Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][NH:16][C:12]=2[N:13]=[CH:14][N:15]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:11]2[C:18]([I:1])=[CH:17][NH:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2[nH]cc(I)c12
Reaction time: 1 h
Yield: 99.2 %

Procedure:
N-Iodosuccinimide (11.6 g) was added to a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (7.52 g) in DMF (49 ml) at room temperature. The mixture was stirred at the same temperature for 1 hour, and water (150 ml) was added to the reaction mixture. The resulting precipitate was collected by filtration, washed with water, and dried to obtain the title compound as a light-yellow solid (13.57 g).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][CH2:12][O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(OCC)=O)C.[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[I:34])[CH:29]=O)[CH3:21].O>O1CCCC1>[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28](/[CH:29]=[C:14](\[O:13][CH2:12][CH3:11])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:31]=[CH:32][C:33]=1[I:34])[CH3:21]
Reactant: CCOC(=O)COCCP(=O)(OCC)OCC
Reactant: CCOCCOc1cc(C=O)ccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCOc1cc(/C=C(\OCC)C(=O)OCC)ccc1I
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
0.26 g (6.87 mmol) of sodium hydride is added portionwise to a solution at 0° C. of 1.75 g (6.87 mmol) of ethyl (diethoxyphosphoryl)ethoxyacetate (prepared according to Example 1b) in 20 mL of tetrahydrofuran. The reaction mixture is stirred for 45 minutes at room temperature and 2 g (6.25 mmol) of 3-(2-ethoxyethoxy)-4-iodobenzaldehyde in 10 mL of tetrahydrofuran are then added dropwise. The reaction is slightly exothermic, and the reaction mixture is maintained at a temperature of 25-30° C. with an ice-water bath. When the temperature has stabilized, the reaction mixture is stirred for 24 hours at room temperature. After addition of 50 mL of water, the reaction medium is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over sodium sulfate. After evaporating under vacuum, the crude product obtained is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture to give 61.2 mg of the (E) isomer of ethyl 3-[3-(2-ethoxyethoxy)-4-iodophenyl]-2-ethoxyacrylate, 1.56 g of a mixture of (Z) and (E) isomers and 270.3 mg of the isomer ethyl (Z)-3-[3-(2-ethoxyethoxy)-4-iodophenyl]-2-ethoxyacrylate in the form of yellow oils.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1.OOS([O-])=O.[K+]>CN(C=O)C.O.C([O-])([O-])=O.[K+].[K+]>[F:12][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]2[N:10]([CH3:11])[C:20]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: O=Cc1cncc(F)c1
Reactant: CNc1cc(C#N)c(F)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(F)c2)nc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-amino-2-fluoro-5-methylamino-benzonitrile (0.15 g, 0.00090 mol) and 5-Fluoro-pyridine-3-carbaldehyde (0.11 g, 0.0090 mol) in DMF (5 mL) and H2O (2 mL) was added OXONE® monopersulphate (0.19 g, 0.0012 mol). The reaction mixture was stirred at room temperature for 5 h, and was diluted with 10% K2CO3 solution to PH˜8-10 and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the crude compound, which was purified by column chromatography to obtain title compound 5-fluoro-2-(5-fluoropyridin-3-yl)-1-methyl-1H-benzimidazole-6-carbonitrile (398) as a brown solid. C14H8F2N4; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.47 (d, 5.4 Hz, 1H), 8.29 (d, J=9.6 Hz, 1H), 7.88 (d, J=9.6 Hz, 1H), 3.98 (s, 3H); MS (M+1): 271.1. HPLC purity: 99.44%.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2SC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>CN(C=O)C>[C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[NH:26][CH2:25][CH2:23][OH:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Reactant: NCCO
Solvent: CN(C)C=O
Product: N=c1c(S(=O)(=O)c2ccccc2)c(NCCO)nc2ccccn12
Temperature: 55 °C
Yield: 10 %

Procedure:
To a one dram vial was added 20 mg (0.0604 mmol) of 3-(benzenesulfonyl)-2-methylsulfanyl-pyrido[1,2-a]pyrimidin-4-ylideneamine and 1.1 equivalents of ethanolamine in 750 ml of DMF. The vial was fitted with a TEFLON® lined cap and heated to 55° C. over night. The resulting product was then purified on a reverse phase preparative HPLC (XTerra™ MS C18 5.0 mM, MeOH/H2O as the eluent) to give 23 mg of the title compound as a brown solid; 10% yield.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>CO>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][CH:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: C=CCN1CCN(c2ccc(N)nc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
300 mg (1.21 mmol) of 1-allyl-4-(6-nitropyridin-3-yl)piperazine from Example 15.1 were dissolved in 20 ml of methanol, after which 2.18 g (9.67 mmol) of tin(II) chloride dihydrate were added and the mixture was stirred at 70° C. for 2 hours. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and this mixture was made alkaline using a dilute aqueous solution of sodium hydroxide and extracted with ethyl acetate. The solid which had precipitated out was filtered off with suction. The phases were then separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated down to dryness, with 183 mg (69% of theory) of the title compound being obtained.
Reaction SMILES: COC1C=CC(C[N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:46][S:47]([CH:50]4[CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=CC=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:36][O:35][C:33]1[N:32]=[C:31]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:30]=[C:29]([O:28][CH:23]2[CH2:22][CH:21]3[N:25]([C:26](=[O:27])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]4[C:18]([C:44]([NH:46][S:47]([CH:50]5[CH2:52][CH2:51]5)(=[O:49])=[O:48])=[O:45])([NH:19][C:20]3=[O:43])[CH2:17]4)[CH2:24]2)[CH:34]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4cc(OC)nc(-c5ccccc5)n4)CN3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCCNC(=O)N3C2)nc(-c2ccccc2)n1
Yield: 8 %

Procedure:
Compound 6g was dissolved in a 1:2 mixture of TFA:DCM (24 ml) and stirred at RT for 1 h. NaHCO3 was added and the organic layer was separated of, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound (19 mg, 8% over two steps), MS (M+H)+639.
Reaction SMILES: [O:1]1[CH2:3][C:2]21[CH2:9][CH:8]1[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:5]([CH2:6][CH2:7]1)[CH2:4]2.C([O-])(O)=O.[Na+].C(OCC)(=O)C>O1CCCC1>[CH:3]([CH:2]1[CH2:4][CH:5]2[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH:8]([CH2:7][CH2:6]2)[CH2:9]1)=[O:1]
Reactant: O=C(OCc1ccccc1)N1C2CCC1CC1(CO1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CC1CC2CCC(C1)N2C(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of EXAMPLE 84A (3.5 g) in tetrahydrofuran (40 mL) was added boron trifluoride diethyl ether complex (0.82 mL). The mixture was stirred at 3-5° C. for 3 hours. Aqueous saturated NaHCO3 was added, followed by ethyl acetate (200 mL). The organic layer was separated, washed with water (twice) and concentrated to dryness. Toluene was added and the mixture was concentrated under vacuum to provide the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:5].[NH2:13][C:14]1[N:18]=[CH:17][NH:16][N:15]=1>C(O)CCC>[C:6]1([CH:4]2[CH2:5][N:18]3[CH:17]=[N:16][N:15]=[C:14]3[NH:13][C:3]2=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1nc[nH]n1
Reactant: C=C(C(=O)OC)c1ccccc1
Solvent: CCCCO
Product: O=C1Nc2nncn2CC1c1ccccc1
Yield: 18.9 %

Procedure:
A solution of 9.01 g (55.6 mmol) 2-phenyl acrylic acid methyl ester and 4.24 g (50.4 mmol) 3-amino-1,2,4-triazole in 41 ml n-butanol was refluxed for 24 hours. The solvent was removed under reduced pressure. The residue was treated with a small amount of ethanol and diethyl ether and cyclohexane were added. The diethyl ether is slowly removed under reduced pressure. The crude 6-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-on precipitated during evaporation, was isolated by filtration and washed with diethyl ether. 6-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-on was recrystallized from a small amount of ethanol. 2.04 g (19%) 6-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-on was isolated (m.p. 184-186° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]5)[C:24]([O:37][CH3:38])=[CH:23][C:22]=4[CH3:39])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[C:40]1(C)C=CC=C[CH:41]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32]6[N:35]=[C:40]([CH3:41])[O:34][N:33]=6)[CH2:30][CH2:31]5)[C:24]([O:37][CH3:38])=[CH:23][C:22]=4[CH3:39])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=N)NO)CC4)c(OC)cc3C)cc12
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5noc(C)n5)CC4)c(OC)cc3C)cc12

Procedure:
2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide was prepared from 2-(4-fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-N-methylbenzofuran-3-carboxamide under similar conditions as described but using PhMe as a solvent. The crude mixture was purified by preparative TLC (20×20 cm×500 um plates, 5% MeOH/CH2Cl2) to give the product, which was further purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 7.95-8.47 min. (UV detection at 220 nm). Analytical TLC Rf=0.38 (5% MeOH/CH2Cl2). 1H NMR (500 MHz, CD3OD) δ 7.97 (dd, J=7.93, 5.49, 2H), 7.87 (s, 1H), 7.62 (d, J=8.24, 1H), 7.58 (s, 1H), 7.33 (d, J=8.55, 1H), 7.27 (t, J=8.39, 2H), 7.11 (s, 1H), 4.05 (s, 3H), 2.96 (s, 3H), 2.54 (s, 3H), 2.36 (s, 3H), 1.60 (m, 2H), 1.45 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=555.34, HPLC Rt=1.735 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=7.75 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.93 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=11.98 min.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[N:18]([CH3:23])[N:19]=[C:20]([CH3:22])[CH:21]=2)[C:8]=1[CH3:24]>C1COCC1.CO>[CH3:23][N:18]1[C:17]([CH2:16][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:25])=[O:4])=[C:8]2[CH3:24])=[CH:21][C:20]([CH3:22])=[N:19]1
Reactant: COC(=O)Cc1c(C)n(Cc2cc(C)nn2C)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cn2c(C)c(CC(=O)O)c3cccnc32)n(C)n1
Reaction time: 18 h

Procedure:
1M Aqueous NaOH (0.5 mL) is added to a stirring solution of [1-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (29 mg, 0.09 mmol) in 1:1 THF/MeOH (2 mL). After 18 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 1, and the resulting precipitate collected by filtration to furnish [1-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=299.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[Cl:41][C:42]1[C:43]([C:52]([F:54])([F:53])[F:55])=[N:44][N:45]([CH2:48][C:49]([N:36]2[CH2:37][CH2:38][N:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=3)[CH2:34][CH2:35]2)=[O:50])[C:46]=1[CH3:47]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Trifluoromethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 7.38 (m, 1H), 7.11 (m, 3H), 5.00 (s, 2H), 3.79 (m, 2H), 3.73 (m, 2H), 3.27 (m, 2H), 3.23 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+H expected=455.0, found 455.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].N([O-])=[O:12].[Na+].FC(F)(F)C(O)=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:12])#[N:2]
Reactant: N#Cc1cccc(CN)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1cccc(CO)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
m-Cyanobenzylamine (13.2 g), sodium nitrite (10.4 g), and dimethylformamide (100 ml) were mixed together, and the mixture was vigorously stirred at room temperature. Trifluoroacetic acid (22.8 g) was added dropwise to the mixture over one hour. After completion of addition, the mixture was further allowed to react at 100° C. for one hour. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.9 g of m-cyanobenzyl alcohol (bp. 128-130° C./400 Pa) (yield 52%). The purity of the product was 98%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][CH2:8][CH2:9]Br.C(N(CC)CC)C>C(#N)C>[CH3:6][O:7][CH2:8][CH2:9][N:2]([CH2:3][CH2:4][OH:5])[CH3:1]
Reactant: COCCBr
Reactant: CNCCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCN(C)CCO
Yield: 31 %

Procedure:
A mixture of 2-(methylamino)ethanol (5.4 g, 72 mmol), 2-bromoethyl methyl ether (10 g, 72 mmol) and triethylamine (10 ml, 72 mmol) in acetonitrile (70 ml) was refluxed overnight. After cooling, the solid was filtered and the filtrate was evaporated. The residue was triturated with ether. The ether layer was separated and evaporated to give 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (3g, 31%).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([I:26])C(=O)C1>C(Cl)Cl>[OH:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]([I:26])=[CH:4][N:3]=1
Reactant: O=C(Nc1cccnc1O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: O=C(Nc1cc(I)cnc1O)OCc1ccccc1
Yield: 65.6 %

Procedure:
To a solution of benzyl (2-hydroxypyridin-3-yl)carbamate (16.1 g, 65.9 mmol) in DCM (500 mL) was added NIS (17.8 g, 79.1 mmol) and the mixture heated at reflux overnight. After cooling, the mixture was filtered to afford benzyl (2-hydroxy-5-iodopyridin-3-yl)carbamate (16 g, 65% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.72 (s, 1H), 7.29-7.40 (m, 5H), 5.21 (s, 2H); MS (ES) m/z 370 (M+H).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][CH:48]([CH3:53])[CH2:49][C:50](Cl)=[O:51].O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:50](=[O:51])[CH2:49][CH:48]([CH3:53])[CH3:47])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(C)CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 2.1 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.400 g, 0.66 mmol) in pyridine (4 mL) was added 3-methylbutanoyl chloride (0.100 mL, 0.80 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.005 g, 5% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 14.20 (br s, 1H), 13.43 (s, 1H), 10.08 (s, 1H), 8.69 (s, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 7.75 (d, 1H), 7.69 (t, 3H), 7.49 (t, 1H), 2.24 (d, 2H), 2.18 (m, 1H), 0.96 (d, 6H); ES-MS (m/z) 361 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:20][O+](C)C.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[NH:11])[O:10][CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=N)C(c1ccc(Cl)cc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.32 g (11 mmol) of 2-(4-chlorophenyl)-3-methylbutyramide in methylene chloride is added, at room temperature, 1.78 g (12 mmol) of trimethyloxonium tetrafluoroborate. After stirring overnight under nitrogen, the resulting solution is poured onto an ice-cold mixture of ether and aqueous sodium bicarbonate. The aqueous layer is discarded, and the ethereal layer is washed with cold water and dried over sodium sulfate. Filtration and concentration in vacuo affords methyl 2-(4-chlorophenyl)-3-methylbutanimidate.
Reaction SMILES: [CH3:1][C@H:2]([CH2:11][NH2:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].C(N([C@H](C1C=CC=CC=1)[C@@H](C)C(OC)=O)[C@H](C)C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][C@@H:2]([CH2:11][NH2:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4]
Reactant: C[C@H](CN)[C@@H](N)c1ccccc1
Agent: COC(=O)[C@H](C)[C@@H](c1ccccc1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Product: C[C@@H](CN)[C@H](N)c1ccccc1

Procedure:
The title compound was prepared as described in the example for the synthesis of the enantiomer, (1R,2R)-2-methyl-1-phenyl-1,3-propanediamine, from methyl(2R,3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-2-methyl-3-phenylpropionate (Davies et al., J. Chem. Soc. Chem. Commun. 1153-1155, 1993). The title compound was obtained as a crystallizing oil, MS (m/z): 165.3 (M+H)+; C10H16N2 requir. 164.3.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([CH:27]=[O:28])=[C:11]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][CH:41]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:12]([C@H:27]([C:36]3[CH:41]=[N:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[OH:28])=[C:11]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)Cc2nc(C3CCOCC3)c(C=O)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: FC(F)(F)c1ccc(Br)cn1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(F)(F)F)nc3)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 5-bromo-2-(trifluoromethyl)pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]2[O:16][C:17]3[C:23]([C:24]([O:26]C)=O)=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH3:29]>>[C:24]([C:23]1[C:17]2[O:16][C:15]([CH:13]3[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12]3)=[N:19][C:18]=2[CH:20]=[CH:21][CH:22]=1)(=[O:26])[NH2:29]
Reactant: COC(=O)c1cccc2nc(C3CN(C(=O)OCc4ccccc4)C3)oc12
Reactant: N
Solvent: O
Product: NC(=O)c1cccc2nc(C3CN(C(=O)OCc4ccccc4)C3)oc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Methyl 2-(1-(benzyloxycarbonyl)azetidin-3-yl)benzo[d]oxazole-7-carboxylate (280 mg, 0.76 mmol) was added to ammonia water (10 ml) and the mixture was stirred at 35° C. for overnight. Then the solid was filtered. 160 mg of benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)azetidine-1-carboxylate was obtained, yield 60%. LC-MS (ESI) m/z: 352 (M+1)+. (M+1)+,
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[CH2:16]([O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[NH:24][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)[CH3:15]
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: CCOc1cccc(N)c1
Product: CCOc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and m-phenetidine (65 μl, 0.486 mmol) similar to Example 11 and isolated as a light tan solid (116 mg, 78%). 1H NMR (CDCl3): 8.86-8.83 (m, 1H), 8.50 (d, J=8.1 Hz, 1H), 7.89-7.83 (m, 1H), 7.42-7.38 (m, 1H), 7.35-7.30 (m, 1H), 7.09 (s, 1H), 6.96-6.84 (m, 2H), 6.76 (d, J=3.3 Hz, 1H), 6.71 (s, 1H), 4.09 (q, J=7.2 Hz, 2H), 2.53 (s, 3H), 1.47 (t, J=7.1 Hz, 3H).