Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:14][CH:9]([CH:10](O)[CH:11]1O)[CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]2=1.CCOC(C)=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO.O>[CH2:21]([N:28]1[CH2:11][CH:1]2[CH2:14][CH:9]([CH2:8][C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=32)[CH2:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: OC1C2Cc3cccnc3C(C2)C1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1ccc(CN2CC3Cc4cccnc4C(C3)C2)cc1
Reaction time: 0.25 h

Procedure:
3-Aza-tricyclo[7.2.1.02,7]dodeca-2(7),3,5-triene-10,11-diol (1.16 g, 6.07 mmol) was stirred in EtOH (40 mL) and was treated with a solution of NaIO4 (1.35 g, 6.07 mmol) in H2O (20 mL). A precipitate forms and the mixture becomes a yellow slurry. After 15 min, the reaction is deemed complete (TLC EtOAc Rf 0.62), diluted with water and extracted with dichloromethane (4×50 mL). The organic layer was washed with H2O (5×50 mL) then dried through a cotton plug and concentrated to an oil. This oil was stirred in DCE (50 mL), treated with benzyl amine (650 mg, 6.07 mmol) then sodium triacetoxyborohydride NaBH(OAc)3 (4.12 g, 19.4 mmol). The mixture was stirred 7 h, then was quenched by addition to saturated sodium carbonate (Na2CO3) solution and EtOAc (˜75 mL each). After stirring 20 min., the layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layer was washed with H2O (50 mL) and saturated aqueous NaCl solution (50 mL) then dried over Na2SO4. Filtration and concentration affords an oil, 1.2 g which was purified by chromatography on silica gel eluting with 50% EtOAc/hexanes to provide pure product as an oil, 802 mg (50%). (TLC EtOAc Rf 0.68); 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J=4.7, 0.6 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.13–7.07 (m, 4H), 6.85 (m, 2H), 3.35 (AB q, ΔAB=27.2, J=13.8 Hz, 2H), 3.08 (s, 1H), 3.02 (dd, J=17.3, 7.0 Hz, 1H), 2.92 (d, J=10.6 Hz, 1H), 2.81 (d, J=10.6 Hz, 1H), 2.74 (d, J=17.3 Hz, 1H) 3.34 (br d, J=10.6 Hz, 2H), 2.17 (br s, 1H), 1.90 (d, J=3.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 160.8, 145.6, 139.2, 134.7, 134.2, 128.1, 128.0, 126.6, 121.0, 62.3, 60.8, 58.9, 38.4, 34.2, 29.8, 28.4; APCl MS m/z 265.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([C@@H:9](O)[CH3:10])=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([C@H:9]([N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](O)c1nc2cc(Cl)ccc2n1CCC(F)(F)F
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](c1nc2cc(Cl)ccc2n1CCC(F)(F)F)n1nc(S(C)(=O)=O)c2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a mixture of (1S)-1-[5-chloro-1-(3,3,3-trifluoropropyl)-1H-benzimidazol-2-yl]ethanol (145 mg, 0.50 mmol) and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine (140 mg, 0.70 mmol) in DCM (15 mL) was added PPh3 (262 mg, 1.0 mmol) and DEAD (170 mg, 1.0 mmol). The mixture was then stirred at room temperature overnight. After the reaction was complete, the mixture was washed by 2 N aqueous solution of NaOH and the organic layer was concentrated in vacuo. The residue was purified by preparative HPLC to afford 1-{(1R)-1-[5-Chloro-1-(3,3,3-trifluoropropyl)-1H-benzimidazol-2-yl]ethyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (56.6 mg).
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:16]2[NH2+:15][C:14]3[C:9](=[CH:10][C:11]([Br:17])=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[C:5](Br)[CH:4]=1.[CH3:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][O:26][CH3:27]>C(Cl)(Cl)Cl>[Br-:17].[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][O:26][CH3:27])[C:5]1[CH:4]=[C:3]([CH3:2])[C:16]2[C:7]([CH:6]=1)=[S+:8][C:9]1[C:14](=[CH:13][CH:12]=[C:11]([N:23]([CH2:24][CH2:25][O:26][CH3:27])[CH2:22][CH2:21][O:20][CH3:19])[CH:10]=1)[N:15]=2
Reactant: COCCNCCOC
Reactant: Cc1cc(Br)cc2c1[NH2+]c1ccc(Br)cc1S2
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: COCCN(CCOC)c1ccc2nc3c(C)cc(N(CCOC)CCOC)cc3[s+]c2c1
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 1-methyl-3,7-dibromophenothiazinium bromide (315 mg, 0.7 mmol) in chloroform (15 mL) kept under argon, bis(2-methoxyethyl)amine (0.52 mL, 3.5 mmol) was added (30 min) with vigorous stirring. The mixture was stirred for 3 h and after that extracted once with aqueous HBr (30 mL, 1% v/v) and then twice with water. The organic layer was dried (Na2SO4), concentrated and dried under vacuum (93 mg, 24% yield). The desired final product was purified by flash chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[CH:10]3)[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([SH:36])[CH2:32][CH2:31]1)([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:24][O:25][C:26](=[O:37])[C:27]([N:30]1[CH2:31][CH2:32][CH:33]([S:36][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[CH:10]4)[C:6]=3[CH:23]=2)[CH2:34][CH2:35]1)([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)N1CCC(S)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Temperature: 120 °C
Yield: 138 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (326 mg, 0.871 mmol), 2-(4-mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (284 mg, 1.307 mmol), Pd2(dba)3 (40 mg, 5 mol %), XantPhos (50 mg, 10 mol %) and DIPEA (0.60 mL, 3.48 mmol) in dioxane (8 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. After cooling to RT, the reaction mixture was diluted with DCM (200 mL) and purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM) affording 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester as an orange oil (614 mg, quantitative yield). LCMS: RT 2.23/2.28 min [M+H]+ 511.3.
Reaction SMILES: [F:1][C:2]1[C:21]([NH2:22])=[C:6]2[CH2:7][S:8](=[O:20])(=[O:19])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[Cl:23]N1C(=O)CCC1=O.CCOCC.O>CN(C)C=O>[Cl:23][C:4]1[CH:3]=[C:2]([F:1])[C:21]([NH2:22])=[C:6]2[C:5]=1[N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[S:8](=[O:20])(=[O:19])[CH2:7]2
Reactant: COc1ccc(CN2c3ccc(F)c(N)c3CS2(=O)=O)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2c3c(Cl)cc(F)c(N)c3CS2(=O)=O)cc1
Temperature: 80 °C
Yield: 93.4 %

Procedure:
A mixture of the title compound of Step C (0.387 g, 1.2 mmol) and N-chlorosuccinimide (0.168 g, 1.26 mmol) in dimethylformamide (6 mL) was heated at 80° C. for 4 h. After completion of the reaction, the mixture was poured into a mixture of ether (25 mL) and water (10 mL). The organic phase was separated, dried (MgSO4) and the solvent was removed on a rotary evaporator. Flash chromatography of the resulting residue afforded 0.4 g of the title compound of Step D. 1H NMR (CDCl3, 400 MHz): δ7.23 (d,2H), 7.03 (d,1H), 6.74 (d,2H), 4.93 (s,2H), 3.84 (s,2H), 3.75 (s,3H).
Reaction SMILES: [CH:1]([C:4]1[O:5][C:6]([CH3:15])=[CH:7][C:8](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:9]=1)([CH3:3])[CH3:2].[C:16]1([C:22]2[CH2:26][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[C:16]1([C:22]2[CH2:26][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]([C:33]3[CH:34]=[CH:35][C:36]([CH:37]=[CH:15][C:6]4[O:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8](=[C:10]([C:11]#[N:12])[C:13]#[N:14])[CH:7]=4)=[CH:39][CH:40]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(N2N=C(c3ccccc3)CC2c2ccccc2)cc1
Reactant: CC1=CC(=C(C#N)C#N)C=C(C(C)C)O1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)C1=CC(=C(C#N)C#N)C=C(C=Cc2ccc(N3N=C(c4ccccc4)CC3c3ccccc3)cc2)O1
Temperature: 75 °C

Procedure:
As shown in the following reaction 9, 0.5 g (2.5 mmol) of 2-(2-isopropyl-6-methyl-pyran-4-ylidene)-malononitrile and 0.815 g (2.5 mmol) of 4-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-benzaldehyde were added into 20 ml of ethanol, and 0.32 g (3.75 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH:4]([OH:12])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(Cl)(Cl)Cl.[CH2:17]([N:24]=[C:25]=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[OH:12][CH:4]([CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][O:2][NH:1][C:25]([NH:24][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:26]
Reactant: CCCCCCCN=C=O
Reactant: NOCC(O)CN1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCNC(=O)NOCC(O)CN1CCCCC1
Reaction time: 20 h

Procedure:
To the solution of 1.23 g (7.1 mmol) of l-aminooxy-2-hydroxy-3-(1-piperidinyl)-propane dissolved in 20 ml of chloroform 1.0 g (7.1 mmol) of heptyl isocyanate was added and the reaction mixture was stirred for 20 hours. Solvent was evaporated in vacuum and the residue was purified by chromatography to give pure colorless oil. White crystalline product was obtained by triturating with petroleum ether.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([CH3:13])=[N:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.N1C=CC=CC=1>CO.C(Cl)Cl>[CH3:13][C:5]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:3][N:4]=1
Reactant: C1CNCCN1
Reactant: Cc1nnc(Br)n1-c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1nnc(N2CCNCC2)n1-c1ccccc1
Reaction time: 22 h

Procedure:
A mixture of 3-bromo -5-methyl-4-phenyl-4H-1,2,4-triazole (4.16 g), 15.07 g of piperazine and 20 ml of pyridine is stirred at 100° under nitrogen for 22 h. The reaction is monitored by TLC (8% methanol/methylene chloride) and after this period of time no change occurs. The mixture is subsequently placed in a Parr bomb and heated in an oil bath at 180° for 24 h. Bomb pressure increases by 40 psi. The mixture is worked up by partitioning between chloroform and water. The organic phase is washed with saturated aqueous sodium bicarbonate (2×) and with saline (2×), dried over sodium sulfate and concentrated to a solid, the product is recrystallized in ethyl acetate. MS [M+H]+243.1484.
Reaction SMILES: [CH:1]12NC(CC1)CC(C1C3C=CC(C4C=CC=CC=4NC(=O)C)=CC=3OC3C1=CC=CC=3)C2.N1C=CC=C(C2C=CC3C(C4CC5NC(CC5)C4)C4C(OC=3C=2)=CC=CC=4)C=1.[O:61]1[CH:65]=[CH:64]C=[C:62]1[CH2:66][N:67]1[CH:72]2[CH2:73][CH2:74][CH:68]1[CH2:69][CH:70]([CH:75]1[C:88]3[CH:87]=[CH:86][C:85]([C:89]4[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=4[NH:95][C:96](=[O:98])[CH3:97])=[CH:84][C:83]=3[O:82][C:81]3[C:76]1=[CH:77][CH:78]=[CH:79][CH:80]=3)[CH2:71]2>>[O:61]1[CH:65]=[CH:64][C:66]([N:67]2[CH:68]3[CH2:74][CH2:73][C:72]2([CH3:1])[CH2:71][CH:70]([CH:75]2[C:88]4[CH:87]=[CH:86][C:85]([C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=5[NH:95][C:96](=[O:98])[CH3:97])=[CH:84][C:83]=4[O:82][C:81]4[C:76]2=[CH:77][CH:78]=[CH:79][CH:80]=4)[CH2:69]3)=[CH:62]1
Reactant: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Reactant: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2Cc1ccco1
Agent: c1cncc(-c2ccc3c(c2)Oc2ccccc2C3C2CC3CCC(C2)N3)c1
Product: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C)(C1)N2c1ccoc1

Procedure:
Using an adaptation of the method described in Procedure 12, substituting N-{2-[9-(8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthen-3-yl]-phenyl}-acetamide, 7b for 3-(3-pyridin-3-yl-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]octane, 3b, title compound N-{2-[9-(8-furan-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthen-3-yl]-phenyl}-acetamide, 13b was obtained as a TFA salt. MS m/z (MH+) 505.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]1[C:15](=O)[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12]1.[NH4+:23].[OH-].Cl>CC(C)=O>[CH3:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]([C:15]([NH2:23])=[O:14])=[N:10]1
Reactant: [NH4+]
Reactant: Cc1c(Cl)cccc1NN=C1N=C(c2ccccc2)OC1=O
Agent: Cl
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1c(Cl)cccc1-n1nc(C(N)=O)nc1-c1ccccc1
Yield: 78.2 %

Procedure:
6.2 g (0.019 mole) of 4-(2-methyl-3-chlorophenylhydrazono)-2-phenyl-oxazoline-5-one (R1 =2--CH3, R2 =3--Cl and R3 =H in the formula II) was added to 60 ml of acetone with stirring. To the resulting mixture, 3 ml of 29% solution of NH4OH (0.024 mole) was added dropwise at room temperature. Then the mixture was refluxed for 25 minutes and heating was stopped. After 3 ml of concentrated hydrochloric acid was added dropwise, and then the mixture was refluxed again for 5 minutes. The obtained reaction mixture was filtered while hot, and 80 ml of water was added to the filtrate. The obtained mixture was allowed to stand for cooling to obtain a product. The product was filtered out, washed with acetone containing water and dried. The crystal was recrystallized from 60 ml of ethanol to obtain 4.8 g of almost colorless crystal, m.p. 198°-200° C., with a yield of 78.2%.
Reaction SMILES: [F:1][CH:2]([F:11])[S:3][CH2:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:1][CH:2]([F:11])[S:3][CH2:4][C:5](=[N:13][OH:14])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)CSC(F)F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(CSC(F)F)=NO

Procedure:
A mixture of 1-difluoromethylthio-3,3-dimethyl-2-butanone (2.21 moles) from example 1, hydroxylamine hydrochloride (2.44 moles) and sodium carbonate (1.22 moles) in aqueous ethanol (1 liter of water and 2.3 liters of ethanol) was heated at its reflux temperature for 7.5 hours. This reaction mixture was poured into water, and the product was extracted into diethyl ether. The ether was washed with water and dried, then the ether extracts were evaporated under reduced pressure leaving a residue of 1-difluoromethylthio-3,3-dimethyl-2-butanone oxime. A pure sample, m.p. 92° to 95°C., was obtained by recrystallization from a mixture of diethyl ether and petroleum ether (b.p. 30° to 60°C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]5[N:28]=[CH:29][N:30](COCC[Si](C)(C)C)[C:31]=5[C:21]=4[O:20][C:19]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(OC(=O)NC1(C2C=CC(C3C(=O)C4C=CC5N(COCC[Si](C)(C)C)C=NC=5C=4OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]5[N:28]=[CH:29][NH:30][C:31]=5[C:21]=4[O:20][C:19]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5ncn(COCC[Si](C)(C)C)c54)c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c4ncn5COCC[Si](C)(C)C)c3=O)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nc[nH]c54)c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution, containing a mixture of (1-{-4-[6-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester and (1-{4-[6-oxo-8-phenyl-3-(2-trimethylsilanyl-ethoxymethyl)-3,6-dihydro-chromeno[7,8-d]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (11 mg, 0.017 mmol), in DCM (1.0 mL) was added TFA (0.25 mL). The reaction mixture was stirred at RT for 18 h. After this time the reaction mixture was concentrated in vacuo. The resultant residue was triturated with DCM (×2) and dried in vacuo to furnish the title compound (7.4 mg, 84%). LCMS (Method E): RT=2.76 min, [M+]+=408. 1H NMR (400 MHz, DMSO-d6): 8.69 (s, 1H), 8.67 (br s, 1H), 8.12 (d, J=8.6 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.71-7.61 (m, 5H), 7.59-7.51 (m, 4H), 2.84-2.75 (m, 2H), 2.74-2.64 (m, 2H), 2.40-2.28 (m, 1H), 2.07-1.95 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[CH2:1]([O:8][C:9]([NH:10][CH2:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:26]([OH:28])=[O:27])[CH:34]=2)=[CH:19][CH:18]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNC(=O)OCc1ccccc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: Cc1noc(-c2ccc(-c3cccc(C(=O)O)c3)cc2)c1CNC(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-carbamic acid benzyl ester and 3-carboxyphenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH3:18])[N:12]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11](/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:16]=1
Reactant: COc1ccc(/C=C/c2nc(C)cc(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(/C=C/c2nc(C)cc(Cl)n2)cc1
Yield: 94.7 %

Procedure:
In analogy to example 12c), by heating (E)-2-[2-(4-methoxy-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (0.3 g, 1.24 mmol) in POCl3 (2.27 ml, 24.76 mmol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(4-methoxy-phenyl)-vinyl]-6-methyl-pyrimidine (0.306 g, 94%) as a light yellow solid. EI mass spectrum, m/e: 260.1 (M calculated for C14H13ClN2O: 260).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1)(=O)=O>CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CS(=O)(=O)c1nccc2ccccc12
Solvent: CO
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nccc3ccccc23)c1
Yield: 18.2 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.04 g) and 1-methylsulphonylisoquinoline (1.70 g) were fused at 135° C. for 51/4 hours. The cooled reaction mixture was taken up in methanol, filtered, evaporated and subjected to medium pressure column chromatography on silica (chloroform:methanol 1:19 - second column using chloroform) to give the title compound (0.56 g) as an oil. This was treated with maleic acid (0.35 g) in warm ethanol to yield, on cooling, 1-[3-[3-(piperidinomethyl)phenoxy]propylamino]isoquinoline dimaleate (0.15 g), m.p. 103°-5° C. (recrystallised from ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:29][C:30]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[S:29][C:30]=3[CH3:31])=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (1.20 g), 4-chloromethyl-5-methyl-2-phenylthiazole (0.95 g), potassium carbonate (1.06 g), and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (10 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (1.46 g, yield: 81%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 73–74%.
Reaction SMILES: C(Cl)(=O)C.[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Cl:46])[C:11]=1[C@H:12]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH2:38][O:39]C2CCCCO2)[CH:36]=1)[CH3:13]>CO>[Cl:46][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:5])[C:11]=1[C@H:12]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH2:38][OH:39])[CH:36]=1)[CH3:13]
Reactant: C[C@@H](Oc1ccc2c(c1)c(/C=C/c1cnn(CCOC3CCCCO3)c1)nn2C1CCCCO1)c1c(Cl)cncc1Cl
Solvent: CO
Solvent: CC(=O)Cl
Product: C[C@@H](Oc1ccc2[nH]nc(/C=C/c3cnn(CCO)c3)c2c1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Charge a 3-neck, 250 mL round bottom flask equipped with an addition funnel, nitrogen inlet, internal temperature probe and magnetic stirrer with methanol (57 mL) and cool in an ice bath. To the resulting solution, add acetyl chloride (20 mL, 281.03 mmol) slowly through an addition funnel. To the solution, add 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazole (7.1 g, 11.59 mmol) dissolved in methanol (40 mL) via addition funnel. After addition is complete, remove the ice bath, warm to RT and stir the mixture for 4 hours. Concentrate the reaction mixture in vacuo to a yellow foam. Dissolve the yellow foam in methanol (10 mL) and add slowly to a saturated aqueous sodium bicarbonate solution (120 mL). Stir the mixture at RT for 30 minutes. Filter the mixture, wash the solid with water (100 mL), and dry under vacuum. Recrystallize the solid from hot EA/methanol/hexanes to give the title compound as a white solid. Yield: 2.1 g (41%). MS (ES) m/z 444 [M+1]+.