours. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. The product crystallized from ethyl acetate and hexane (0.96g; 89%), m.p. 165-167° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:3]1.C(N(CC)CC)C.[C:30]([CH2:34][CH2:35][C:36](Cl)=[O:37])([O:32]C)=[O:31].O.[OH-].[Li+].Cl>C(Cl)Cl.O>[OH:22][C@@H:20]([C:9]1[N:8]([C@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:36](=[O:37])[CH2:35][CH2:34][C:30]([OH:32])=[O:31])[CH2:3]2)[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=1)[CH3:21]
Reactant: COC(=O)CCC(=O)Cl
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCNC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCC(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R)-1-{1-[(3S)-piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (30.0 mg, 0.0885 mmol) (Example 50, step 4) and triethylamine (37.0 μL, 0.266 mmol) in methylene chloride (0. 5 mL) was added 3-(carbomethoxy)propionyl chloride (12.0 μL, 0.0974 mmol). The resulting mixture was stirred at room temperature for 2 h. Water and dichloromethane were added and the layers separated. The organic was concentrated. The crude residue was taken up in methanol (0.5 mL), tetrahydrofuran (50 μL), and water (40 μL). Lithium hydroxide, monohydrate (18 mg, 0.44 mmol) was added and the mixture stirred at room temperature for 3 h. The mixture was made slightly acidic by adding 1N HCl then concentrated. The mixture was dissolved in dichloromethane, stirred, filtered and concentrated to give 37 mg of clean, crude acid. LCMS calculated for C19H23N4O4S (M+H)+: m/z=403.1. Found: 403.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH3:34][C@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][O:44][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:33])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:36]1
Reactant: C[C@@H]1CN(CCO)CCN1C
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)[C@H](C)C5)ccn34)c12
Temperature: 95 °C
Yield: 33 %

Procedure:
7-Fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 1, Step A), 0.300 g, 0.678 mmol), (R)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.536 g, 3.39 mmol), and potassium t-butoxide (0.456 g, 4.07 mmol) were combined in t-butanol in a pressure tube. The tube was sealed and warmed to 95° C. for 16 hours, then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (10% MeOH/DCM/0.5% NH4OH) of the crude material followed by trituration with ether gave 136 mg (33%) of the title compound. MS (APCI), positive scan, m/z=581.1 (M+H). [α]D=−5.3° (c=1.0, CHCl3).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH3-]C#N.[Na+].N>C(O)C.C(O)(=O)C>[CH:15]1([NH:18][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC1CC1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
1 g (5 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate is dissolved in 40 mL of ethanol with 10% of acetic acid. 0.28 mL (4.2 mmol) of cyclopropylamine is added. After 30 minutes, 0.53 g (36 mmol) of NaBH3CN is added and the reaction medium is stirred for one hour at room temperature. The reaction is stopped by addition of aqueous ammonia solution and the organic products are then extracted with ethyl acetate. The organic phase is dried and then evaporated. The crude product obtained is chromatographed on silica gel (eluent: 55/45 heptane/ethyl acetate). 0.8 g of tert-butyl 4-cyclopropylamino-piperidine-1-carboxylate in the form of a colourless oil is obtained in a yield of 79%.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:14]=23)=[C:8]([F:30])[CH:7]=1)=[O:4].[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.O.ClCCl>[Br:33][C:21]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][C:13]=2[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:31])[F:32])=[CH:7][C:8]=2[F:30])[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[CH:20]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc(NC(=O)C(F)(F)F)cc3F)ccnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(Cc3ccc(NC(=O)C(F)(F)F)cc3F)ccnc21

Procedure:
200 mg (0.38 mmol) of 2,2,2-trifluoro-N-{3-fluoro-4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]phenyl}acetamide and 68.5 mg (0.38 mmol) of N-bromo-succinimide in 8 ml of carbon tetrachloride are heated at reflux for 20 min. After cooling, the mixture is diluted with water and dichloromethane and extracted. The organic phase is separated off, dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.COC(C1N=C(CN2CCCC2)[N:13]([C:22]2[CH:27]=[CH:26][C:25](Cl)=[CH:24]C=2C(=O)C2C=CC=CC=2)N=1)=O.COC(C1N=C(CN2CCCCC2)N(C2C=CC(Cl)=CC=2C(=O)C2C=CC=CC=2)N=1)=O>>[NH:1]1[CH2:6][CH2:5][CH2:3][CH2:2]1.[NH:13]1[CH2:22][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1nc(CN2CCCC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: C1COCCN1
Agent: COC(=O)c1nc(CN2CCCCC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Product: C1CCNC1
Product: C1CCNCC1

Procedure:
By a procedure analogous to that of Example 1 there are obtained, with the use of 2.9 g (0.041 mole) of pyrrolidine and 3.0 g (0.041 mole) of piperidine, instead of morpholine, crude 1-(2-benzoyl-4-chlorophenyl)- 5-[(1-pyrrolidinyl)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester and crude 1-(2-benzoyl-4-chlorophenyl)-5-(piperidinomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, respectively.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:13][CH:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[I:23]I.C(OCC)(=O)C.C1C=CC=CC=1>C(Cl)Cl>[CH2:10]([O:9][C:8]([N:7]([CH2:13][C@H:14]1[O:20][C@@H:18]([CH2:19][I:23])[CH2:17][CH2:16][CH2:15]1)[CH2:6][C:5]1[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=1)=[O:12])[CH3:11].[CH2:10]([O:9][C:8]([N:7]([CH2:13][C@@H:14]1[O:20][C@@H:18]([CH2:19][I:23])[CH2:17][CH2:16][CH2:15]1)[CH2:6][C:5]1[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=1)=[O:12])[CH3:11]
Reactant: C=CCCCC(O)CN(Cc1ccc(F)cc1)C(=O)OCC
Reactant: II
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)N(Cc1ccc(F)cc1)C[C@@H]1CCC[C@H](CI)O1
Product: CCOC(=O)N(Cc1ccc(F)cc1)C[C@H]1CCC[C@H](CI)O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51 %
Yield: 17 %

Procedure:
To a solution of ethyl N-(p-fluorobenzyl)-N-(2-hydroxy-6-heptenyl)carbamate (1.0 g, 2.5 mmol) in methylene chloride (15 ml) was added iodine (1.26 g, 4.95 mmol) and the mixture was stirred at room temperature for 15 hours and then heated under reflux for further 7 hours. The reaction mixture was diluted with methylene chloride (50 ml) and washed successively with saturated aqueous sodium hydrogen carbonate (50 ml), 10% aqueous sodium thiosulfate (50 ml×2), saturated aqueous sodium hydrogen carbonate (50 ml) and saturated aqueous sodium chloride (50 ml), dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was chromatographed using silica gel column to give cis-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]-2-iodomethyltetrahydropyrane (560 mg, yield 51%) and trans-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]-2-iodomethyltetrahydropyrane (190 mg, yield 17%) from the fraction from ethyl acetate-benzene (1/30).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][CH3:12])=[N:6][CH:5]=1.[OH-].[Li+].CO>O1CCOCC1.O>[Br:10][C:8]1[C:7]([O:11][CH3:12])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cnc(OC)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COc1ncc(C(=O)O)cc1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
5-Bromo-6-methoxy-nicotinic acid methyl ester (W. J. Thompson et al., J. Org. Chem. 49 (1984), 5237-5243; 2.00 g, 8.13 mmol) was dissolved in dioxane (40 ml), lithium hydroxide (40 ml of a 1 M solution in water) was added and subsequently sufficient methanol to achieve complete dissolution. The mixture was stirred at 60° C. for 2 h. The methanol was evaporated in vacuo and the remaining mixture was acidified with 2 N hydrochloric acid and extracted with EA. The combined extracts were dried over sodium sulfate, filtered and evaporated to dryness to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[N:29][CH:28]=[CH:27]2.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:30]1[C:31]2[C:26](=[CH:25][C:24]([NH:23][C:11](=[O:13])[CH:10]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccsc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E47) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E48).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:21]([NH:28][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCNCc4ccccc4)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, benzylamine, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 20B, except that the reaction mixtures were poured directly onto a column and eluted with a step gradient consisting of dichloromethane and 5% methanol in dichloromethane. Purity by LC/MS=77%, [M+H]+=363.