Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[S:13]1CC(O)S[CH2:15][CH:14]1O.C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:13][CH:14]=[CH:15][C:8]=1[C:6]([C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: Cc1ccc(C(=O)CC#N)cc1
Reactant: OC1CSC(O)CS1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(=O)c2ccsc2N)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 130.2 %

Procedure:
To a suspension of 4-methylbenzoylacetonitrile (0.325 g; 2.042 mmol) and p-dithiane-2,5-diol (0.155 g; 1.018 mmol) in ethanol (4.3 mL) cooled at 0° C. was added triethylamine (0.283 mL; 2.042 mmol). After 10 min at room temperature, the reaction mixture was heated under reflux for 2 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (10-25%) in heptane to afford the title compound (0.288 g; 65%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12](Br)=[CH:13][C:8]=3[S:7](=[O:16])(=[O:15])[C:6]=2[CH:17]=1.C([Sn](CCCC)(CCCC)C([O:25][CH2:26][CH3:27])=C)CCC.[O:36]1CCO[CH2:38][CH2:37]1>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>[O:15]=[S:7]1(=[O:16])[C:6]2[CH:17]=[C:2]([C:37](=[O:36])[CH3:38])[CH:3]=[CH:4][C:5]=2[C:9]2[CH:10]=[CH:11][C:12]([C:26](=[O:25])[CH3:27])=[CH:13][C:8]1=2
Reactant: C1COCCO1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=S1(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1ccc2c(c1)S(=O)(=O)c1cc(C(C)=O)ccc1-2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 3,7-dibromodibenzo[b,d]thiophene 5,5-dioxide (600 mg, 1.604 mmol), Tributyl(1-ethoxyvinyl)tin (2.251 mL, 6.67 mmol) and Pd(Ph3P)4 (185 mg, 0.160 mmol) in 1,4-dioxane (15 mL) were degassed with nitrogen for 10 min then it was heated at 90° C. for overnight under nitrogen. The reaction mixture was cooled to room temperature and 15 mL of 10% HCl was added then stirred for 1 h. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine. The organics were dried (Na2SO4) and concentrated. The crude material was purified on silica gel using 0-100% ethyl acetate in hexane. The desired fractions were concentrated to give a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([NH2:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.[Cl:13][C:14]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[C:18](Cl)[N:17]=[C:16]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:15]=1>>[Cl:13][C:14]1[N:15]=[C:16]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:17]=[C:18]([NH:12][S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: Cc1ccc(NS(N)(=O)=O)nc1
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C)cn1
Yield: 17 %

Procedure:
According to the procedure described in referential Example 1e), 5-methyl-pyridine-2-sulfamic acid amide (252 mg, Referential Example 20) was reacted with 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (410 mg, Referential Example 1d)) to give 5-methyl-pyridine-2-sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-amide (100 mg). tR=4.02 min (LC); [M+H]+=499.33 (ES+);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][N:12]([CH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.B.CSC.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:35][CH:36]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1ccc(NCCN(Cc2ccc(OC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Yield: 37 %

Procedure:
In 5 ml toluene, 0.25 g (0.50 mmol) of the compound from Example 3-1 is treated with 0.30 ml of 2 M borane-dimethyl sulphide solution in tetrahydrofuran, and the mixture is heated at the boil for 2 hours. The mixture is then stirred in the presence of 5 ml of 2 N sodium carbonate solution for 1 hour and the organic phase is washed with water and with saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and the solvent is distilled off, and the residue is then purified using silica gel flash chromatography (cyclohexane/dichloromethane 3:1→cyclohexane/ethyl acetate 10:1). This gives the target compound in a yield of 37%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[NH:28]1[CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[N:28]1([CH2:2][CH2:3][O:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[NH:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=4[O:23][CH3:24])[N:13]=3)=[CH:7][C:6]=2[CH3:27])[CH2:31][CH2:30][CH2:29]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: C1CNC1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-[4-(2-bromoethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (216 mg, 0.50 mmol) in DMF (5 mL) was added azetidine (154 mg, 2.70 mmol). The reaction mixture was stirred at room temperature for 2 days. The solid was collected by filtration, washed with methanol, ethyl acetate, and water, and dried under vacuum to give the title compound as a white solid. Yield: 58 mg (28%). MP 204-205° C. 1H NMR (400 MHz, DMSO-d6): δ 7.85 (s, 2H), 6.71 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 1H), 3.70 (t, J=6.0 Hz, 2H), 3.18 (t, J=6.8 Hz, 4H), 2.70 (t, J=6.0 Hz, 2H), 2.26 (s, 6H), 1.97 (m, 2H). MS (ES) m/z: 410.20 (M+1) (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.ClC1C=CN=C2C=C(C3SC=CN=3)SC=12.Br[C:40]1[N:41]=[CH:42][N:43]([CH3:45])[CH:44]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:40]3[N:41]=[CH:42][N:43]([CH3:45])[CH:44]=3)[S:10][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: Cn1cnc(Br)c1
Agent: Clc1ccnc2cc(-c3nccs3)sc12
Product: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Yield: 29 %

Procedure:
Starting from the compound 98 (scheme 19), following the procedure described above for the synthesis of compound 10 (scheme 2, step 2, example 12) but replacing 2-bromothiazole with 4-bromo-1-methyl-1H-imidazole, title compound 224 was obtained in 29% yield. MS (m/z): 250.1 (100%), 252.1 (37%) (M+1).
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:23][C:24]1[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:29]=[CH:28][C:25]=1[CH2:26][OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C=O)c(OCCCCCCCCCCCCCCCCCCCCCC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(CO)c(OCCCCCCCCCCCCCCCCCCCCCC)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Under an argon atmosphere, 2,4-bis(docosyloxy)benzaldehyde (2.99 g, 3.96 mmol) was dissolved in a mixed solvent of dehydrating tetrahydrofuran (60 mL) and methanol (6.0 mL), sodium borohydride (375 mg, 9.91 mmol) was added, and the mixture was stirred at 40° C. for 2 hr. After completion of the reaction, purified water (2.0 mL) was added dropwise to decompose unreacted sodium borohydride and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, methanol was added, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (2.77 g, 92.9%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[OH-:23].[K+].O>C(O)(C)(C)C>[C:1]([C:3]1[C:8]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:23])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (R)-tert-butyl 2-((2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate (3.62 g, 11.9 mmol, EXAMPLE 1 Step 1) in tert-butanol (110 mL) was added potassium hydroxide pellet (10.0 g, 179 mmol) at room temperature. The resulting mixture was stirred at 80° C. for 0.5 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (dichloromethane to methanol/dichloromethane 1:15) to give 3.43 g (90%) of the title compound as a white amorphous powder.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl.[Cl:64][CH2:65][CH:66]1[NH:69][C:68](=[O:70])[CH:67]1[NH2:71].O>C(Cl)Cl.C(N(CC)CC)C>[Cl:64][CH2:65][CH:66]1[NH:69][C:68](=[O:70])[CH:67]1[NH:71][C:27](=[O:28])[C:26]([C:24]1[N:25]=[C:21]([NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[S:22][CH:23]=1)=[N:30][O:31][C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)NC1CCl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1C(=O)NC1CCl)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.67 h

Procedure:
A mixture of 1.527 g of the syn isomer of sodium 2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetic acid, 419 mg of tosyl chloride and 15 ml of methylene chloride was stirred for 40 minutes and then a solution of 342 mg of 4-chloromethyl-3-amino-2-oxo-azetidine hydrochloride in 15 ml of methylene chloride and 0.6 ml of triethylamine was added thereto. The mixture was stirred for 2 hours and water was added thereto with stirring. The decanted aqueous phase was extracted with methylene chloride and the combined organic phases were dried, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with ether to obtain 736 mg of syn isomer of 4-chloromethyl-3-[2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetamido]-2-oxo-azetidine.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>CN(C=O)C>[CH:16]1([CH2:15][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([S:2][CH3:1])[C:11]=3[N:10]=[CH:9]2)[CH2:18][CH2:17]1.[CH:16]1([CH2:15][N:10]2[C:11]3[C:3]([S:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[N:8]=[CH:9]2)[CH2:18][CH2:17]1
Reactant: BrCC1CC1
Reactant: CSc1cccc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cccc2c1ncn2CC1CC1
Product: CSc1cccc2ncn(CC3CC3)c12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2 g of 4-methylsulfanyl-1H-benzoimidazole were dissolved in 20 ml of dry DMF. 0.6 g of sodium hydride (60% strength in mineral oil) were added portionwise at 0° C. After stirring for 1 h at 20° C., the mixture was cooled to 0° C. and bromomethylcyclopropane (1.5 ml) was added. The reaction mixture was stirred for 18 h at 20° C. The solvent was evaporated in vacuo and the residue was taken up in water and EA (100 ml each). The phases were separated, the aqueous phase was extracted with EA, and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography (100 g silica gel; DCM/EA, gradient from 100:0 to 80:20) to yield 1.2 g of 1-cyclopropylmethyl-4-methylsulfanyl-1H-benzoimidazole and 0.8 g of 1-cyclopropylmethyl-7-methylsulfanyl-1H-benzoimidazole.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:13])[CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:22][C:23](Cl)=[O:24].Cl.[OH-].[K+]>ClCCl.O>[CH2:1]([N:8]1[CH:9]([CH3:13])[CH2:10][CH2:11][O:12][CH2:22][C:23]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1CCOCC(=O)N1Cc1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 3-benzylamino-butan-1-ol (0.50 g, 2.8 mmol) and triethylamine (0.84 mL, 6.0 mmol) in dichloromethane was added chloroacetylchloride (0.26 mL, 3.3 mmol) at 0° C. and stirred for one hour. The reaction mixture was poured into 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in 2-propanol (20 mL) and potassium hydroxide (0.66 g, 10 mmol) was added to the mixture at room temperature. After stirring for 18 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residual material was purified by flash column chromatography on silica gel (hexane/ethyl acetate=100/0 to 1/1 as an eluant) to afford 4-benzyl-5-methyl-[1,4]oxazepan-3-one (0.32 g, 1.4 mmol, 52%) as yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Temperature: 0 °C
Yield: 44 %

Procedure:
2,3-Dichlorobenzoic acid, obtained from Aldrich, (40 g, 0.21 mole) was added portion wise to a −20° C. concentrated H2SO4, obtained from Acros, (233 mL) solution which was fitted with a mechanical overhead stirrer. During the addition process, a separate flask containing concentrated H2SO4 (50 mL) was cooled to 0° C. and fuming HNO3, obtained from Acros, (16.6 mL) was slowly added. This solution was then added dropwise to the 2,3-Dichlorobenzoic acid solution at a rate which kept the reaction mixture at or slightly below −15° C. After the addition was complete the resulting solution was allowed to warm to 10° C. over 3 hours. The crude solid material was filtered through a fritted filter funnel, washed with cold H2O (200 mL), and dried under a stream of air followed by high vacuum to yield 21.7 g (44%) of product (246) which contained 4% of the undesired regioisomer (2,3-Dichloro-6-nitrobenzoic acid 247) based on 1H NMR analysis. The filtrate was slowly poured over ice and additional solid precipitated. This solid was observed to be a 3:1 mixture of 2,3-dichloro-6-nitrobenzoic acid (247) to 2,3-dichloro-5-nitrobenzoic acid (246) based on 1H NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[S:24][C:14]=2[N:15]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[SH:10][CH2:11][CH2:12][C:13]([O:15]C)=O.C(N(CC)C(C)C)(C)C.[O:26]1CCOC[CH2:27]1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:9][C:5]1[CH:4]=[CH:3][C:2]([S:10][CH2:11][C:12](=[C:13]=[O:15])[O:26][CH3:27])=[CH:8][C:6]=1[NH2:7]
Reactant: COC(=O)CCS
Reactant: C1COCCO1
Reactant: Nc1cc(Br)ccc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=C=O)CSc1ccc(F)c(N)c1

Procedure:
To a mixture of 5-bromo-2-fluoroaniline (4.15 g), methyl 3-mercaptopropionate (2.62 g), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.63 g) and N,N-diisopropylethylamine (5.64 g) in 1,4-dioxane (80 mL) was added tris (dibenzylidene -acetone) dipalladium(0) (0.3 g), and the mixture was heated for reflux under an argon atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1−5/1−2/1) to give 2-fluoro-5-(2-methoxy -carbonylethylthio)aniline (4.62 g). This material was dissolved in tetrahydrofuran (120 mL). To the solution was added potassium tert-butoxide (1 mol/L tetrahydrofuran solution, 80.6 mL) at −78° C., and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid (81 mL), and the mixture was warmed to room temperature and stirred for 5 minutes. The mixture was poured into ethyl acetate, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (1.85 g).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].C([CH2:16][C:17](Cl)=[O:18])C=C.[CH3:20][C:21]([CH3:23])=O>FC(F)(F)C(O)=O>[CH2:23]([CH:4]([N+:5]([CH3:8])([CH3:6])[CH3:7])[C:3]([C:17](=[O:18])[CH3:16])([CH2:9][C:10](=[O:11])[O-:12])[OH:2])[CH:21]=[CH2:20]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: CC(C)=O
Reactant: C=CCCC(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(C(O)(CC(=O)[O-])C(C)=O)[N+](C)(C)C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of carnitine hydrochloride (9 grams; 0.045 moles) in 15 cc of trifluoroacetic acid, 0.13 moles of allyl acetyl chloride were added. The resulting solution was kept at 45° C. for 4 hours. Subsequently, acetone was added to the solution, the unreacted carnitine was separated and ethyl ether was added, thus obtaining a precipitate. The raw material thus obtained was purified by precipitation from isopropanol--ethyl ether. 9.5 grams of product were obtained. Yield 66%.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]([N:11]2[C@H:18]3[C@H:13]([CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17]3)[CH2:12]2)=[O:10])[O:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:18]12[N:11]([C:9]([C:8]3[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=3[C:5]3[O:4][N:3]=[C:2]([CH3:1])[N:6]=3)=[O:10])[CH2:12][C@H:13]1[CH2:14][CH2:15][NH:16][CH2:17]2
Reactant: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCNC[C@H]32)n1
Reaction time: 2 h

Procedure:
The product of Step B (645 mg, 1.63 mmol), DCM (8 mL), TFA (3 mL) were stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in DCM and treated with Dowex 550 A resin. After stirring for 2 h the resin was removed by filtration and the filtrate was concentrated in vacuo to a colorless oil which was taken on to the next step without further purification. MS (ESI) mass calculated for C16H18N4O2, 298.14; m/z found, 299.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[NH:21]1[C:30]2[CH2:29][CH2:28][C:27](=O)[CH2:26][C:25]=2[CH:24]=[CH:23][C:22]1=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH:27]1[CH2:28][CH2:29][C:30]3[NH:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]=3[CH2:26]1)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: NCCCNc1c2c(nc3cc(Cl)ccc13)CCCC2
Reactant: O=C1CCc2[nH]c(=O)ccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1ccc2c([nH]1)CCC(NCCCNc1c3c(nc4cc(Cl)ccc14)CCCC3)C2
Reaction time: 24 h
Yield: 36.6 %

Procedure:
To a mixture of N1-(6-Chloro-1,2,3,4-tetrahydro-acridin-9-yl)-propane-1,3-diamine (50 mg, 0.17 mmoL), 1,5,7,8-Tetrahydro-quinoline-2,6-dione (31 mg, 0.19 mmoL) in 5 mL methylene chloride, was added sodium triacetoxyborohydride (110 mg, 0.52 mmoL) and a catalytic amount of acetic acid. After stiring at room temperature for 24 h, the reaction was stopped by adding saturated sodium bicarbonate. The mixture was extracted with methylene chloride three times. The combined methylene chloride extract was dried, filtered and concentrated. Purification by column chromatography on silica gel column with 10% MeOH/1% ammonium hydroxide in methylene chloride provided the desired product (27.6 mg, 0.063 mmoL, 37%).