Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([C:35]1[N:40]=[CH:39][C:38]2=[CH:41][CH:42]=[C:43]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[O:50][CH3:51])[N:37]2[N:36]=1)=O.C([O-])(=O)C.[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:35]4[N:40]=[CH:39][C:38]5=[CH:41][CH:42]=[C:43]([C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=6[O:50][CH3:51])[N:37]5[N:36]=4)=[C:25]([O:30][CH3:31])[CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 110 °C
Yield: 87.5 %

Procedure:
A mixture of 4-[1-(4-Amino-3-methoxy-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid benzyl ester (0.62 g, 0.0015 mol), 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.3 g, 0.0009 mol) and Potassium acetate (0.59 g, 0.0060 mol) in N,N-Dimethylformamide (10 mL) was heated at 110° C. for 40 hr. The solvent was evaporated and the residue chromatographed on silica gel prep plates 2× with ethyl acetate-IPA (20-1) giving 4-(1-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-4-yl)-piperazine-1-carboxylic acid benzyl ester as a tan solid (0.51 g, 9%). MP: 75-76° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 8.80 (s, 1H), 7.84-7.81 (d, 1H, J=8.40 Hz), 7.48 (s, 1H), 7.45-7.35 (m, 7H), 7.20 (s, 1H), 7.18 (s, 1H), 7.12-7.02 (t, 1H), 6.95-6.89 (q, 2H, J=4.68 Hz), 6.62 (d, 1H), 6.38-6.35 (q, 1H) 5.08 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.70-3.65 (d, 2H), 3.39 (br, 8H), 2.70-2.51 (m, 3H), 1.87-1.78 (m, 2H), 1.60-1.52 (m. 2H).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc(C)ccc2Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 3-methoxyphenylboronic acid (152 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (79 mg, yield 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([C:19](OC(C)(C)C)=O)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.C=O.[BH3-]C#N.[Na+]>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C)C1)O2

Procedure:
(±)-(E)-3-{1′-Methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester was synthesized starting from Intermediate 5 (300 mg, 0.88 mmol), according to the procedure described in Example 40, Step A, using formaldehyde (0.85 ml, 1.1 mmol) and NaBH3CN (68 mg, 1.1 mmol). The product was obtained as a white solid (240 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O.O>C(O)(=O)C.C(OCC)(=O)C>[Cl:22][C:10]1[NH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:12]([S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])[CH:11]=1
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cc(Cl)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00323 mol) in acetic acid is treated with thionyl chloride (0.43 g, 0.00323 mol), stirred for 30 minutes, poured into water and decanted to obtain a residue. The residue is dissolved in ethyl acetate and the organic solution is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark syrup. Flash chromatography of the syrup using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as a yellow solid (0.43 g, mp 109°-112° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>O>[N:40]1([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([O:20][C:21]4[C:22]([CH3:31])=[N:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:32][CH3:33])[CH:44]=[CH:43][N:42]=[CH:41]1
Reactant: c1c[nH]cn1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCn1ccnc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 57.4 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and imidazole (26 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 57%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])/[C:3](/O)=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH2:20]([O:22][C:23](=[O:28])/[CH:24]=[C:25](\[NH2:27])/[CH3:26])[CH3:21]>C(#N)C>[CH2:20]([O:22][C:23](=[O:28])[C:24]1[C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:27][C:25]=1[CH3:26])[CH3:21]
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)nc1C
Yield: 34.1 %

Procedure:
To an acetonitrile (50 ml) solution of (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethyl-phenyl)-but-2-en-1-one (4.7 g, 17 mmol; D. Barrett, P. D. Bentley, T. R. Perrior, Synthetic Commun. 1996, 26, 3401–3406) was added ethyl-3-aminocrotonate (4.27 g, 33 mmol) under an argon atmosphere. The mixture was heated at reflux for 12 h. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/ethyl acetate) to yield 2.2 g (5.8 mmol, 35%) of the title compound as yellow crystals.
Reaction SMILES: C([Li])CCC.[OH:6][CH2:7][C:8]1[N:12]=[C:11]([CH3:13])[O:10][N:9]=1.CN(C)CCN(C)C.[C:22](=[O:24])=[O:23]>CCCCCC.O1CCCC1>[OH:6][CH2:7][C:8]1[N:12]=[C:11]([CH2:13][C:22]([OH:24])=[O:23])[O:10][N:9]=1
Reactant: O=C=O
Reactant: Cc1nc(CO)no1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)Cc1nc(CO)no1
Temperature: 35 °C
Yield: 55 %

Procedure:
Under anhydrous conditions, a solution of approximately 1.2 mol of n-butyl lithium in n-hexane was added dropwise over 3 hours to an efficiently cooled solution of 66 g (0.58 mol) of 3-hydroxymethyl-5-methyl-1,2,4-oxadiazol and 87 ml of N,N,N',N'-tetramethyl ethylene diamine in 1200 ml of tetrahydrofuran and during the addition, the reaction temperature was not allowed to rise above -70° C. The reaction mixture was stirred for 1 hour at -70° C. and under efficient cooling, dried gaseous carbon dioxide was passed over the surface of the stirred reaction mixture for ten hours at -70° C. Subsequently, the temperature was allowed to rise gradually to -5° C. and the formed precipitate was collected by vacuum filtration and was washed with dry ethyl acetate and with n-hexane. The precipitate was dissolved slowly by adding it in small portions to a stirred icy-cold mixture of 500 ml of water and 500 ml of diethyl ether and concentrated phosphoric acid was added till the pH was 4.0. The layers were separated and the organic layer discarded. The water-layer was further acidified to a pH of 2.0 and subsequently evaporated in vacuo. Remnants of water in the residue were removed in vacuo with the help of benzene and the residue was dried in vacuo over phosphorous pentoxide for 16 hours. The syrupy product was stirred with 500 ml of acetone at about 35° C. and the acetone was decanted. This was repeated once whereupon the residue became a solid mass which was transferred to a filter and repeatedly stirred with 500 ml portions of acetone until according to thin-layer chromatograms the filtrate no longer contained the desired compound. All filtrates were combined (total of about 4000 ml) and concentrated in vacuo to a volume of about 300 ml. 600 ml of ethyl acetate were added and the resulting solution was again concentrated in vacuo to a final volume of about 250 ml. The resulting crystalline precipitate was vacuum filtered, washed with dry ethyl acetate and with carbon tetrachloride. After drying in vacuo, 41 g of 3-hydroxymethyl-1,2,4-oxadiazol-5-yl-acetic acid were obtained with melting and decomposition taking place between about 96° and 98° C. The filtrate was evaporated in vacuo and the oily residue was repeatedly stirred with small volumes of dichloromethane. The resulting solid was transferred to a filter and washed with ethyl acetate and carbon tetrachloride. After drying, the second crop of said product weighed 14.1 g and melted with extensive decomposition at 92°-96° C. According to thin-layer chromatograms, IR and PMR spectra both crops were virtually identical for a total of 45.1 g (about 55% yield) of about 96% purity.
Reaction SMILES: I[C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:6]([O:15][CH:16]([CH3:18])[CH3:17])[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[CH:21](N(CC)C(C)C)([CH3:23])[CH3:22].C#CC>CN(C=O)C.[Cu]I>[CH:16]([O:15][C:6]1[C:5]([O:19][CH3:20])=[CH:4][CH:3]=[C:2]([C:22]#[C:21][CH3:23])[C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])([CH3:18])[CH3:17]
Reactant: COc1ccc(I)c(NC(=O)C(F)(F)F)c1OC(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: [Cu]I
Agent: C#CC
Solvent: CN(C)C=O
Product: CC#Cc1ccc(OC)c(OC(C)C)c1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of the product of Step B (0.275 g; 0.681 mmol), Cl2Pd(PPh3)2 (0.058 g; 0.083 mmol); CuI (0.025 g; 0.13 mmol), anhydrous N,N-diisopropyl ethylamine (1 ml) in anhydrous DMF (5 ml) was cooled to −40° C., degassed under reduced pressure and saturated with dry N2. To it, propyne gas (0.5 g; 12.4 mmol) was added at −40° C. The reaction flask was sealed with septum and allowed to warm up to room temperature and stirred overnight at room temperature than evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexane/ethyl acetate, 8:2) to give the title compound (0.171 g; 79% yield) as creamy solid. 1H-NMR (CDCl3) 1.21 (d, 6H, J=6.16 Hz); 2.00 (s, 3H); 3.86 (s, 3H); 4.43 (m, 1H, J=6.16 Hz); 6.79 (d, 1H, J=8.67 Hz); 7.14 (d, 1H, J=8.67 Hz); 7.72 (broad s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:15][C:16](C)([O-:18])C.[Na+].C(OCC)(=O)C.Cl>C(OC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:16]([CH3:15])=[O:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)Cc1ccccc1OC
Agent: Cl
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(C)=O)c1ccccc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of ethyl 2-methoxyphenyiacetate (11.6 g), sodium tert-butoxide (12.7 g) and ethyl acetate (15.8 g) in diisopropylether was heated at 70° C. for 2.5 hours and stirred at room temperature overnight. Ethyl acetate and hydrochloric acid (2M) were added and the organic phase dried (magnesium sulphate) and evaporated. The residue was distilled in vacuo to give ethyl 2-(2-methoxyphenyl)acetoacetate as a liquid (8.5 g), NMR 1.15 and 1.13(t,3h), 1.8 and 2.2(s,3H), 3.75 and 3.85(s,3H), 4.1-4.3(2q,2H), 5.15(s,1H), 6.9-7.3(m,4H), 13.1(s,1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][NH2:20])[N:14]=[CH:13]1>>[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][NH:20][C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:14]=[CH:13]1
Reactant: O=C(O)CCc1ccccc1
Reactant: NCCCc1c[nH]cn1
Product: O=C(CCc1ccccc1)NCCCc1c[nH]cn1

Procedure:
The preparation is carried out as in Example 1 with 10 mmol of 3-phenylpropanoic acid and 3-(1H-imidazol-4-yl)propanamine as the amine component. The title compound is purified by chromatography and recrystallized in the hydrogenmaleate form from ethyl acetate/acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:16])[N:12]([CH2:14]Cl)[N:13]=2)[CH:5]=[CH:6][CH:7]=1>C(NC)CCC>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:16])[N:12]([CH2:14][N:12]([CH2:11][CH2:10][CH2:9][CH3:8])[CH3:14])[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc(-c2cccc(Br)c2)nn1CCl
Agent: CCCCNC
Product: CCCCN(C)Cn1nc(-c2cccc(Br)c2)ccc1=O
Reaction time: 8 h
Yield: 190.1 %

Procedure:
4.5 g of 6-(3-bromophenyl)-2-chloromethyl-3(2H)-pyridazinone were heated with 10 ml of N-butyl-N-methylamine at 100°-110° C. on an oil bath for 2 hours. After the reaction mixture had been left to cool, the excess amine was distilled off under reduced pressure. To the resulting residue were added 100 ml of ethyl acetate and the mixture was left to stand overnight. The insolubles were removed by filtration and the filtrate was concentrated by evaporation under reduced pressure to a volume of about 20 ml. 100 ml of hexane and 20 ml of benzene were added to the concentrate and, after adding a small amount of active carbon, the mixture was filtered. The filtrate was concentrated by evaporation under reduced pressure and the residue was dried at 50° C. under a pressure of 13 Pa (0.1 mmHg) for 2 hours, to afford 5.0 g (yield 94%) of the desired Compound No. 13, in the form of a pale brown oil, nD23 =1.5918.
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:29]1[C:30]2[C:37](=[CH:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)[C:36](=[O:45])[NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C.CC(O)C>O>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:23][CH2:24][N:25]([C:29]4[C:30]5[C:37](=[CH:38][C:39]6[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=6)[C:36](=[O:45])[NH:35][C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:26][CH2:27]3)[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCNCC1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccncc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(c2ncnc3c2C(=Cc2ccncc2)C(=O)N3)CC1

Procedure:
Combine {2-[4-(3-chloro-4-fluoro-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-dimethyl-amine tris hydrochloride (0.5 g; 0.0013 mol; 1.0 equiv); 4-chloro-5-[1-pyridin-4-yl-methylidene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.34 g; 0.0013 mol; 1.0 equiv); DIPEA (1.7 mL; 0.0098 mol; 7.6 equiv); 2-propanol (15 mL) and microwave at 80° C. for 20 min. Cool and dilute with water. Extract with EA and wash with brine. Concentrate the crude and purify by reverse phase HPLC to give the title compound as a mixture of E and Z isomers (0.04 g; 5.4%). MS (ES+): m/z=573 (M+H). (Note: All olefin compounds are mixtures of E and Z isomers.)
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH2:8][CH2:7]2)[N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][NH:3]1.S(Cl)(Cl)=O.C(N(CC)CC)C.[NH2:37][C:38]1[CH:43]=[C:42]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)[CH:41]=[CH:40][C:39]=1[NH:49]C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.CN(C=O)C>[NH2:49][C:39]1[CH:40]=[CH:41][C:42]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)=[CH:43][C:38]=1[NH:37][C:17]([C:14]1[S:13][C:12]([N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:4][NH:3][C:2]3=[O:1])[CH2:7][CH2:8]2)=[N:16][CH:15]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=C(O)c1cnc(N2CCC3(CC2)C(=O)NCN3c2ccccc2)s1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1cnc(N2CCC3(CC2)C(=O)NCN3c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)-1,3-thiazole-5-carboxylic acid (60 mg, 0.16 mmol) was made 0.25 M in anhydrous DCM and to this stirring solution was added catalytic DMF followed by 3 equivalents thionyl chloride (179 mg, 1.5 mmol). The resulting solution was stirred at ambient temperature under nitrogen for 1 hour. The reaction mixture was then concentrated in vacuo and azeotroped once with toluene to remove excess thionyl chloride. The residue was made 0.5M in anhydrous DCM and to this stirring solution was added 3 equivalents triethylamine (48 mg, 0.48 mmol) followed by 1 equivalent tert-butyl 2-amino-4-thien-2-ylphenylcarbamate (30 mg, 0.16 mmol). The resulting mixture was stirred at ambient temperature for 14 hours. The reaction mixture was then diluted with 4M TFA in DCM and allowed to stir at ambient temperature. After one hour the reaction mixture was concentrated in vacuo and purified by reverse phase chromatography: MS (ESI+): cal'd [M+H]+531.1, obs'd 531.1.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:45])[C:14]2=[O:15])[N:3]=1.C(CN)O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([NH2:34])[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:45])[C:14]2=[O:15])[N:3]=1
Reactant: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccccc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Solvent: NCCO
Solvent: Cc1ccccc1
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 82.5 °C
Reaction time: 2 h

Procedure:
1800 kg (3 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthine are heated to 80-85° C. in 18 liters of toluene. Subsequently, 1.815 liters (30 mol) of ethanolamine are added to the suspension at 75-80° C. To complete the reaction, the mixture is stirred at 80-85° C. for 2 hours, in the course of which the solids go into solution. Subsequently, the phases are separated. The ethanolamine phase is washed twice with warm toluene (4 liters each time). The combined toluene phases are washed twice with 8 liters each time of water at 75-80° C. From the toluene phase, 22 liters of toluene are distilled off under reduced pressure. 4 liters of tert.-butyl methyl ether are metered at 40-50° C. to the resulting suspension and subsequently cooled to 0-5° C. The product is isolated by filtration, washed with tert.-butyl methyl ether and suction-dried. The moist crude substance is subsequently heated to reflux with 5 times the amount of absolute ethanol and the hot solution is clarified by filtration through activated carbon. After the filtrate has been cooled to 20° C. and crystallization has set in, it is diluted to double the volume with tert.-butyl methyl ether. The suspension is cooled to 2° C., stirred for a further 2 hours, filtered with suction and dried at 45° C. in a vacuum drying cabinet.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C>Cl.C(O)(C)C>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([N:12]2[CH2:11][CH:10]3[CH:14]([CH2:15][NH:8][CH2:9]3)[CH2:13]2)=[O:24])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccc(Br)cc3)CC2C1
Agent: Cl
Solvent: CC(C)O
Product: O=C(c1ccc(Br)cc1)N1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.7 %

Procedure:
1.2 5-(4-Bromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (1.1 g; 2.78 mmol) is dissolved in 15 ml of HCl/Isopropanol (5-6N) and then stirred at RT for 2 hrs. The reaction mixture is reduced to dryness under vacuo to yield 0.90 g (97.5%) (4-bromo-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone 2.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:30][CH:29]=2)[C@H:10]([O:47][CH2:48][C@H:49]([OH:53])[CH2:50][O:51][CH3:52])[CH2:9]1)=O)(C)(C)C.Cl>CO>[OH:53][C@H:49]([CH2:50][O:51][CH3:52])[CH2:48][O:47][C@H:10]1[C@H:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:32][CH:33]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13][NH:8][CH2:9]1
Reactant: COC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOc2ccccc2C#N)cc1
Agent: Cl
Solvent: CO
Product: COC[C@@H](O)CO[C@@H]1CNC[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOc2ccccc2C#N)cc1

Procedure:
In analogy to the procedure described in example 1 (l) the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the 2-[3-[4-[(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile as colorless oil; MS: 627 (M+H)+.