Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4](Br)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[OH:19][C:13]1[CH:18]=[CH:17][C:16]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([C:16]5[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=5)([CH2:5]4)[CH2:3]2)[CH2:9]3)=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: BrC12CC3CC(C1)CC(Br)(C3)C2
Solvent: CO
Product: Oc1ccc(C23CC4CC(C2)CC(c2ccc(O)cc2)(C4)C3)cc1
Temperature: 185 °C
Reaction time: 5 h

Procedure:
1,3-Bis(4-hydroxyphenyl)adamantane (1,3-BPA) was synthesized as an aromatic diol monomer. First, 1,3-dibromoadamantane (1.876 g, 6.38 mmol) and phenol (28.1 mL, 0.32 mol) was added to a 50 mL 3-bulb flask, slowly heated to 185° C. under nitrogen atmosphere and stirred for 5 hours. After dissolving in 10 mL methanol, followed by precipitating in water (200 mL) at 60° C., the precipitate was filtered from the hot solution and then purified with MC and water. Thus obtained 1,3-BPA was recrystallized with MC to obtain pure 1,3-BPA (yield: 75%) of the following structure. Melting temperature was 200° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B.[Na].O>C(O)(C)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)cc2)cc1
Agent: B
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
4'-Octyloxy-4-formyl-biphenyl (30 g) was suspended in isopropyl alcohol (100 ml), followed by pouring in the resulting suspension, a suspension of sodium boron hydride (1.22 g) in isopropyl alcohol (100 ml), stirring the mixture at 70° C. for 4 hours, adding 6H-HCl (20 ml) and water (10 ml), stirring the mixture at 70° C. for 2 hours, allowing to stand overnight, filtering and collecting the resulting crystals and recrystallizing from ethanol to obtain 4'-octyloxy-4-hydroxymethyl-biphenyl (28.5 g) having a m.p. of 141.6° C. This product (16 g) together with thionyl chloride (12 g) were heated for 6 hours, followed by distilling off excess thionyl chloride and recrystallizing the residue from toluene-heptane to obtain 4'-octyloxy-4-chloromethyl-biphenyl (IIa-8) (14.8 g) having a m.p. of 101° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([F:14])=[C:12]2[C:7]([CH:8]=[C:9](/[CH:17]=[CH:18]/[C@H:19]3[CH2:24][CH2:23][C@H:22]([C@H:25]4[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[C:10]([F:16])=[C:11]2[F:15])=[CH:6][CH:5]=1)[CH3:2].[H][H]>[C].[Pd].O1CCCC1>[CH2:1]([O:3][C:4]1[C:13]([F:14])=[C:12]2[C:7]([CH:8]=[C:9]([C:17]3[CH:6]=[CH:5][CH:4]=[CH:13][C:18]=3[C@H:19]3[CH2:24][CH2:23][C@H:22]([C@H:25]4[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:10]([F:16])=[C:11]2[F:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/c3cc4ccc(OCC)c(F)c4c(F)c3F)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccccc3-c3cc4ccc(OCC)c(F)c4c(F)c3F)CC2)CC1

Procedure:
The crude production of (E)-7-ethoxy-3-[2-[trans-4-(trans-4-butylcyclohexyl)cyclohexyl]ethenyl]-1,2,8-trifluoronaphthalene (16.6 g), 5% palladium-carbon (with 10% moisture) (3.1 g), tetrahydrofuran (100 ml) were added in an autoclave and reacted for 4 hours at room temperature under 4 atm of hydrogen. The reaction solution was filtrated with celite, and the filtrate was concentrated. Then, 7-ethoxy-3-[2-[trans-4-(trans-4-butylcyclohexyl)cyclohexyl]phenyl]-1,2,8-trifluoronaphthalene (9 g) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:38][S:35]([N:32]1[CH2:31][CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:24][CH:25]=2)[CH2:34][CH2:33]1)(=[O:36])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(OCC3CCNCC3)cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
Trifluoroacetic acid (2.98 g, 1.97 mL, 26.10 mmol) is added to a solution of 4-[4-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 2.61 mmol) in dichloromethane (13 mL). The mixture is stirred at 23° C. for 30 min. 2 M aq. sodium hydroxide is added. The resulting white precipitate is filtered and washed with water. The mother liquor is extracted with dichloromethane. The combined organic layers are dried over anhydrous sodium sulfate, filtered, and the solvent is removed to obtain a white solid which is combined with the initial precipitate and dried under high vacuum for 16 h. Diethyl ether is added and the solid is filtered and washed with ethyl acetate to obtain 0.810 g of an off-white solid. MS (m/z) 351 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1cccc(Br)c1
Product: Clc1ccc(-c2nn(Cc3cccc(Br)c3)c3c2CCNCC3)cc1
Yield: 48 %

Procedure:
The title compound (0.04 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 3-bromobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H19BrClN3, 415.05. found, m/z 416.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-6.86 (m, 8H), 5.36 (s, 2H), 3.30-3.27 (br m, 4H), 3.06-3.04 (m, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:17]([O:21][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: CCCCO
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, butanol and DBU in THF. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1ccccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.8 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-fluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.5 mg, 53.9% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.65 (m, 1H), 7.41 (s, 1H), 7.40–7.10 (m, 5H), 7.05 (m, 2H), 6.97 (apparent d, 1H, J=8.7 Hz), 6.86 (m, 2H), 6.79 (apparent dt, 1H, J=2.4, 7.9 Hz), 5.31 (apparent dd, 1H, J=4.5, 8.0 Hz), 3.39 (m, 2H), 2.97 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.5 Hz), 2.3–2.1 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 475.7 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:40][OH:41].C(N(CC)CC)C>O1CCCC1.CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]([NH:40][OH:41])=[NH:24])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1C#N
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1C(=N)NO
Temperature: 150 °C
Yield: 50.9 %

Procedure:
To a solution of 300 mg of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-benzonitrile in 1.8 mL of tetrahydrofuran and 2 mL of methanol was added 387 mg of hydroxylamine hydrochloride followed by 0.62 mL of triethylamine. The resulting mixture was heated to 150° C. under microwave irradiation for 10 minutes. After allowing it to cool down to room temperature, the mixture was concentrated under reduced pressure and dichloromethane/water were added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 50/ethyl acetate 50) to give 162 mg of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-hydroxy-2-methoxy-benzamidine.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:13][CH2:12]2)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.O>ClCCl.I[Si](C)(C)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]([CH:14]1[CH2:13][CH2:12][N:11]([CH2:10][C:4]2[C:3](=[O:2])[NH:8][C:7]([CH3:9])=[CH:6][N:5]=2)[CH2:16][CH2:15]1)=[O:26]
Reactant: COc1nc(C)cnc1CN1CCC(C(=O)Cc2ccccc2F)CC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: O
Product: Cc1cnc(CN2CCC(C(=O)Cc3ccccc3F)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27.2 %

Procedure:
After dissolving 352 mg of 1-[1-(3-methoxy-5-methyl-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone in 3 ml of dichloromethane, 0.5 ml of iodotrimethylsilane was added and the mixture was stirred for 45 minutes at room temperature. Next, 2 ml of iodotrimethylsilane was added and the mixture was further stirred for 2 hours at room temperature. Water was added to the reaction solution, the mixture was rendered alkaline with sodium carbonate, and extraction was performed with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: ethyl acetate/methanol). Diethyl ether was added and the mixture was filtered to obtain the title compound (92 mg, 27% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].COC(N1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])=O.O1CCCC1.Cl>C(=O)(O)[O-]>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][N:8]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])[CH3:11]
Reactant: CCOC(CCCN)OCC
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCOC(CCCN1C(=O)C=CC1=O)OCC
Reaction time: 0.25 h

Procedure:
As shown in FIG. 2, to a solution of 4-aminobutyraldehyde diethylacetal (5 g, 31 mmol) in 100 ml of saturated bicarbonate was added N-methoxycarbonylmaleimide (4.91 g, 31.6 mmol) at 0° C. (icebath). After 15 minutes, tetrahydrofuran (100 ml) was added at room temperature and the resultant mixture stirred for 1 hour. The resultant mixture was then acidified with 1 N hydrochloric acid to pH 6-7 and extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate/petroleum ether 1:2 to yield 4-maleimidobutyraldehyde diethylacetal as a yellow oil (4.31 g; 58%), TLC Rf=0.65, ethyl acetate/hexane 1:1.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[NH:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:7]1=O>>[N:1]1[NH:2][C:3](=[S:4])[N:5]=[C:7]2[C:9]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[NH:6]2
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(N)=S
Product: S=c1nc2[nH]c3ccccc3c2n[nH]1

Procedure:
In the general synthetic scheme, thiosemicarbazide is reacted with isatin to form 5H-1,2,4-triazino[5,6-b]indole-3(2H)-thione. This product is alkylated with an appropriate halo-derivative to provide the sulfur-substituent desired in the final product. ##STR3##
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:41]=[CH:40][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:31](=[O:39])[N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[C:20]([CH:30]=2)[O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][CH:6]=1.[C:42](OC1C=CC=CC=1)(=[O:44])[CH3:43].C(N(CC)CC)C>C(Cl)Cl>[C:42]([N:2]=[N:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:31](=[O:39])[N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[C:20]([CH:30]=2)[O:21][C:22]([CH3:28])([CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:40][CH:41]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)Oc1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C=NN)cc2)ccc1C(=O)N(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(CN=NC(C)=O)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 0.85 g (1.4 mmol) of ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride in 10 ml of methylene chloride is added 0.39 g (2.8 mmol) of phenyl acetate and 1 ml of triethylamine. The mixture is stirred at room temperature for 2 days and then poured onto a silica gel column and eluted with 80% ethyl acetate/hexane, and then pure ethyl acetate to give ethyl 5-[5-[4-[(acetylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate as a foam; CHN calculated for C33H47N3O7.0.5H2O:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(COc2cccnc2N)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (1.80 g, 0.0078 mol), 4chlorophenyl isothiocyanate (1.58 g, 0.0094 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.2 g (70.5%), m.p. 136°-138 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[CH2:16]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=O)[CH:27]=2)[N:22]=[C:21]([NH:31][CH3:32])[N:20]=1)[CH3:17].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:29][C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([NH:31][CH3:32])[N:20]=[C:19]3[O:18][CH2:16][CH3:17])[C:9](=[O:11])[N:10]=1
Reactant: O=C1CSC(NCc2ccccc2Cl)=N1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4ccccc4Cl)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-(2-chloro-benzylamino)-thiazol-4-one (example 13a, 38.5. mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 45 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 2-(2-chloro-benzylamino)-5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-thiazol-4-one as a brown solid: 43.2 mg (59.5%), MS: m/e 454 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[N:3]=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1.CCOC(C)=O>O>[ClH:1].[ClH:1].[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH:40][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[N:3]=2)[CH2:36][CH2:35]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNS(=O)(=O)c3ccc(C(F)(F)F)cc3)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
The operation is carried out as in Stage 2 of Example 10 starting from 188 mg of the product obtained in Stage 1 above and 440 mg of trans-1,4-diaminocyclohexane and the reaction medium is heated to approximately 140° C. for approximately 3 hours, left to return to 80° C., 5 ml of AcOEt then 5 ml of warm water are added, the reaction medium is left to return to ambient temperature, followed by extracting with 2×5 ml of ethyl acetate, washing with 5 ml of saturated sodium chloride, then drying. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 90/10/1, 5 ml of 1.4N hydrochloric acid/ ethanol is added, the reaction medium is left to crystallize, followed by filtering, rinsing with 5 ml of ether and drying under vacuum. In this way 148 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Cl:1]
Reactant: Cc1cccc(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CBr)c1Cl
Temperature: 25 °C

Procedure:
A solution of 2-chloro-m-xylene (5.00 g, 35.60 mmol), NBS (5.70 g, 32.03 mmol), and a catalytic amount of benzoyl peroxide (100 mg) in CCl4 was refluxed for 1 hour. After cooling to room temperature the resulting mixture was filtered and the filtrate was distilled off. Purification by column chromatography using pentane as the eluant followed by distillation afforded the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) δ 2.39 (s, 3H), 4.61 (s, 2H), 7.08-7.23 (m, 2H), 7.25-7.30 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CN=2)[CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:6]2[N:1]=[CH:2][C:3]([C:7]3[C:15]4[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=4)[NH:9][N:8]=3)=[CH:4][CH:5]=2)[CH2:21][CH2:20]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1

Procedure:
According to the procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2-yl)piperazine (67 mg, 0.22 mmol), the title compound was obtained as a beige solid (57 mg, 99%). 1H NMR (400 MHz, CD3OD) δ ppm 10.11 (s, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.8, 2.3 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 3.83-3.78 (m, 4H), 3.01 (t, J=5.0 Hz, 4H), 2.67 (s, 3H); MS ESI 322.1 (100) [M+H]+, calcd for [C18H19N5O+H]+ 322.16.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:8][CH:7]=1)=[O:4].[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>CN(C=O)C>[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:8][CH:7]=1)=[O:4]
Reactant: CCCCOc1ccc(NC(=O)CBr)cc1
Reactant: Nc1ccccc1F
Solvent: CN(C)C=O
Product: CCCCOc1ccc(NC(=O)CNc2ccccc2F)cc1
Temperature: 0 °C
Yield: 45.2 %

Procedure:
A solution of 4-((bromoacetyl)amino)-1-butoxybenzene (1.0 g, 3.5 mmol) and 2-fluoroaniline (1.0 g, 0.87 mL, 8.8 mmol) in anhydrous DMF (30 mL) was heated to 90°-100° C. overnight with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then extracted with CH2Cl2 (3×50 mL). The layers were separated and the organic layer was dried (MgSO4), filtered and then concentrated to an oily residue. Purification by chromatography, eluting with hexane-ethyl acetate (2:1), afforded 0.50 g (45%) of the title compound, mp 92°-94° C.: 1H NMR (DMSO-d6) δ9.86 (s, 1H), 7.47 (d, J=8.8, 2H), 7.04 (ddd, J=9.6, J=8.0, J=1.2, 1H), 6.94 (dt, J=8.0, J=0.8, 1H), 6.86 (d, J=9.6, 2H), 6.63-6.58 (m, 2H), 5.73 (bt, J=2.0, 1H), 3.90 (q, J=6.0, 2H), 3.46 (s, 2H), 1.68-1.64 (m, 2H), 1.44-1.40 (m, 2H), 0.91 (t, J=5.6, 3H); 13C NMR (DMSO-d6) δ168.24, 154.69, 150.90 (d, J=236), 136.46, 131.79, 124.73 (d, J=3.5), 120.79, 116.22 (d, J=6.3), 114.48 (d, J=5.6), 114.33 (d, J=126), 112.11 (d, J=3.6), 67.21, 46.57, 30.75, 18.70, 13.66; MS (El, m/z) 316 (M+).