Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:14]([O-:16])=[O:15])[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:23][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([N+:14]([O-:16])=[O:15])[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)=[CH:20][CH:19]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: COc1cc([N+](=O)[O-])c2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c2nc(OCc3ccc(Cl)cc3)ccc2c1
Temperature: 0 °C
Yield: 84 %

Procedure:
A mixture of 48 g (0.2 mole) of 2-chloro-6-methoxy-8-nitroquinoline, 42.78 g (0.3 mole) of 4-chlorobenzyl alcohol, 27.6 g (0.2 mole) of anhydrous potassium carbonate, and 200 ml N,N-dimethyl formamide was heated under nitrogen at ca. 155°-160° for 18 hr. The mixture was cooled, diluted with ice water, stirred, collected, and washed with water. The crude solid was leached with a little 95% ethanol at 70° and then recrystallized from that solvent. A 84% yield of 2-(4-chlorobenzyloxy)-6-methoxy-8-nitroquinoline resulted; mp 129.5°-133.5°.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][C:4]=1F.[OH2:16].C(Cl)Cl.[CH3:20]O>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][C:4]=1[O:16][CH3:20]
Reactant: O=S(=O)(c1ccc(Br)c(F)c1)C1CC1
Reactant: O
Reactant: CO
Agent: [Na]
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)C2CC2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Sodium (95 mg, 4.12 mmol) was added portionwise to MeOH (2 mL). After stirring at room temperature for 1 hour, this solution was added dropwise to a suspension of 1-bromo-4-(cyclopropylsulfonyl)-2-fluorobenzene (Preparation 32, 115 mg, 0.41 mmol) in MeOH (2 mL), and the resulting mixture stirred at 60° C. for 16 hours. After cooling to room temperature, water (10 mL) and CH2Cl2 (10 mL) were added, and the resulting mixture partitioned. The aqueous was extracted with CH2Cl2 (2×10 mL), and the combined organic layers washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography eluting with heptanes/CH2Cl2 1:2 afforded the title compound as a colourless solid in 73% yield, 88 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH2:13]O)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.COC1C=C2C(C=C(C=O)C=N2)=CC=1.O=S(Cl)[Cl:31]>C(Cl)Cl>[ClH:31].[Cl:31][CH2:13][C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc(CO)cnc2c1
Agent: COc1ccc2cc(C=O)cnc2c1
Solvent: ClCCl
Product: COc1ccc2cc(CCl)cnc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of (7-methoxyquinolin-3-yl)methanol MDE 32006 (219 mg, 1.16 mmol) in dry CH2Cl2 (12 mL) at 0° C. under N2 in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (1.68 mL, 23.16 mmol) and the mixture was stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-7-methoxyquinoline hydrochloride MDE 32012 as an off-white solid (246 mg, 87% yield).
Reaction SMILES: ClC1C(C)=C(S(O[C@H:12]([CH3:31])[CH2:13][C:14]2[N:18]=[C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[CH3:30])(=[O:22])=[O:21])[S:16][N:15]=2)(=O)=O)C=CC=1.[F:33][C:34]1[CH:35]=[C:36]([SH:40])[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[Cl:29][C:25]1[C:24]([CH3:30])=[C:23]([S:20]([NH:19][C:17]2[S:16][N:15]=[C:14]([CH2:13][C@H:12]([S:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=3)[CH3:31])[N:18]=2)(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(C[C@@H](C)OS(=O)(=O)c2cccc(Cl)c2C)ns1
Reactant: Fc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(C[C@@H](C)Sc2cccc(F)c2)ns1

Procedure:
(R)-2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-1-methylethyl 3-chloro-2-methylbenzenesulfonate (example 98), 3-fluorothiophenol (1 eq) and sodium carbonate (1 eq) in CH3CN were heated overnight. Standard work-up and purification yielded the desired product.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]CC)=[O:26])=[CH:20][C:19]=3[CH3:30])=[CH:14][CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4].C(O)(=O)C>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[CH3:30])=[CH:14][CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(CC(=O)O)ccc1-c1ccc(-c2nc(C(N)=O)c(C)nc2C)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Powdered potassium hydroxide (65.9 mg, 1.17 mmol) was added in one portion to ethyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-methylbiphenyl-4-yl)acetate (Intermediate 12-1; 79 mg, 0.20 mmol) in tert-butanol (2 mL) at 45° C. under nitrogen. The resulting solution was stirred at 45° C. for 1 hour. The mixture was treated with acetic acid (0.090 mL, 1.57 mmol) in ethanol (1 mL) and stirred at room temperature for 10 minutes. The mixture was then evaporated under vacuum to give an off white solid. This was triturated with water (10 mL), filtered off and washed with water (10 mL), before drying under vacuum to give desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][Zn]C>>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:35])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: C[Zn]C
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Product: Cc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (200 mg, 0.384 mmol) mmol) and dimethylzinc (384 μl, 0.768 mmol) at 80° C. for 3 hours, the title compound was obtained as a solid (60 mg, 31% yield). MS (ESI): 500.8 [M+H]+
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSSC.Cl.[Br:28][CH2:29][C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:31]>C1COCC1>[Br:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[OH:31]
Reactant: O=C(CBr)c1cccnc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: C1CCOC1
Solvent: CSSC
Product: O[C@H](CBr)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
(S)-2-Methyl-CBS-oxazaborolidine (1M in toluene, 189 μL, 0.18 mmol) and borane-methyldisulfide complex (2M in toluene, 100 μL) in THF (11 mL) was allowed to stir at room temperature for 10 min. Then, the rest of BH3—S(CH3)2 (2M in toluene, 1.33 mL, 2.85 mmol) was added to the reaction solution followed by a suspension of 3-(bromoacetyl)pyridine hydrochloride (0.5 g, 1.78 mmol) in THF (11 mL). The heterogeneous reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then cooled to 0° C. and quenched with MeOH (1.5 mL). After 5 min of stirring, the solvent was removed and the resulting residue was diluted with CH2Cl2. The solution was treated with saturated NaHCO3 and the organic phase was separated. The aqueous phase was re-extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 0.24 g of (S)-2-bromo-1-pyridin-3-yl-ethanol as a colorless oil (66%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1.Cl[C:13]1[C:18]2=[CH:19][N:20]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[N:21]=[C:17]2[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[N:20]1[CH:19]=[C:18]2[C:13]([NH:3][C:4]3[N:5]=[CH:6][CH:7]=[C:8]([CH:9]=3)[C:10]#[N:11])=[N:14][CH:15]=[CH:16][C:17]2=[N:21]1
Reactant: N#Cc1ccnc(N)c1
Reactant: Fc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccnc(Nc2nccc3nn(-c4c(F)cccc4Cl)cc23)c1
Reaction time: 0.08 h
Yield: 10.2 %

Procedure:
Sodium hydride (12 mg, 0.30 mmol) was added to a solution of 2-amino-4-cyanopyridine (36 mg, 0.30 mmol) in DMF (2 mL) in a microwave vial and stirred for 5 minutes. 4-Chloro-2-(2-chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine (76 mg, 0.27 mmol) was added and then the vial was sealed, purged with nitrogen and irradiated at 150° C. for 10 minutes in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (50% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (10 mg, 10% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.77 (dd, J=5.2, 0.9 Hz, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.85 (s, 1H), 7.81-7.80 (m, 2H), 7.73 (d, J=8.2 Hz, 1H), 7.67 (t, J=9.0 Hz, 1H), 7.58 (dd, J=7.3, 0.9 Hz, 1H). LCMS (Method B): RT=2.98 min, m/z: 365 [M+H+].
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=2)=[O:12])=[CH:9][CH:8]=1.C(O)(=O)[CH2:27][C:28]([OH:30])=[O:29].N1C=CC=CC=1.N1CCCCC1.Cl>>[F:25][C:2]([F:24])([F:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
5.00 g (14.2 mMol) of 4-formylphenyl 4-(4,4,4-trifluorobutoxy)benzoate and 3.00 g (28.4 mMol) of Malonic acid are dissolved in 18 ml (227.1 mMol) of Pyridin.1.21 g (14.2 mMol) of Piperidin are added to the suspension which is allowed to react at 100° C. under argon for 1.5 h. The yellow solution is then thrown on ice. The solution is carefully acidified to pH=1-2 with a 25% HCl solution and is stirred for 15 min. The product is filtrated off and dried at room temperature under vacuum for 10 h to give 5.2 g of (2E)-3-(4-{[4-(4,4,4-trifluorobutoxy)benzoyl]oxy}phenyl)acrylic acid as white powder.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:28]=[CH:29][C:30]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:9]([NH:11][C@H:12]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:16][CH:15]=[CH:14][CH2:13]2)=[O:10])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:44])C=1>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:28]=[CH:29][C:30]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:9]([NH:11][CH:12]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:16][CH:15]3[CH:14]([O:44]3)[CH2:13]2)=[O:10])[CH2:2][CH2:3]1
Reactant: COc1ccc([C@H]2CC=CC[C@H]2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(C2CC3OC3CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Yield: 68 %

Procedure:
37.7 g of (±)-cis-3,4-bis-cyclopropylmethoxy-N-[6-(3,4-dimethoxyphenyl)cyclohex-3-enyl]benzamide (compound F1) are dissolved in 470 ml of dichloromethane and treated with 27.4 g of m-chloroperbenzoic acid. After stirring over night at room temperature, the reaction mixture is extracted with sodium hydrogencarbonate solution and water, the organic phase is dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 4/4/1. 26.5 g of the title compound are obtained.
Reaction SMILES: [CH3:1][CH:2]([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][CH:18]([CH3:22])[C:19](O)=[O:20])[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>O1CCCC1>[CH3:22][CH:18]([S:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][S:6][CH:2]([CH3:1])[CH2:3][OH:4])[CH2:19][OH:20]
Reactant: CC(SCCCCCCCCCCSC(C)C(=O)O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CO)SCCCCCCCCCCSC(C)CO
Yield: 83.7 %

Procedure:
A solution in tetrahydrofuran of 7 g (0.0200 mole) of (±)-2,15-dimethyl-3,14-dithia-1,16-hexadecanedioic acid was slowly poured under a current of nitrogen into an agitated suspension of 2.3 g (0.0605 mole) of LiAlH4 in tetrahydrofuran. The reaction medium was then heated under reflux for 3 hours 15 mins. After neutralisation of the excess reducing agent with ethyl acetate and aqueous alkali, the reaction mixture was filtered and then the solvents were eliminated from the filtrate. The residue was separated between water and methylene chloride. The organic phase was recovered and then washed to neutrality and dried. The solvent was evaporated under reduced pressure and the residue was washed by trituration with petroleum ether. After filtration, 5.4 g of a white crystalline powder was obtained which was insoluble in water. (H is understood that the (+) and (-) isomers can be separated from the racemic form by known methods).
Reaction SMILES: CCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CO[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20][CH2:19]2.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1>>[CH3:13][C:12]1[CH:7]=[CH:8][C:9]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:11]=1
Reactant: CCCCCCCCCCCCC
Reactant: COc1ccc2c(c1)CCCC2
Agent: Cc1ccccc1-c1ccccc1C
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
In a reaction flask was placed NiCl2(dcpb) (38.0 mg, 0.0655 mmol), dcpb (34.6 mg, 0.0768 mmol), tridecane (164.5 mg, 0.892 mmol, as an internal standard), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (169.3 mg, 1.044 mmol). The solvent in the Grignard reagent (1 M in ether, 3.0 mmol) was exchanged with t-AmOMe (5.0 mL) and this solution added to the above catalyst mixture under a nitrogen atmosphere at room temperature. The resulting solution was stirred for several minutes at room temperature and then warmed to 80° C. for 15 hours. A sample was withdrawn and quenched into saturated aqueous ammonium chloride and was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (0.363 mmol, 35% yield), bitoluene (0.216 mmol), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (0.429 mmol) in the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][C:11]([O:14][C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:16])([CH3:13])[CH3:12].[H-].[Na+]>O1CCCC1>[C:21]([O:20][C:18]([N:17]([CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)[C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 82.2 %

Procedure:
A solution of 3-bromobenzylbromide (7.5 g, 30 mmol) and di-tert-butyliminodicarboxylate (6.5 g, 30 mmol) in anhydrous tetrahydrofuran (80 ml) was treated portionwise with sodium hydride (1.2 g, 60% dispersion in mineral oil). After stirring at ambient temperature for 7 hours the reaction mixture was partitioned between saturated aqueous ammonium chloride solution (90 ml) and ethyl acetate (2 lots of 250 ml). The combined organic layers were washed with brine (75 ml ), then dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of pentane and dichloromethane (2:1, v/v) to give 3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-bromobenzene as a pale yellow oil (9.52 g). A sample of this material (2.0 g, 5.2 mmol) was dissolved in anhydrous dimethylsulfoxide (30 ml) and the solution was treated with potassium acetate (1.52 g, 15.5 mmol), bis(pinacolato)diboron (1.45 g, 5.7 mmol), and [1,1′-bis-(diphenylphosphino)ferroceno]-dichloropalladium (II)-dichloromethane complex (0.13 g, 0.16 mmol). This mixture was stirred at 80° C. under an atmosphere of nitrogen for 5 hours, then cooled and then partitioned between water (100 ml) and diethyl ether (4 lots of 75 ml). The combined organic layers were washed twice with brine (75 ml), then dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of pentane and dichloromethane (2:1, v/v) to give B-{3-[N,N-bis-(tert-butoxycarbonyl)-aminomethyl]-phenyl}-pinacolato-boron as a colorless oil (1.08 g). 1H NMR (CDCl3, 500 MHz): δ 7.78 (s, 1H), 7.70 (m, 1H), 7.39 (m, 1H), 7.30 (m, 1H), 4.79 (s, 2H), 1.27 (s, 18H), 1.35 (s, 12H). MS(EI): 434(M++H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[H-].[Na+].[CH2:14](Br)[CH3:15].CO>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:14][CH3:15])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCBr
Reactant: CCc1cccc(NC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1cccc(N(C#N)CC)c1
Temperature: 82.5 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A suspension of m-ethylphenylcyanamide (2.26 g, 15.45 mmol) and sodium hydride (820 mg, 34.2 mmol, pre-washed thrice with hexane) in anhydrous THF (20 ml) was heated at 80-85° C. for 2.5 hours. After it was allowed to cool to room temperature ethyl bromide (4.66 g, 42.76 mmol) was added and continued stirring at room temperature for 6 hours. Methanol (20 ml) followed by water (40 ml) were added and then extracted with dichloromethane (3×25 ml). Concentration of the organic layer followed by quick flash chromatography afforded the title compound (2.36 mg, 88%) as a light yellow liquid:
Reaction SMILES: [F:1][C:2]([C:5]1[NH:9][N:8]=[N:7][N:6]=1)([F:4])[F:3].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24](=[O:27])[CH2:25]Cl>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24](=[O:27])[CH2:25][N:6]1[C:5]([C:2]([F:4])([F:3])[F:1])=[N:9][N:8]=[N:7]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: FC(F)(F)c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1C(F)(F)F)c1ccc(Cl)cc1Cl

Procedure:
Trifluoromethyl tetrazole was made according to the procedure published in Tetrahedron Letters 38(7):1257-1260. A mixture of tetrachlorosilane (5 mmol) and sodium azide (15 mmol) in dry acetonitrile (10 ml) and trifluoromethyl acetamide (5 mmol) was refluxed and stirred with the exclusion of moisture. The reaction mixture was poured into ice cold sodium carbonate solution and extracted with chloroform (3×20ml). The solvent was distilled off under reduced pressure to yield trifluoromethyl tetrazole (MS: MH—=136.7) which was used without further purification. Trifluromethyl tetrazole (1 mmol), Cs2CO3 (1.3 mmol) and 1-(2,4-dichlorophenyl)-2-chloroethan-1-one (1 mmol) were refluxed in DMF(2 ml) overnight. The reaction mixture was cooled and concentrated in vacuo, and then extracted into ethyl acetate and dried over sodium sulfate. The extract was further purified by column chromatography on silica gel to yield 1-(2,4-dichlorophenyl)-2-[5-(trifluoromethyl)(1,2,3,4-tetraazolyl)]ethan-1-one. 1 mmol of 1-(2,4-dichlorophenyl)-2-[5-(trifluoromethyl)(1,2,3,4-tetraazolyl)]ethan-1-one was heated to 80° C. in neat DMF-DMA for six hours. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether. 1 mmol of the above enaminone, 1 mmol of amino {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}carboxamidine hydrochloride and 3 mmol of Cs2CO3 were dissolved in DMF and heated to 90° C. for fourteen hours. The reaction mixture was concentrated in vacuo and extracted into ethyl acetate and the residue after solvent evaporation was purified by column chromatography eluting with 5-10% methanol in methylene chloride to yield {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}{4-(2,4-dichlorophenyl)-5-[5-(trifluoromethyl)(1,2,3,4-tetraazolyl)]pyrimidin-2-yl}amine as a yellow powder after lyophilization.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[CH2:18]1[O:20][CH2:19]1>CO.C1(C)C=CC=CC=1>[CH3:2][O:3][CH2:4][C@H:5]1[N:6]([CH2:18][CH2:19][OH:20])[CH2:7][CH2:8][O:9][CH2:10]1
Reactant: C1CO1
Reactant: COC[C@@H]1COCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CO
Product: COC[C@@H]1COCCN1CCO
Reaction time: 48 h

Procedure:
To a mixed solution of (3R)-3-(methoxymethyl)morpholine hydrochloride (4.71 g) and triethylamine (4.11 ml) in methanol (110 ml) was added 5.8M ethylene oxide (22 ml) in toluene solution at room temperature. After the reaction mixture was stirred at the same temperature for two days, it was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of dichloromethane and methanol (20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 2-[(3R)-3-methoxymethylmorpholino]ethanol (4.67 g) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([S:22][C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[ClH:21].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][C:17]=1[S:22][C:23]([F:26])([F:24])[F:25].[ClH:21]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)c(SC(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: FC(F)(F)Sc1cc(NC2CCNCC2)ccc1Cl

Procedure:
4-(4-Chloro-3-trifluoromethylsulfanyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (580 mg; 1.41 mmol, prepared in accordance with Example 15) is dissolved in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) is slowly added under stirring. After 60 minutes reaction time, the mixture is concentrated under reduced pressure and co-evaporated twice with dichloromethane (10 mL). The crude residue is then diluted in dioxane (2 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added under stirring. A solid is formed which is then filtered and dried under high vacuum to afford the desired product as hydrochloride (484 mg; 1.40 mmol).