Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](I)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].O1CCCC1.C1([Li])C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[N:38]/[S:39]([C:41]([CH3:44])([CH3:43])[CH3:42])=[O:40])=[CH:33][CH:32]=1.CO.C(O)(=O)C>>[C:41]([S:39]([NH:38][CH:37]([C:34]1[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][CH:35]=1)[C:4]1[C:3]([C:1]#[N:2])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][C:5]=1[C:14]([OH:16])=[O:15])=[O:40])([CH3:44])([CH3:42])[CH3:43]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1I
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Cl)cc1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)S(=O)NC(c1ccc(Cl)cc1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylic acid (1.44 g, 3.96 mmol, prepared as in WO2009/154741) was suspended in anhydrous tetrahydrofuran (80.0 mL, 986 mmol), sonicated under nitrogen atmosphere for 10 min, and cooled in an acetone-dry ice bath for 10 minutes. Phenyllithium (1.8M in n-butyl ether, 8.81 mL, 15.9 mmol) was added dropwise over 7 minutes. The suspension was stirred with cooling for 5 minutes, at which point the cooling bath was removed and the suspension was stirred without cooling for 7 minutes. Reaction mixture was recooled in an acetone-dry ice bath for 10 minutes, at which point a solution of N—[(E)-(4-chlorophenyl)methylene]-2-methylpropane-2-sulfinamide (2.91 g, 11.9 mmol) in anhydrous tetrahydrofuran (20.0 mL, 246 mmol) was added dropwise over 8 minutes, and the mixture was stirred with cooling for 30 minutes. The mixture was quenched with methanol (5.0 mL, 120 mmol) and then acetic acid (1.0 mL, 18 mmol), and allowed to warm to room temperature. The volatiles were removed in vacuo, and the residue was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with 2×EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via column chromatography (gradient elution: AcOH/MeOH/DCM, 0/0/100 to 0.5/4.5/95) afforded 3-{[(tert-butylsulfinyl)amino](4-chlorophenyl)methyl}-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a mixture of diastereomers. Major diastereomer: 1.19 g, yield 62.2%. (FA) ES+ 482; ES− 480; 1H NMR (400 MHz, CDCl3) δ 7.31-7.33 (m, 2H), 7.15-7.17 (m, 2H), 6.14 (br s, 2H), 3.87-3.89 (m, 4H), 3.60-3.63 (m, 4H), 1.21 (s, 9H). Minor diastereomer: (0.292 g, yield 15.3%). (FA) ES+ 482; ES− 480; 1H NMR (400 MHz, CDCl3) δ 7.26-7.34 (m, 4H), 6.29-6.38 (m, br, 2H), 3.84-3.86 (m, 4H), 3.56-3.60 (m, 4H), 1.35 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:13].Cl.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:20][C:19]=2[CH2:18][CH2:17]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:13])[C:28](=[O:29])/[CH:27]=[CH:26]/[C:21]1[CH:22]=[N:23][C:24]2[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: CNCc1cccc2c1ccn2C
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cccc2c1ccn2C)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 40 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of N-methyl(1-methyl-1H-indol-4-yl)methanamine (418 mg, 2.40 mmol), 3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid hydrochloride (617 mg, 2.42 mmol), HOBt (327 mg, 2.42 mmol) and DIPEA (1.71 mL, 9.82 mmol) in anhydrous DMF (40 mL) was added EDC hydrochloride (460 mg, 2.40 mmol). The mixture was stirred overnight at 40° C. Water (60 mL) was added and the solution was stirred for 1 h. The reaction mixture was extracted with CH2Cl2 (3×100 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated to give a red solid which was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford (E)-N-methyl-N-((1-methyl-1H-indol-4-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (320 mg, 36%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.64-10.61 (m, 1H), 8.36-8.32 (m, 1H), 8.07-7.98 (m, 1H), 7.56-7.51 (m, 1H), 7.37-7.23 (m, 3H), 7.19-7.09 (m, 1H), 6.92-6.79 (m, 1H), 6.49-6.48 (m, 1H), 5.05-4.87 (m, 2H), 3.78-3.77 (m, 3H), 3.01-2.82 (m, 5H), 2.54-2.52 (m, 2H); ESI MS m/z 375 [C22H22N4O2+H]+.
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]\[CH2:33][NH:34][OH:35])[CH:28]=[CH:29][CH:30]=1.Cl>C1COCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]/[CH2:33][N:34]2[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:35]2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC/C(=C/CNO)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Reactant: O=C=NC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC/C(=C\Cn1oc(=O)[nH]c1=O)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
N-(Chlorocarbonyl)isocyanate (0.12 ml, 1.5 mmol) was added dropwise to a cold (-5° C.) mixture of (Z)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-hydroxylamine (0.65 g, 1.5 mmol) in THF (10 ml). The mixture was stirred for 30 minutes, then poured into HCl (1N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 /MeOH) silica gel (hexane/EtOAc 2/1) gave a white solid (0.48 g, 64% yield, mp 126°-127° C.).
Reaction SMILES: [ClH:1].C(O[N:5]=[CH:6][C:7]1[CH:22]=[CH:21][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=1)C.[Cl-].[NH4+:24].N>C(O)C>[ClH:1].[C:6]([C:7]1[CH:22]=[CH:21][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=1)(=[NH:5])[NH2:24]
Reactant: [NH4+]
Reactant: CCON=Cc1ccc(OCCCCC(=O)OCC)cc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)CCCCOc1ccc(C(=N)N)cc1
Temperature: 25 °C
Yield: 106.1 %

Procedure:
A mixture of ethyl 5-[4-{1-(ethoxy)iminomethyl}phenoxy]valerate hydrochloride (28.2 g), ammonium chloride (4.8 g), ethanol solution of ammonia (42 ml) in ethanol (300 ml) was stirred and refluxed for 15 hours. After cooled to room temperature, the mixture was filtrated, and the filtrate was evaporated in vacuo, and the resulting precipitate was washed with diethyl ether to give ethyl 5-(4-amidinophenoxy)valerate hydrochloride (27.28 g).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH:13]([CH3:17])[CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:6]([CH:13]([CH3:17])[CH2:14][CH2:15][O:16][S:1](=[O:4])(=[O:3])[NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(CCO)Oc1ccccc1
Reactant: NS(=O)(=O)Cl
Product: CC(CCOS(N)(=O)=O)Oc1ccccc1
Yield: 67 %

Procedure:
The title compound was prepared by procedures of Example 16 from sulfamoyl chloride and 3-phenoxy-1-butanol. The viscous oil obtained was purified by high pressure chromatography using a Waters Associates Prep LC/System 500A; PrepPAK 500® silica and methylene chloride as eluting agent at a flow rate of 200 ml/min. Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give 12.7 g (67%) of title compound as a yellow, viscous oil.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:10][CH2:9][CH2:8][N:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCCN1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
Add NaH (3.2 g, 80 mmol) portionwise to a 0° C. solution of 2-pyrrolidin-1-yl-ethanol (9.4 mL, 80 mmol) in DMF (180 mL). Stir the reaction 15-20 min until gas evolution ceases. Add a solution of 1-chloro-2-methoxy-4-nitro-benzene (15.0 g, 80 mmol) in DMF (100 mL) via cannula. Warm the reaction to 130° C. and stir for approximately 18 h. Cool to RT and dilute with EtOAc (300 mL). Wash with water (2×100 mL). Extract the organic layer with 1 N HCl (3×150 mL). Wash this acidic layer with EtOAc (100 mL) then basify by adding 1 N NaOH (500 mL) until pH=8-9. Extract the now basic aqueous layer with CH2Cl2 (3×150 mL). Dry the organic layer over Na2SO4 and concentrate to provide 8.5 g (40%) of the desired product as an orange solid. MS/ES m/z 267.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]#[CH:20].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.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.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:20]#[C:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12]
Reactant: C#CCOCCOC
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COCCOCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.6 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (1.0 g, 3.36 mmol) and 3-(2-methoxyethoxy)prop-1-yne (766 mg, 6.72 mmol) in ethyl acetate (12 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, and then treated with bis(triphenylphosphine) palladium(II) dichloride (236 mg, 10 mol %) followed by copper(I) iodide (64 mg, 10 mol %) and diisopropylamine (681 mg, 6.74 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours and then filtered through Celite. The filtrate was purified by column chromatography on silica using a 1:1 mixture of methyl tert-butyl ether and iso-hexane as eluent to give 5-chloro-7-[3-(2-methoxyethoxy)prop-1-yn-1-yl]-1,3-benzodioxol-4-amine (816 mg, 86%) as a dark orange oil; solidified on standing; NMR Spectrum: (CDCl3) 3.40 (s, 3H), 3.58 (m, 2H), 3.74 (m, 2H), 4.06 (s, 2H), 4.42 (s, 2H), 6.01 (s, 2H), 6.88 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[NH:12][C:11](=[S:22])[NH:10]2)=[CH:5][CH:4]=1.[Na].[CH2:24](I)[CH3:25].O>CO.CN(C)C=O>[CH2:24]([S:22][C:11]1[NH:12][C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)[CH3:25]
Reactant: COc1ccc([C@H]2NC(=S)N[C@H]2c2ccc(OC)cc2)cc1
Reactant: CCI
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCSC1=N[C@@H](c2ccc(OC)cc2)[C@@H](c2ccc(OC)cc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12 g of cis-4,5-bis-(p-methoxyphenyl)-imidazolidine-2-thione are added to a solution of 0.88 g of sodium in 13 ml of methanol. The mixture is then diluted with 200 ml of dimethylformamide and left to stand overnight, 4 ml of ethyl iodide are added and the mixture is stirred for 5 hours at room temperature and poured into 300 ml of water. The crystals which have precipitated out are filtered off with suction and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated and the residue is dissolved in acetone. The acetone solution is rendered weakly acid with methanolic hydrochloric acid (4.5μ) and the cis-2-ethylthio-4,5-bis-(p-methoxyphenyl)-imidazoline hydrochloride which has precipitated is filtered off. In order to liberate the base, this hydrochloride is treated with 2 N sodium hydroxide solution and the crude base is then rcrystallised from isopropanol/petroleum ether. cis-2-Ethylthio-4,5-bis-(p-methoxyphenyl)-imidazoline with a melting point of 92°-93° is obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(#N)C>[Br-:14].[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N+:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(Oc2cccnc2)cc1
Solvent: CC#N
Product: CCOC(=O)C[n+]1cccc(Oc2ccccc2)c1
Product: [Br-]

Procedure:
To a solution of 17.1 g of 3-phenoxypyridine [J. Amer. Chem. Soc 59, 297 (1937)] in 100 ml of acetonitrile is added 16.7 g of ethyl bromoacetate and the solution is refluxed for 8 hours. The resulting mixture is concentrated at reduced pressure and the crystalline solid is isolated by filtration to yield 1-(2-ethoxy-2-oxoethyl)-3-phenoxypyridinium bromide; mp 125°-126° C. after recrystallization from acetonitrile-diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]([C:18]3[CH:27]=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[C:16](=[O:17])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:31]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:31])[N:15]([C:18]3[CH:27]=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[C:16](=[O:17])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]n(-c3cnc4ccccc4n3)c(=O)c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (prepared according to the method of Example 75, Step A, 250 mg, 0.68 mmol) in dimethylformamide (2 mL) at 0° C. with stirring under nitrogen was added sodium hydride (60% dispersion in mineral oil, 41 mg, 1.02 mmol). After 10 min, iodomethane (51 μL, 0.82 mmol) was added. This mixture was allowed to stir at 0° C. for 2 h, quenched by addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (4×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (40% ethyl acetate/hexanes) to give 164 mg (63%) of the title compound of Example 75, Step B as a yellow foam. 1H NMR (CDCl3, 250 MHz) δ 9.71 (s, 1H), 8.15 (dd, 1H), 8.02 (m, 1H), 7.80-7.70 (c, 2H), 4.29 (s, 2H), 4.14 (t, 2H), 3.79 (s, 3H), 2.72-2.67 (c, 2H), 1.50 (s, 9H); MS (APCI) 382 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:29]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 3.7 g of 4-methoxyphenylhydrazine hydrochloride and 3 ml of triethylamine are boiled under reflux for 2 h in 75 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 179-181° C.
Reaction SMILES: [OH:1][C@@H:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C@@H:2]([CH3:11])[C:3]([N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C[C@H](O)C(=O)N1CCOCC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80° C. for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=4/1 to ethyl acetate) to give 4-[(S)-2-hydroxypropionyl]-morpholine (69.4 g) as a pale yellow oily substance. p-Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[(S)-2-hydroxypropionyl]morpholine (69.4 g) in dichloromethane (300 ml), to which 3,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=8/1 to ethyl acetate) to give 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=O)=[N+:2]=[N-:3].S(Cl)([Cl:17])=O>CN(C)C=O.C(Cl)Cl>[N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([Cl:17])=[O:14])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NCc1ccccc1CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCc1ccccc1CC(=O)Cl

Procedure:
2-Azidomethylphenylacetic acid (19.1 g., 0.1 mole) was dissolved in 800 ml. of methylene chloride. To this solution was added slowly thionyl chloride (26 g., 0.2 mole) and 0.5 ml. of dimethylformamide as catalyst. The reaction mixture was heated at reflux temperature under nitrogen atmosphere for 1 hour. The methylene chloride solution was concentrated with the aid of vacuum and the residue oil (checked by IR spectroscopy-carboxyl 1800 cm-1 and azido group at 2010 cm-1) was picked up in 100 ml. of acetone and placed into a dropping funnel for use directly in the subsequent acylation reaction.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[CH3:24])[C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:16]=[N:15][C:9]2[NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:8]=2[CH:7]=1.CCN(CC)CC.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:13]1[CH2:14][C:8]2[CH:7]=[C:6](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:18][C:19]3[O:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]=3[CH3:24])=[O:17])[CH:16]=[N:15][C:9]=2[NH:10][CH2:11][CH2:12]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCCN3)oc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCNc2ncc(/C=C/C(=O)N(C)Cc3oc4ccccc4c3C)cc2C1
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A solution of (E)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-3-(2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (105 mg, 0.280 mmol) in CH2Cl2 (6 mL) was treated with Et3N (0.05 mL, 0.36 mmol) followed by acetic anhydride (27 μL, 0.29 mmol). After stirring for 1.5 h, the mixture was diluted with CH2Cl2 (100 mL) and washed with H2O (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated to a tan residue. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 96:4) gave the title compound (89 mg, 76%) as a colorless residue and as a mixture of amide rotamers: MS (ESI) m/e 419 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6](Cl)=[O:7])(=O)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:26][C@H:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:28]([NH2:30])[CH3:29])=[C:22]([CH3:25])[CH:23]=3)[CH:18]=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:26][C@H:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@@H:28]([NH:30][C:5](=[O:4])[CH2:6][OH:7])[CH3:29])=[C:22]([CH3:25])[CH:23]=3)[CH:18]=[N:17]2)=[CH:14][CH:15]=1
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)N
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)NC(=O)CO
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Acetoxyacetyl chloride (0.071 mL, 0.66 mmol) was added to a solution of (1R,2S)-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yloxy)-1-phenylpropan-2-amine (62 mg, 0.17 mmol) and triethylamine (0.18 mL, 1.3 mmol) in THF (2.5 mL) at r.t. The mixture was stirred overnight and concentrated. The residue was dissolved in methanol (2 mL) and 28% ammonia (2 mL) and stirred at r.t. overnight. The title compound (57 mg, 80%) was obtained after purification by semi-preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:13][NH2:14].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:20]=O.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:11])([F:12])[F:10])=[CH:4][C:3]=1[CH2:13][NH:14][CH2:20][C:19]1[CH:22]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=1
Reactant: Cc1cc(Br)c(CN)cc1C(F)(F)F
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
A mixture of (2-bromo-4-methyl-5-(trifluoromethyl) phenyl) methanamine (189 mg, 0.705 mmol) and 3,5 bistrifluoromethyl benzaldehyde (170 mg, 0.705 mmol) in anhydrous toluene (10 mL) was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (25 mL). Sodium triacetoxyborohyride (373.5 mg, 1.76 mmol) was added and the mixture was stirred for 18 hours at room temperature. The mixture was poured into a mixture of saturated NaHCO3 (50 mL) and ethyl acetate (50 mL) and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried with anhydrous sodium sulfate, filtered and concentrated to give the title compound (98.4%). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 2H) 7.76(s, 1H) 7.58(s, 1H) 7.41 (s, 1H) 3.92(s, 2H) 3.89(s, 2H) 2.44(s, 3H)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1OC
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)c(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.