Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[C:30]([N:34]1[C:38]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[C:37]([C:46]2[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=2[OH:53])[CH:36]=[N:35]1)([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:30]([N:34]1[C:38]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[C:37]([C:46]2[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=2[O:53][C:8]2[CH:7]=[CH:6][C:5]([S:10]([N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[C:14]3[S:18][N:17]=[CH:16][N:15]=3)(=[O:11])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])[CH:36]=[N:35]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: CC(C)(C)n1ncc(-c2cc(Cl)ccc2O)c1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3-c3cnn(C(C)(C)C)c3NC(=O)C(F)(F)F)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 150 mg, 0.35 mmol) in dimethyl sulfoxide (10 ml) was added N-[1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-5-yl]-2,2,2-trifluoroacetamide (Preparation 209, 131 mg, 0.36 mmol) and potassium carbonate (135 mg, 0.86 mmol) and the flask was purged with nitrogen (×3). The resulting suspension was stirred at room temperature for 18 hours before pouring into sodium hydroxide (1 M aqueous solution) and extracting with dichloromethane. The combined organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a pale yellow oil. This was purified by column chromatography (80 g silica gel column) eluting with ethyl acetate:heptane (1:1, by volume) to furnish the title compound as a pale yellow oil, 157 mg, 59% yield.
Reaction SMILES: Br[C:2]1[C:3]([Cl:17])=[CH:4][C:5]([NH2:16])=[N:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:3]1[C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)=[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[C:5]([NH2:16])[CH:4]=1
Reactant: OB(O)c1cncnc1
Reactant: Nc1cc(Cl)c(Br)c(C#Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1cc(Cl)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-4-chloro-6-(2-phenylethynyl)pyridin-2-amine C3a (1.0 g, 3.25 mmol), pyrimidin-5-ylboronic acid (604 mg, 4.88 mmol), Tetrakis(triphenylphosphine)palladium(0) (375 mg, 0.33 mmol), sodium carbonate (aqueous solution, 2 mol/l, 4.88 ml, 9.75 mmol) and ACN (15 ml) is stirred in a sealed tube at 120° C. until C3a is almost completely consumed. The mixture is then concentrated in vacuo and the product purified by NP chromatography. Yield: 420 mg (42%). HPLC-MS: M+H=307.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[N:5]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[O:21][CH3:22])[C:3]=1[C:23](=[O:25])[NH2:24].[Br-].[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:29]=1[CH2:30][Zn+]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([CH2:30][C:29]2[C:28]([Cl:27])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:36])[N:5]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[O:21][CH3:22])[C:3]=1[C:23](=[O:25])[NH2:24]
Reactant: Clc1cccc(Cl)c1C[Zn+]
Reactant: COC(=O)c1ccc(Nc2nc(SC)nc(N)c2C(N)=O)c(OC)c1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(N)c2C(N)=O)c(OC)c1
Temperature: 100 °C

Procedure:
A suspension of the product of Example 10B (1.1 g, 3.0 mmol), IM (2,6-dichlorobenzyl)zinc(II) bromide in tetrahydrofuran (30 mL, 30 mmol) and tetrakis(triphenylphosphine) palladium(0) (347 mg, 0.3 mmol) in tetrahydrofuran (50 mL) was heated in a sealed tube at 100° C. under nitrogen for 16 hours. The cooled mixture was washed with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (200-300 mesh) eluting with 3/1 petroleum ether/ethyl acetate to give the title compound. MS: 476 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:28][N:27]1[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([CH:7]=1)[O:8][CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:28][N:27]1[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38]
Reactant: Oc1cc(Cl)ccc1CCc1ccccc1
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1cc(Cl)ccc1CCc1ccccc1

Procedure:
680 mg of 5-chloro-2-(2-phenylethyl)phenol (prepared as described in Preparation 9) were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 360 mg of potassium t-butoxide and 1000 mg of (2S,4R)-2-(2-chloroethyl)-4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1 .38 g (yield 91%) of the title compound as an oily substance.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.CCN(C(C)C)C(C)C.[NH2:18][C@@H:19]([CH3:35])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=2)=[N:22]1>C(Cl)Cl>[Cl:34][C:28]1[CH:27]=[C:26]([C:23]2[CH:24]=[CH:25][N:21]([CH2:20][C@@H:19]([NH:18][C:6]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[O:8])[CH3:35])[N:22]=2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc[nH]n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc[nH]n1
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a mixture of 1H-pyrazole-3-carboxylic acid (89 mg, 0.767 mmol) in DCM (5 ml), was added DIPEA (0.40 ml, 2.30 mmol). O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniutnhexafluorophosphate (HBTU, 291.0 mg, 0.767 mmol) at RT. The mixture was stirred for 15 min and solid (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) was added. The reaction was stirred overnight at RT. The solvent was evaporated and water was added. The pH of the water phase was adjusted to 9-10 and the product was extracted to DCM. The organic layer was washed with water and brine, dried over Na2SO4 and evaporated. The crude product was purified with flash chromatography (DCM/EtOAc gradient) to give title compound 100 mg. 1H-NMR (400 MHz; d6-DMSO): δ 1.11 (d, 3H), 4.36 (m, 3H), 6.58 (t, 1H), 6.93 (d, 1H), 7.79 (m, 1H), 7.82 (d, 1H), 7.98 (d, 2H), 8.08 (bs, 1H), 8.25 (d, 1H), 13.20 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:20]=1)[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44](O)[CH:45]([CH3:47])[CH3:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:44]([O:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:20]=1)[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=[O:6])[CH:45]([CH3:47])[CH3:46]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(O)cc(OC(C)C)c2)nc1
Reactant: CC(C)CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)cc(OC(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl 6-[(3-hydroxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate (0.300 g, 0.91 mM), triphenylphosphine (0.238 g, 0.91 mM), iso-butanol (0.084 ml, 0.91 mM) and THF (8 ml) were combined and diisopropylazodicarboxylate (0.18 ml, 0.91 mM) was added dropwise. The mixture was stirred for 15 mins at ambient temperature. The reaction was concentrated under reduced pressure and the resulting brown oil was purified by column chromatography on Kieselgel 60, eluting with a gradient of 50–100% methylene chloride in iso-hexane and then 20% ethyl acetate in methylene chloride to give methyl 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate as a colourless solid (0.232 g); [M+H]+ 387; [M−H]− 385.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[Cl:8][CH2:9][CH2:10][NH2:11]>C1(C)C=CC=CC=1>[Cl:8][CH2:9][CH2:10][NH:11][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4]
Reactant: NCCCl
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: COCC(C=O)NCCCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. β-Chloroethylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-β-chloroethylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [CH:1](O)=O.C=O.N.C.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([OH:26])[C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[N:15]([NH:27][CH3:28])[CH:14]=[C:13]([C:29]([OH:31])=[O:30])[C:12]2=[O:32]>>[F:8][C:9]1[CH:10]=[C:11]2[C:12](=[O:32])[C:13]([C:29]([OH:31])=[O:30])=[CH:14][N:15]3[C:16]2=[C:17]([C:18]=1[N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)[O:26][CH2:28][N:27]3[CH3:1]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)c(O)c21
Reactant: O=CO
Agent: C=O
Agent: N
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OCN4C)CC1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To the dark brown reaction mixture of step 6) containing 12 340 ml of 85% formic acid (ca. 7.5 mol) were added dropwise during 5 minutes without exceeding a temperature of 50° C. In the temperature range of 40°-50° C. 75.0 ml of aqueous 36.5% formaldehyde (ca. 1.0 mol) were added over 5 minutes and the resulting brown suspension was heated to 70° C. for 30 minutes, during which time gas evolution occurred. After cooling to 5°-10° C. 300 ml of 25% aqueous ammonia (ca. 4 mol) were added and the resulting black solution was stirred for 30 minutes. To this solution 9 g of activated charcoal were added and the resulting black suspension was stirred for 15 minutes and filtered through a glass fibre filter. The filtrate was extracted with 5 portions of 1000 ml, in total 5000 ml, of methylene chloride. The combined extracts were filtered through a glass fibre filter to remove small amounts of insoluble by-products, and the dark brown filtrate was evaporated in a rotary evaporator at 50° C./20 torr to dryness to yield 107.6 g of brown crystals. The crystals were taken up in 400 ml of ethanol and the resulting slurry was stirred for 1 hour at 0°-5° C., filtered, and the filter cake was washed with 100 ml of ethanol to yield after drying at 50° C./35 torr overnight 83.7 g of crude 1 as yellow crystals. This crude material was suspended in a mixture of 835 ml of ethanol, 415 ml of toluene and 415 ml of water (deionized) and heated to reflux. From the clear yellow solution formed 835 ml of solvent mixture was distilled off, whereby the temperature rose from 74°-78° C., and a yellow precipitate was formed. The suspension was cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was washed with 3 portions of 60 ml, in total 180 ml, of ethanol to yield after drying at 50° C./35 torr overnight as the product 77.71 g (43% relative, to 6) of 1 as yellow crystals of m.p. 265°-268° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1>>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=3)[CH:5]=[CH:6][CH:7]=2)[CH:15]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1nc(-c2cccc(Br)c2)c[nH]1
Product: Nc1nc(-c2cccc(-c3cccnc3)c2)c[nH]1

Procedure:
In a similar manner to Example 33, Step 1, the Suzuki coupling reaction of the bromide from Step 1 of Example 37 (126 mg, 0.31 mmol) and pyridin-3-yl-boronic acid (96 mg, 0.78 mmol) afforded 4-(3-pyridin-3-yl-phenyl)-1H-imidazol-2-ylamine, after washing with 1N aqueous sodium hydroxide, as an off-white solid (51 mg, 69% yield). LC/MS (m/z 237.2 (M+H)+); HPLC Rt: 0.81 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=O)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[S:45])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (211 mg, 0.45 mmol) in toluene (15 mL) was added lawesson's reagent (181 mg, 0.45 mmol) under nitrogen. The resulting mixture was heated under reflux for 2 h. After cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 5% MeOH in dichloromethane) to give the title compound as a yellow solid (124 mg, 57%). 1H NMR (500 MHz, CDCl3): 9.47 (1H, br s), 7.30-7.24 (7H, m), 7.18 (1H, s), 7.16-7.14 (2H, m), 5.17 (2H, s), 5.04 (1H, br s), 2.55-2.25 (4H, m), 2.10-2.01 (1H, m), 1.85-1.76 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:23](=[O:38])[NH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:26]=2[OH:37])[CH2:17][CH2:16]1)=O)(C)(C)C>>[ClH:1].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:23](=[O:38])[NH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:26]=2[OH:37])[CH2:17][CH2:16]1
Reactant: COc1cc(NC(=O)N(Cc2ccccc2)CC2CCN(C(=O)OC(C)(C)C)CC2)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(NC(=O)N(Cc2ccccc2)CC2CCNCC2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
4N hydrogen chloride-dioxane solution (15 ml) was added to 1.50 g of 2-[3-(1-tert-butoxycarbonylpiperidin-4-yl)methyl-3-phenylmethylureido]-4-methoxy-6-tert-butylphenol, and the mixture was stirred at room temperature for 2 hours. Then, the mixture was evaporated to dryness under reduced pressure and the residue was recrystallized from an ethanol solution to give 0.912 g of 2-[3-(4-piperidylmethyl)-3-phenylmethylureido]-4-methoxy-6-tert-butylphenol hydrochloride (yield: 69%, melting point: 195°-196° C.).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10])=[O:25]
Reactant: COc1ccccc1C(=O)O
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Product: COc1ccccc1C(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-methoxy-benzoic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6](=[O:26])[N:7]([CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[C:8](=[O:18])[N:9]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=1.O[C:28]1[CH:42]=[CH:41][C:31]([O:32][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=1>>[O:18]=[C:8]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[C:6](=[O:26])[C:5]([NH:4][CH2:3][CH2:2][O:1][C:28]2[CH:42]=[CH:41][C:31]([O:32][C:33]([CH3:39])([CH3:40])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=2)=[N:10][N:9]1[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: O=c1c(NCCO)nn(CCCC(F)(F)F)c(=O)n1CCCC(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCNc2nn(CCCC(F)(F)F)c(=O)n(CCCC(F)(F)F)c2=O)cc1

Procedure:
Compound 41 (oil) is prepared from triazine 9a and from intermediate 10c according to synthesis method 2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:30][CH3:31])=O)C.[N:32]([C:35]1[CH:43]=[CH:42][C:38]2[O:39][CH2:40][O:41][C:37]=2[CH:36]=1)=[C:33]=[O:34]>>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:30][CH3:31])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:32]([C:35]3[CH:43]=[CH:42][C:38]4[O:39][CH2:40][O:41][C:37]=4[CH:36]=3)[C:33]2=[O:34])[CH2:22][CH2:21]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc4c(c3)OCO4)c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c12
Yield: 64.9 %

Procedure:
4-(3-Benzo[1,3]dioxol-5-yl-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (110 mg) was prepared from 4-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.31 mmol) and 5-isocyanato-benzo[1,3]dioxole (0.465 mmol) following general procedure C. LCMS: m/z 547 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 25 h
Yield: 90.8 %

Procedure:
To a solution of 6-(benzyloxy)-4-chloro-7-methoxyquinazoline (3.3 g, 0.01097 mol) and 3-aminophenol (1.2 g, 0.01097 mol) in THF (70 mL), Cs2CO3 (5.36 g, 0.0164 mol) was added at room temperature. The reaction mixture was stirred at 75° C. for 25 hr. The mixture was filtered and the solid was washed with ethyl acetate (100 mL). The organic phase was washed with water, brine and dried over MgSO4. The solvent was evaporated under vacuum and the solid was triturated with ethyl ether (20 mL). The solid was filtered and washed with ethyl ether to afford 3-(6-(benzyloxy)-7-methoxyquinazolin-4-yloxy)aniline (3.72 g, 90% yield). 1HNMR (DMSO-d6): δ 8.55 (s, 1H), 7.66 (s, 1H,), 7.46 (m, 8H), 7.08 (t, 1H), 6.49 (d, 1H), 6.40 (m, 2H), 5.30 (s, 2H), 4.02 (s, 3H). LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [CH2:1]([CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[Cr](Cl)([O-])(=O)=O.CCOCC>C(Cl)Cl>[CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of dilinoleyl methanol (2.0 g, 3.8 mmol) and anhydrous sodium carbonate (0.2 g) in 100 mL of CH2Cl2 was added pydimium chlorochromate (PCC, 2.0 g, 9.5 mmol). The resulting suspension was stirred at room temperature for 60 min. Ether (300 mL) was then added into the mixture, and the resulting brown suspension was filtered through a pad of silica gel (300 mL). The silica gel pad was further washed with ether (3×200 mL). The ether filtrate and washes were combined. Evaporation of the solvent gave 3.0 g of an oily residual as a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 250 mL) eluted with 0-3% ether in hexanes. This gave 1.8 g (90%) of dilinoleyl ketone (V). 1H NMR (400 MHz, CDCl3) δ: 5.25-5.45 (8H, m, 4×CH═CH), 2.78 (4H, t, 2×C═C—CH2-C═C), 2.39 (4H, t, 2×COCH2), 2.05 (8H, q, 4×allylic CH2), 1.45-1.7 (4H, m), 1.2-1.45 (32H, m), 0.90 (6H, t, 2×CH3) ppm.
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][CH2:8][CH2:9][S:10][C:11]1[N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:6])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][C:17]1[N:16]2[C:11]([S:10][CH2:9][CH2:8][NH:7][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:12][CH:13]=[CH:14][C:15]2=[N:19][CH:18]=1
Reactant: CC(C)OC(=O)NCCSc1cccc2nccn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)NCCSc1cccc2ncc(Br)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of 5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine (279 mg, 1 mmole) in chloroform (5 ml) was added N-bromosuccinimide (187 ml, 1.05 mmoles) and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 296 mg of the desired product (82.7%, colorless solid).