Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH2:12][CH:13](OC)[O:14][CH3:15])=[CH:7][N:6]=1)=[O:4].CCN(CC)CC.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH:12]=[CH:13][O:14][CH3:15])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(CC(OC)OC)nc1N
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC=Cc1cnc(C(=O)OC)c(N)n1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 215.2 %

Procedure:
To a solution of 3-amino-5-(2,2-dimethoxy-ethyl)-pyrazine-2-carboxylic acid methyl ester (300 mg, 1.244 mmol) and Et3N (1.213 ml, 8.70 mmol) in DCM (10 ml) at −10° C. was added dropwise trimethylsilyl trifluoromethanesulfonate (0.809 ml, 4.48 mmol). The reaction mixture was stirred at room temperature for 100 min. A saturated solution of NaHCO3 was added and the mixture was extracted twice with DCM. The combined organic layers were washed with NH4Cl solution and brine, dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a brown oil (560 mg). The resulting crude material (mixture of E and Z) was directly used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH2:34][CH:35]([OH:38])[CH2:36][OH:37].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:34][CH:35]([OH:38])[CH2:36][OH:37])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: OCC(O)CI
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 7.34 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:28]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][C:36]=2[N:37]2[CH2:42][C@H:41]([CH3:43])[C@H:40]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C@H:39]([NH:49]C(=O)OC(C)(C)C)[CH2:38]2)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=O)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:49][C@H:39]1[C@@H:40]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C@@H:41]([CH3:43])[CH2:42][N:37]([C:36]2[CH:35]=[CH:34][N:33]=[CH:32][C:31]=2[NH:30][C:28]([C:13]2[C:12]([NH2:11])=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:29])[CH2:38]1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N[C@@H]1[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
To a solution of tert-butyl methyl [(3R,4S,5S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (30 mg, 0.039 mmol) in MeOH (2.0 mL) and THF (1.0 mL), 10% Pd on carbon (6.9 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 90 min. The mixture was then filtered and concentrated under reduced pressure. The resulting residue was dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The residue was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (11 mg, 52%). LCMS calc. for C27H35N8O4 (M+H)+: m/z=535.3. Found: 535.4.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])[CH:2]([CH3:4])[CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[F:36])[C:30](Cl)=[O:31])#[N:26]>O1CCCC1>[F:36][C:35]1[CH:34]=[CH:33][C:29]([C:30](=[O:31])[CH2:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:14])=[CH:28][C:27]=1[C:25]#[N:26]
Reactant: CC(=O)c1ccccc1OCC(C)C
Reactant: N#Cc1cc(C(=O)Cl)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)COc1ccccc1C(=O)CC(=O)c1ccc(F)c(C#N)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68338.9 %

Procedure:
To a solution of 1-(2-isobutoxyphenyl)ethanone (9.0 g, 0.047 mol) in tetrahydrofuran (150 mL) under N2 at −78° C. was added a 1.0 M solution of lithium hexamethyl disilazide in hexanes (100 mL, 2.2 eq) over 5 minutes. The reaction was stirred at −78° C. for 1 h. To the reaction solution was added 3-cyano-4-fluorobenzoyl chloride (8.6 g, 0.047 mmol) in tetrahydrofuran (28 mL) over 5 minutes at −78° C. The reaction mixture was then removed from the dry ice bath and allowed to stir for 1 h. The reaction was quenched with 1N HCl then partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with acetonitrile and filtered yielding 10.9 g (90%) of 2-fluoro-5-(3-(2-isobutoxyphenyl)-3-oxopropanoyl)benzonitrile and was submitted to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][F:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[H-].[Na+].[N+:27](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:27][N:14]1[C:15]([C:19]([F:21])([F:22])[F:20])=[CH:16][C:17](=[O:18])[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH2:9][CH2:10][F:11])[C:2]([Br:1])=[CH:3][C:4]=2[F:24])[C:13]1=[O:23]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(OCCF)c(Br)cc1F
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCF)c(Br)cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-[4-bromo-2-fluoro-5-(2-fluoroethoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (0.4 g) in N,N-dimethylformamide (10 ml) are added dropwise to a suspension of 60% sodium hydride (0.05 g) in N,N-dimethylformamide (10 ml) at 5° to 10° C. The mixture is allowed to stir at 10° to 20° C. for additional 30 minutes. To the mixture, 2,4-dinitrophenoxyamine (0.22 g) is added slowly at 10° to 20° C., followed by stirring at room temperature for one hour. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give 1-amino-3-[4-bromo-2-fluoro-5-(2-fluoroethoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione.
Reaction SMILES: [C:1]1([C:7]([OH:12])([CH3:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:20][C:19]1[CH:21]=[CH:22][C:16]([S:13]([O:10][CH2:9][CH2:8][C:7]([OH:12])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CC(O)(CCO)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC(C)(O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of 3-phenylbutane-1,3-diol (68 g, 0.41 mol) in dry CH2Cl2 (500 mL) was added dropwise a solution of TsCl (78 g, 0.41 mol) and triethylamine (71 mL, 0.45 mol) in dry CH2Cl2 (500 mL) at 0° C. The mixture was stirred overnight. The mixture was poured into water and separated. The aqueous layer was extracted with CH2Cl2 (200 mL) twice. The organic layer was combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography to give 3-hydroxy-3-phenylbutyl 4-methylbenzenesulfonate (62 g, 42%). 1H NMR (400 MHz, CDCl3): δ=1.55 (s, 3H), 1.93 (w, 1H), 2.19˜2.24 (q, 2H), 2.45 (s, 3H), 3.87˜4.01 (m, 1H), 4.09˜4.16 (m, 1H), 7.19˜7.34 (m, 7H), 7.68˜7.76 (d, 2H).
Reaction SMILES: [CH:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([CH3:13])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]1([C:17](=O)[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1>>[CH:1]1([N:7]2[C:11]3[N:12]=[C:17]([CH:14]4[CH2:15][CH2:16]4)[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]=3[C:9]([CH3:13])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(C2CCCCC2)n1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCCC1

Procedure:
The title compound was prepared in the same manner as described for intermediate 37 using 1-(1-cyclohexyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 2.79 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (514 mg, 2.79 mmol). The final product was collected as a solid, 0.827 g (91%). LCMS E-S (M+H)=328.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.10 (m, 3 H), 1.20-1.30 (m, 1 H), 1.37 (t, J=7.07 Hz, 3 H), 1.41-1.52 (m, 2 H), 1.70 (d, 1 H), 1.79-1.98 (m, 6 H), 2.30-2.38 (m, 1 H), 2.54 (s, 3 H), 4.42 (q, J=7.07 Hz, 2 H), 4.60-4.74 (m, 1 H), 7.44 (s, 1 H).
Reaction SMILES: C[O-].[Na+].[ClH:4].[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]([C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:13]=1)=[O:11].Cl>COCCOC.C(Cl)(Cl)Cl.C(O)C.O1CCOCC1.CO>[ClH:9].[ClH:4].[NH:7]([C:10]([C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:13]=1)=[O:11])[C:6]([NH2:8])=[NH:5]
Reactant: Cc1c(C(=O)Cl)cn(-c2ccnc3ccccc23)c1C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: COCCOC
Product: Cc1c(C(=O)NC(=N)N)cn(-c2ccnc3ccccc23)c1C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
1.78 g (33 mmol) of sodium methoxide are added at a temperature in the region of 20° C. under an argon atmosphere to 20 mL of methanol. After complete dissolution, 3.34 g (35 mmol) of guanidine hydrochloride are added. After stirring at a temperature in the region of 20° C. for 0.5 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is suspended in 25 mL of 1,2-dimethoxyethane and then again concentrated to dryness. The residue is suspended in a mixture of 75 mL of tetrahydrofuran and 50 mL of dichloromethane at a temperature in the region of 20° C. under an argon atmosphere and then 1.17 g (4.1 mmol) of 3-chlorocarbonyl-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole, dissolved in 25 mL of chloroform, are added thereto. After stirring at a temperature in the region of 20° C. for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 100 mL of water. After filtering, a gum is obtained, which gum is triturated in 50 mL of methanol and filtered. The solution obtained is partially concentrated to a volume of 5 to 10 mL and then purified by silica gel chromatography [eluent: chloroform/methanol (90/10 and then 70/30 by volume)]. After concentrating the fractions under reduced pressure, an oil is obtained, which oil is dissolved in ethanol and to which is added 4 mL of a 5.3N solution of hydrochloric acid in dioxane. The solution obtained is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in a mixture of isopropanol and isopropyl acetate. 0.96 g of 3-guanidinocarbonyl-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole dihydrochloride is thus obtained in the form of a yellow solid which decomposes at a temperature of greater than 260° C. Mass spectrum (EI): m/e 307 (M+) m/e 248. IR spectrum (KBr): 3371, 3103, 2622, 1694, 1599, 1495, 1423, 1308, 1251, 1194, 1093 and 754 cm−1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[CH3:19][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:8])[CH3:19]
Reactant: C[Mg]Br
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde were dissolved in 100 ml tetrahydrofuran. At 0° C. 3.38 ml of an one molar solution of methylmagnesium bromide in tetrahydrofuran were added dropwise. The cooling bath was removed and the reaction mixture stirred at room temperature for one hour. Then the reaction mixture was poured on 100 ml ice cold saturated NH4Cl solution and extracted five times with portions of 80 ml ethyl acetate. The combined organic layers were washed with 100 ml brine then dried over MgSO4. The solvent was evaporated to obtain 2.7 g crude 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol as pale yellow solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22]>O1CCOCC1>[ClH:22].[NH2:14][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][OH:13]
Reactant: CC(C)(C)OC(=O)NC(CO)CCOCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(CO)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-(benzyloxy)-1-(hydroxymethyl)propylcarbamate (5 g, 17 mmol) is dissolved in 4 N hydrochloric acid in dioxane (21 mL) and stirred for 3 h at room temperature. The solution is concentrated under reduced pressure to give the title compound in pure form. ESI MS m/z 196.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:25])=[CH:6][C:7]2[O:11][CH:10]=[C:9]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:8]=2[CH:24]=1)[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[OH:25][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:24][C:8]2[C:9]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[CH:10][O:11][C:7]=2[CH:6]=1
Reactant: C=CCc1cc2c(-c3cc(OC)c(OC)c(OC)c3)coc2cc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc2c(-c3cc(OC)c(OC)c(OC)c3)coc2cc1O
Reaction time: 0.33 h

Procedure:
A solution of 5-allyl-6-hydroxy-3-(3,4,5-trimethoxyphenyl)benzofuran (300 mg) in ethyl acetate (2 ml) containing 5% palladium-on-charcoal was hydrogenated for 20 minutes. The mixture was filtered and the filtrate was evaporated to give 6-Hydroxy-3-(3,4,5-trimethoxyphenyl)-5-propylbenzofuran.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:10]=[C:11]([NH:14]C(=O)C)[S:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[O:1]([CH2:8][C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1nc(COc2ccccc2)cs1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nc(COc2ccccc2)cs1
Temperature: 60 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a solution of N-(4-phenoxymethyl-thiazol-2-yl)-acetamide (40 mg, 0.16 mmol) in THF (2 ml) was added 6N HCl (2 ml). The reaction was heated at 60° C. for 3 hours following by stirring at room temperature overnight and then heated at 60° C. for additional 3 hours. The solution was concentrated to afford 4-phenoxymethyl-thiazol-2-ylamine (HCl salt) as a brown viscous oil (35 mg, 90% ). LC/MS m/z 207.09 (M+1)+; HPLC Rt: 1.137 min
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.CN(C)P(N(C)C)(N(C)C)=O.C(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([Cl:23])=[O:9]
Reactant: Cc1ncsc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ncsc1C(=O)Cl
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1, 7.2 g (0.05 mole) of 4-methylthiazole-5-carboxylic acid were suspended in 100 ml of toluene, followed by the addition of 0.02 g of hexamethylphosphoramide Under heating and reflux, phosgene was blown at a rate of 1.2 l/hr for 2.5 hours (0.13 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 8.0 g of 4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 99.2% an d99.0%, respectively. NMR (δCDCl 3/TMS, ppm): 2.88(3H,s).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:14][CH2:15][C:16]([N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: O=C(Cl)CCl
Product: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21

Procedure:
Using the procedure outlined in Description 4, the title compound was prepared from 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (4.41 g, 25 mmol) and chloroacetyl chloride (2.2 ml, 27.6 mmol) as a dark brown solid (5.853 g). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.49 (br, 1H), 8.00 (dd, 1H), 7.33 (d, 1H), 4.27 (s, 2H), 3.86 (m, 2H), 2.90 (t, 2H), 2.09 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(-c2cnccc2C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccncc1-c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-(4-methylpyridin-3-yl)thiophene-2-carboxylate (0.200 g, 0.809 mmol) was dissolved in ethanol (5 ml). 2 M sodium hydroxide solution (0.809 ml, 1.617 mmol) was added and the mixture was stirred at RT overnight. Ethanol was evaporated and water (5 ml) was added. The product was precipitated during the addition of 2 M HCl. The product was filtered and dried to give 98 mg. 1H-NMR (400 MHz; d6-DMSO): δ 2.43 (s, 3H), 7.38 (d, 1H), 7.39 (d, 1H), 7.77 (d, 1H), 8.46 (d, 1H), 8.59 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N:18]=[N+]=[N-])[N:15]=[C:14]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[Pd]>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([NH2:18])[N:15]=[C:14]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCOc1cc(N=[N+]=[N-])nc(N2CCOCC2)n1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCOc1cc(N)nc(N2CCOCC2)n1)C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
[2-(6-azido-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester was dissolved in a mixture of tetrahydrofuran (200 mL) and methanol (20 mL). To the solution was added 10% palladium on carbon (2 g) and the reaction was stirred under an atmosphere of hydrogen for 24 hours. The reaction was then filtered through celite and evaporated to give [2-(6-amino-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (5.0 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C.[C:53](Cl)(=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:53]([N:40]1[CH2:41][CH2:42][N:37]([C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])[CH2:38][CH2:39]1)(=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Reaction time: 16 h
Yield: 40.3 %

Procedure:
A solution of 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (30 mg, 47 μmol) and N,N-diisopropylethylamine (41 μL, 0.24 mmol) in dichloromethane was treated with benzoyl chloride (11 μL, 95 μmol) and stirred for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (14 mg, 40%) as a solid. LCMS for C29H27ClN6O (M+H)+: m/z=511.1. 1H NMR (400 MHz, DMSO-d6): δ 9.54 (br s, 1H), 9.38 (br s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.47-7.43 (m, 4H), 7.12-7.02 (m, 3H), 6.87-6.82 (m, 2H), 3.79 (br s, 2H), 3.49 (br s, 2H), 2.97 (s, 4H), 2.87-2.79 (m, 4H).
Reaction SMILES: [CH:1]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(=O)(O)[O-].[Na+]>CO>[CH:1]1([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1c[nH]cn1
Reactant: BrC1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: c1cn(C2CCCCCC2)cn1

Procedure:
Cycloheptyl bromide (10.0 g, 0.0565 mole) was added dropwise to a refluxing mixture of imidazole (385 g, 0.0565 mole) and sodium bicarbonate (4.75 g, 0.0565 mole) im methanol (100 ml). After addition was complete the mixture was heated under reflux for a further 24 hours.
Reaction SMILES: [C:1]([O:5][C:6](N1C[C@@H](C)N2[C@H](CC3C2=NC(Br)=CC=3)C1)=O)(C)(C)[CH3:2].[C:23]([O:27][C:28]([N:30]1[CH2:42][C@@H:41]([CH3:43])[N:40]2[C@H:32]([CH2:33][C:34]3[C:39]2=[N:38][C:37]([OH:44])=[CH:36][CH:35]=3)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[H-].[Na+].COCCBr>>[C:23]([O:27][C:28]([N:30]1[CH2:42][C@@H:41]([CH3:43])[N:40]2[C@H:32]([CH2:33][C:34]3[C:39]2=[N:38][C:37]([O:44][CH2:2][CH2:1][O:5][CH3:6])=[CH:36][CH:35]=3)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Agent: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCOc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 22 intermediate b), from (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and 2-bromoethyl methyl ether.