Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:14])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1](=[O:14])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCC/C=C/CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCCCCC/C=C/C=O

Procedure:
To undecyl aldehyde (5.0 g) dissolved in methylene chloride was added (carbomethoxymethylene)-triphenylphosphorane (14.7 g), and the mixture was stirred for 2 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans-2-tridecenoic acid (55.2 g). To the methyl ester dissolved in tetrahydrofuran was added lithium aluminium hydride (0.9 g) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was distributed into ethyl acetate and water, and the ethyl acetate layer was dried, concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (50:1) to give trans-2-tridecenol (3.2 g). To the solution of the trans-2-tridecenol in methylene chloride were added pyridinium chlorochromate (3.2 g) and Celite (5.0 g), and the mixture was stirred. The reaction mixture was filtered and concentrated to give trans-2-tridecenal (1.7 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3]1.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[C:29](Cl)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=2)=[O:27])=[CH:21][CH:20]=1>CO>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[C:29]([NH:1][CH:2]3[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3]3)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: NC1CCS(=O)(=O)C1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NC2CCS(=O)(=O)C2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
To a suspension of 3-amino-1,1-dioxotetrahydrothiophene (345 mg, 2.01 mmol) in methanol (5 mL) was added DIPEA (350 μL) followed by 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (200 mg, 0.67 mmol). The mixture was allowed to stir for 16 h. The resulting mixture was poured into ice-water and the resulting solids were collected by filtration. The solids were washed with ethyl acetate and hexanes and were dried. This afforded 147 mg (0.37 mmol, 55% yield) of the titled product as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.78 (d, 1H), 8.65 (s, 1H), 7.65 (m, 2H), 7.18 (m, 2H), 4.87 (m, 1H), 3.52 (m, 1H), 3.35–3.04 (m, 3H), 2.50, M, 1H), 2.22 (m, 1H); MS (EI) m/z 395.05 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[O:7])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)CCl
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCN(CC)C(=O)COC(=O)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-aminobenzoic acid (1.37 g. 0.01 mole), 2-chloro-N,N-diethylacetamide 2.0 ml, 0.015 mole) and 1.8-diazabicyclo[5.4.0]-undec-7-ene (1.52 g, 0.01 mole) in benzene (20 ml) was stirred at 80° C. for 4 h and then evaporated in vacuo. The residue was taken up in ethyl acetate. After washing with 5% sodium bicarbonate and water the ethyl acetate extract was dried and evaporated in vacuo leaving crude title compound. Recrystallization from ethanol-water gave 1.5 g (60%). Mp 135°-136° C.
Reaction SMILES: OS1C2C=CC=CC=2N=C1.C1(N=C=NC2CCCCC2)CCCCC1.N[CH:27]1[C:34](=[O:35])[N:33]2[CH:28]1[S:29][CH2:30][C:31](C1SC(NC3C=NC=CC=3)=NC=1)=[C:32]2C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O.CON=C(C1N=C(NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)SC=1)C(O)=O>CN(C)C=O.C(O)(=O)C>[O:35]=[C:34]1[N:33]2[CH:28]([S:29][CH2:30][CH:31]=[CH:32]2)[CH2:27]1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CSC12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O[SH]1C=Nc2ccccc21
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1CC2SCC=CN12
Reaction time: 0.5 h
Yield: 517.2 %

Procedure:
1-Hydroxybenzothiazole (3.24 g) and N,N'-dicyclohexylcarbodiimide (4.95 g) are added to a solution, cooled to 5° C., of 7-amino-2-benzhydryloxycarbonyl-3-[2-(pyridin-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene (10.83 g) and the syn isomer of 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid (10.65 g) in dry N,N-dimethylformamide (200 cc). The mixture is stirred for 30 minutes at +5° C. and then for 4 hours at 20° C. Acetic acid (1 cc) is added to the reaction mixture and the precipitate is then filtered off. The filtrate is diluted with ethyl acetate (900 cc) and the organic phase is washed successively with distilled water (2×500 cc), a decinormal solution of hydrochloric acid (500 cc), a semi-saturated solution of sodium bicarbonate (500 cc), distilled water (2×500 cc) and a semi-saturated solution of sodium chloride (500 cc). After the organic phase has been dried over magnesium sulphate and filtered and the filtrate concentrated under reduced pressure (30 mm Hg; 4 kPa), a hard yellow foam is obtained which is purified by chromatography on a column (height 61 cm, diameter 4.8 cm) containing silica gel (0.06-0.20 mm), elution being carried out with a 25/75 (by volume) mixture of cyclohexane and ethyl acetate (2 liters) and ethyl acetate (500 cc) and 250 cc fractions being collected. Fractions 5 to 14 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. This gives the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-3-[2-pyridin-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (14.6 g) in the form of a hard, bright yellow foam.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[Cl:30])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:29].[NH2:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[Cl:30])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2Cl)cc1
Reaction time: 2 h

Procedure:
To (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(2′,5′-dichlorobiphenyl-4-yl)butanoate (1.09 g, 2.33 mmol) is added a solution of 4 M HCl in 1,4-dioxane (5.81 mL, 23.3 mmol) at room temperature. After stirring for 2 hours, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(2′,5′-dichlorobiphenyl-4-yl)butanoate hydrochloride. Next, a solution of the product, succinic anhydride (280 mg, 2.80 mmol) and DIPEA (0.489 mL, 2.80 mmol) in dichloromethane (15 mL) is allowed to stir for 2 hours. The reaction is quenched with 1 M aqueous HCl and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(2′,5′-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (553 mg) as a white solid; HPLC retention time=1.02 minutes (condition B); MS (m+1)=452.14; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.2 Hz, 3 H) 2.47-2.67 (m, 6 H) 2.89 (A of ABX, Jab=13.7 Hz, Jax=7.8 Hz, 1 H) 3.00 (B of ABX, Jab=13.7 Hz, Jbx=6.7 Hz, 1 H) 4.12-4.24 (m, 2 H) 4.49-4.57 (m, 1 H) 6.53 (br d, J=8.8 Hz, 1 H) 7.23-7.26 (m, 3 H) 7.32-7.40 (m, 4 H).
Reaction SMILES: [OH-:1].[K+].[N:3]1([CH2:14][CH2:15][C:16](N)=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=O)[C:4]1=[O:5].C1C[O:22]CC1>>[OH:1][C:14]1[C:15]([CH3:16])=[C:6]([C:4]([OH:22])=[O:5])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: NC(=O)CCN1C(=O)C(=O)c2ccccc21
Agent: [K+]
Product: Cc1c(O)nc2ccccc2c1C(=O)O

Procedure:
Potassium hydroxide (1N, 100.0 ml) is added to a mixture of 5-fluoroisatin acetamide (IV, 8.44 g) and THF (33 ml). The mixture is heated at reflux for 1 hr, allowing the THF to distill off. The mixture is then cooled to 5° and is extracted with methylene chloride (3×50 ml). The basic layer is neutralized with hydrochloric acid (4N, 16.3 ml) and the resulting solids collected and washed with water (200 ml) and methylene chloride (100 ml) to give 6-fluoro-2-hydroxyquinoline-4-carboxylic acid (V), mp >293°; IR (mineral oil) 1714, 1648, 1623, 1508, 1436, 1261, 1255, 1244, 1234 and 1222 cm-1 ; NMR (d6 -DMSO) 12.20, 8.04, 7.35-7.60 and 7.00 δ; MS (El, m/e) 207, 162, 135 and 107.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7]O.P(Br)(Br)[Br:12]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7][Br:12]
Reactant: Cc1ccc(Br)cc1CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cc1ccc(Br)cc1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 181.2 %

Procedure:
24.4 g (121 mmol) of 5-bromo-2-methylbenzyl alcohol was dissolved in 200 ml of anhydrous diethyl ether, and to the resulted solution was dropped 16.4 g (60.7 mmol) of phosphorus tribromide under ice cooling. The mixture was stirred further for 3 hours under ice cooling, then, the reaction solution was poured into ice water, then, separated. The organic layer was washed with water, saturated sodium bicarbonate solution and saline sequentially, dried over anhydrous magnesium sulfate, then, concentrated to obtain 29.1 g (110 mmol) of 5-bromo-2-methylbenzyl bromide in the form of brown solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure B to give, after purification by reverse HPLC, 10 mg of 221. MS (Q1) 491 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Li]CCCC.[CH:35](=[O:37])[CH3:36].C(O)(C(F)(F)F)=O>CCOCC.C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:23]3[CH:28]=[CH:27][C:26]([CH:35]([OH:37])[CH3:36])=[CH:25][CH:24]=3)[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(c3ccc(Br)cc3)Oc3ccccc3O2)CC1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(O)c1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(4-bromo-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 277) (742 mg, 1.61 mmol) in Et2O (20 mL) cooled to −78° C. was added BuLi (2.5M in Hexanes, 0.80 mL, 2.0 mmol) and the mixture was stirred at −10° C. for 1 hour. The mixture was cooled to −78° C., acetaldehyde (0.5 mL) was added and the mixture was warmed to room temperature and stirred for 30 minutes. Work-up and purification gave the desired substrate. To the substrate in CH2Cl2 (3 mL) were added H20 (2 drops) and TFA (1 mL) and the mixture was stirred at room temperature for 1 hour to afford 1-[4-(2-piperidin-4-yl-benzo[1,3]dioxol-2-yl)-phenyl]-ethanol as a pale yellow solid (170 mg, 32% over 2 steps) after basic work-up and purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([NH2:38])[CH2:36][CH3:37].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:38][CH2:35][CH2:36][CH3:37])=[O:33])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCN
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propylamine (21 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the solution was purified by HPLC by development with chloroform/methanol to give 30 mg (yield 47%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN(C1C=CC=CN=1)C>ClCCl>[C:36]([N:18]1[CH2:19][CH2:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:16][CH2:17]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCCC2C(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccccc3)CCC2C(=O)OC(C)(C)C)cc1

Procedure:
tert-Butyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl)-1,4-diazepane-5-carboxylate (0.425 g, 0.96 mmol) in dichloromethane at 25° C. (10 mL) was treated with triethylamine (0.28 mL, 2.02 mmol) followed by benzoyl chloride (0.12 mL, 1.06 mmol) and dimethylaminopyridine (10 mg). After 18 hours aqueous workup gave tert-butyl 1-benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylate. 1H NMR (dmso-d6, 300 MH): 1.24 (s, 9H, t-bu), 1.82(s, 3H, CH3 ), 2.0-4.0 (m, 81, CH2 ), 4.65 (s, 1H, CM, 4.85 (s. 21H, CH2 ), 7.0-7.9 (m, 9H, ArH). Treatment with trifluoroacetic acid (4 mL) in dichoromethane (10 mL) for 6hours gave, after concentration in vacuo followed by chromatography on silica gel eluting with dichloromethane/methanol, 1-benzoyl4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylic acid as a foam (0.328 g).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:20][CH:19]4[CH2:21][CH:16]3[CH:17]=[CH:18]4)=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH3:24])[C:5]1=[O:6])[CH2:2][CH3:3].[H][H]>C(O)C.[Pd]>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:20][CH:19]4[CH2:21][CH:16]3[CH2:17][CH2:18]4)=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH3:24])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4C=CC3C4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC3C4)nc2n(CCC)c1=O
Yield: 39.1 %

Procedure:
1.0 g (3.1 mmol) of 1,3-dipropyl-8-(5-norbornen-2-yl)xanthine are hydrogenated under pressure in 30 ml of ethanol, with the addition of palladium/charcoal, until no further uptake of hydrogen can be detected. The catalyst is filtered off, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel (Ch2Cl2/CH3OH 99:1). 0.4 g of the title compound are obtained in the form of white crystals (39% of theory), m.p. 136°-138° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([NH:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1.Cl.[N:23]([O-])=[O:24].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N:18]([CH3:19])[N:23]=[O:24])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1
Reactant: CNc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N(C)N=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.9 g. of 2,4-diamino-5-[3,5-dimethoxy-4-(methylamino)-benzyl]pyrimidine in 40 ml. of 1N hydrochloric acid was treated dropwise with a solution of 830 mg. of sodium nitrite in 10 ml. of water with stirring and ice-cooling. The mixture was stirred for 3 hours at room temperature and then sodium carbonate was added to obtain an alkaline reaction. The precipitate was removed by filtration with suction, washed with water and recrystallized from methanol, whereby there was obtained 2,4-diamino-5-[3,5-dimethoxy-4-(methylnitrosoamino)-benzyl]-pyrimidine having a melting point of 249°-250° C. (decomposition).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[CH3:32])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1ccccc1C=O
Product: Cc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-methylbenzaldehyde. MS (ESI) m/z 483.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[H][H].[Cl:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[CH2:11]Br>O1CCCC1>[CH2:3]([O:5][CH2:11][C:10]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:9]=1[Cl:8])[CH3:4]
Reactant: CCO
Reactant: [H][H]
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetrahydrofuran (50 ml) was added to stirred sodium hydride (1.26 g, 0.053 mole) under a nitrogen atmosphere while being cooled in an ice-water bath. Absolute ethanol (5 ml) was then added dropwise and the reaction stirred until hydrogen evolution ceased. A solution of 2-chloro-4-fluorobenzyl bromide (10.62 g, 0.0475 mole ) in tetrahydrofuran (10 ml) was then added to the reaction mixture. The reaction mixture was allowed to stir at ambient temperature overnight. Ethanol and tetrahydrofuran were removed under reduced pressure. The reaction mixture was diluted with diethyl ether (200 ml), washed with water (4×75 ml), dried (magnesium sulfate) and concentrated under reduced pressure to remove solvent. The residue was distilled at low pressure yielding 5.27 g of 2-chloro-4-fluorobenzyl ethyl ether, b.p. 67°-68° C./10 mm Hg. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([NH:13][C:14]2[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([C:21]3[N:25]=[C:24](C(Cl)(Cl)Cl)[O:23][N:22]=3)[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[C:7]1([NH:13][C:14]2[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([C:21]3[N:25]=[C:24]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[O:23][N:22]=3)[N:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: Nc1nc(Nc2ccccc2)nc(-c2noc(N3CCCCC3)n2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
Piperidine (0.483 mL, 4.902 mmol) was added to a solution of 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 134, 0.913 g, 2.451 mmol) in dioxane (4 mL) at room temperature. The reaction mixture was stirred at room temperature for two days before being concentrated. The resulting residue was dissolved in EtOAc and water, and washed successively with 1M aq. HCl and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by flash chromatography (heptane:EtOAc 3:2) to afford the title compound (100 mg, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(Br)c1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a vigorously stirred suspension of 3-bromo4-hydroxy-5-methoxy-benzaldehyde (15.20 g, 65.8 mmol), AlCl3 (9.65 g, 72.4 mmol) in CH2Cl2 (100 mL) at 0° C. with exclusion of moisture was added pyridine (22.90 g, 290 mmol, 23.4 mL) to keep the temperature below 32° C. The resulting clear dark solution was heated to reflux for 24 hours and cooled to RT. The mixture was poured into a slurry of 1 N HCl and ice. The CH2Cl2 layer was removed and the aqueous suspension was extracted with ether till clear. The combined ether layers were dried over anhydrous magnesium sulfate, filtered and evaporated to a volume of approximately 200 mL and cooled to 0° C. for 2 hours. The resulting suspension was collected by filtration and dried under high vacuum to give 10.12 g of 3-bromo-4,5-dihydroxybenzaldehyde (71%) as a tan solid. 1H NMR (500 MHz; CDCl3): δ 7.18 (s, 1H); 7.37 (d, J=2.0 Hz, 1H); 8.48 (brs, 1H); 9.40 (brs, 1H); 9.56 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:19](Cl)[O:20][CH2:21][CH2:22][O:23][CH3:24]>C(Cl)Cl>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COCCOCCl
Reactant: O=Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 4-hydroxy-benzaldehyde (3.7 g, 30 mmol) and diisopropylethylamine (7.6 mL) in CH2Cl2 (60 mL) was added MEMCl (5.0 mL) in CH2Cl2 (17 mL) dropwise at 0° C. The mixture was stirred at RT for 3 h, quenched with Hcl (60 mL, 0.5 N). The mixture was extracted with CH2Cl2. The organic phase was washed with NaOH solution (1 N) and water. The separated organic phase was dried under Na2SO4, filtered and concentrated to give 6.2 g of product (97%) which was pure enough to be used to the next reaction without further purification. 1HNMR (200 MHz, CDCl3): δ 3.36 (s, 3H), 3.54 (m, 2H), 3.83 (m, 2H), 5.41 (s, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 9.90 (s, 1H).