Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)[CH3:2].C([BH3-])#N.[Na+].[CH:30](=O)[CH2:31][CH3:32]>C(O)(=O)C.O1CCCC1>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:30][CH2:31][CH3:32])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Yield: 90.1 %

Procedure:
Following general procedure Q and using 4-[(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 79, 0.2 g, 0.64 mmol), sodiumcyanoborohydride (0,121 g, 1.92 mmol) and propionaldehyde (1 mL, 13.7 mmol) in 5 mL of acetic acid and 5 mL of tetrahydrofuran, the title compound (0.22 g, 90%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 2H, J=9.0 Hz), 7.08 (s, 2H), 6.90 (s, 1H), 6.67 (d, 2H, J=8.9 Hz), 4.31 (q, 2H, J=7.1 Hz), 3.66 (t, 2H, J=7.8 Hz), 1.77-1.64 (m, 2H) 1.54 (s, 6H), 1.50 (s, 6H), 1.34 (t, 3H, J=7.1 Hz), 0.94 (t, 3H, J=7.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)C(Cl)=O.CO.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11][CH3:12])[CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1cc(Br)cc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc(SC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 3-bromo-5-methylsulfanyl-benzoic acid (2.2 g, 8.9 mmol), methylene chloride (100 mL), and DMF (5 drops) at 0° C. was added oxalyl chloride (1.0 mL, 12 mmol). The mixture was slowly warmed to room temperature and stirred at room temperature overnight. Methanol (5.0 mL, 120 mmol) and N,N-diisopropylethylamine (5.0 mL, 29 mmol) were added and the mixture was stirred at room temperature for 3 h and then concentrated. The residue was purified by silica gel column (0-50% EtOAc/hexane) to yield an oil. 1H NMR (400 MHz, CDCl3): δ 7.91 (t, 1H, J=1.6 Hz), 7.81 (t, 1H, J=1.6 Hz), 7.52 (t, 1H, J=1.6 Hz), 3.92 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CS(C)=O>[NH2:9][C:3]1[C:2]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:7][C:6]([Br:8])=[CH:5][N:4]=1
Reactant: NCc1ccc(O)cc1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CS(C)=O
Product: Nc1ncc(Br)nc1NCc1ccc(O)cc1
Yield: 11.7 %

Procedure:
A solution of 3,5-dibromo-pyrazin-2-ylamine (220 mg, 0.87 mmol) and 4-aminomethyl-phenol (225.0 mg, 1.83 mmol) in DMSO (2.5 mL) was heated at 98° C. under nitrogen for 24 hours. HPLC showed that 35% of product was formed and 40% of starting material presented. The reaction solution was partitioned between EtOAc and water. After condensation of organic layer, the residue was purified on a silica gel column eluting with 3% methanol in dichloromethane to provide 4-[(3-amino-6-bromo-pyrazin-2-ylamino)-methyl]-phenol (30 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[C:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[C:36][CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(C#CC2CCCC2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C#CC5CCCC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-cyclopentylethynyl-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([N:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N2CCCCC2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N2CCCCC2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]2[C:19]#[N:20])=[O:7])=[CH:4][CH:3]=1.[NH2:23][OH:24]>CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]2[C:19](=[N:23][OH:24])[NH2:20])=[O:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc2c(c1)C=CC(C#N)N2C(=O)c1ccc(Cl)cc1
Solvent: CO
Product: Cc1ccc2c(c1)C=CC(C(N)=NO)N2C(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of 1-(4-chlorobenzoyl)-6-methyl-1,2-dihydroquinoline-2-carbonitrile (200 mg) in methanol (1 mL) was added cold 1M hydroxylamine in methanol (971 μL). The reaction mixture was warmed to ambient conditions and stirred overnight. The methanol is removed in vacuo and the crude product is purified by liquid chromatography (gradient elution of acetonitrile (0.02% trifluoroacetic acid)/water (0.02% trifluoroacetic acid) through a reverse phase C18 column) to give the titled compound (25 mg, 11% yield) as a pale yellow solid. (M+H)+−342.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[CH3:12][CH:13]([S-:15])[CH3:14].[Na+]>C(#N)C>[CH:13]([S:15][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:14])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CC(C)[S-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)SCc1ccccc1[N+](=O)[O-]
Temperature: 35 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
In a 250 ml three-necked flask equipped with a stirrer, dropping funnel and thermometer, 17.2 g (0.1 mol) 2-nitrobenzylchloride in 20 ml acetonitrile are added dropwise to 10.3 g (0.105 mol) sodium 2-propanethiolate in 75 ml acetonitrile, with cooling to maintain the temperature at 30-40° C. The suspension is stirred for another 16 hours at 40-50° C. To complete the reaction, another 6 g sodium 2-propanethiolate (0.061 mol) are added and stirring is continued another 24 hours at 40-50° C. The reaction is cooled and the solvent removed under vacuum. The residue is dissolved in methyl tert-butyl ether, washed and dried over sodium sulfate. The sodium sulfate is removed by filtration, and the solution is concentrated under vacuum. The crude product is purified by column chromatography (silica gel, 50:1 cyclohexane/ethyl acetate). 11.8 g (92% purity by HPLC, 51.2% theoretical yield) of 1-[1-(isopropylthio)methyl]-2-nitrobenzene are obtained as a brown oil [logP (pH 2.3)=3.28].
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([O:20]CC)=O)[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:24][C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=2)=[O:20])[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(O)c2ccccc21

Procedure:
Ethyl 1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (159 mg, 0.5 mmol) and tert-butyl 4-aminobenzoate (193 mg, 1 mmol) are suspended in anhydrous toluene (4 ml) and are microwave-heated with the container open (the parameters are the following: power=200 W, temperature=120° C., execution time=7 min, hold time=10 min).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12](I)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30].C(N(CC)CC)C>CN(C)C=O.ClCCl.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][Cl:25])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(N)c2c(n1)c(I)cn2COCc1ccccc1
Reactant: C#CCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(N)c2c(n1)c(C#CCCCCl)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a degassed suspension of 5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine (2.768 g, 6.34 mmol), copper (I) iodide (0.242 g, 1.269 mmol), and bis(triphenylphosphine)palladium(II)dichloride (0.445 g, 0.634 mmol) in anhydrous N,N-dimethylformamide (40 mL) was added a solution of 5-chloropent-1-yne (0.781 g, 7.61 mmol) and triethylamine (1.231 mL, 8.88 mmol) in anhydrous N,N-dimethylformamide (20 mL) dropwise over 2 minutes. The reaction was stirred at ambient temperature for 17 hours. The reaction was concentrated in vacuo and the resultant brown oil partitioned between water (500 mL) and ethyl acetate (500 mL). The organic was separated and the aqueous back extracted with ethyl acetate (250 mL). The combined organics were washed with brine (400 mL), dried (MgSO4), filtered and concentrated in vacuo. The sample was dissolved in dichloromethane and purified by chromatography on silica (Si) (2×100 g) using a 0-100% ethyl acetate-cyclohexane gradient over 60 minutes. The appropriate fractions were combined and evaporated in vacuo to give a red oil. The sample was dissolved in dichloromethane and purified by chromatography on silica using a 0-100% ethyl acetate-cyclohexane gradient over 80 minutes. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid. (1.13 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][C:12](SC)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH:20]([OH:36])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:24]=1.C(OCC)C>C(Cl)(Cl)Cl>[OH:36][CH:20]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:24]=1)[CH2:19][NH:18][C:12]1[NH:11][C:10](=[O:17])[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:14][N:13]=1
Reactant: NCC(O)COc1cccc(CN2CCCCC2)c1
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cc2cnc(NCC(O)COc3cccc(CN4CCCCC4)c3)[nH]c2=O)cn1
Reaction time: 2.5 h
Yield: 38.9 %

Procedure:
A mixture of 5-(6-methyl-3-pyridinylmethyl)-2-methylthio-4(3H)-pyrimidinone (1.24 g) and 1-amino-3-[3-[1-piperidinylmethyl]phenoxy]-2-propanol (Compound A) (1.32 g) was heated at 120° for 1.5 h and then at 130°-140° for 2.5 h. The resulting brown glass was dissolved in chloroform (25 ml) and added to stirred dry diethyl ether (250 ml) to precipitate a white solid (1.5 g). This solid was recrystallised from ethyl acetate to give the title compound (0.9 g) as a white solid, m.p. 115°-117°.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[CH2:5]2)[CH2:3][O:2]1.CS(O[CH:21]1[CH2:24][N:23]([C:25]([C:27]2[O:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:30][N:31]=2)=[O:26])[CH2:22]1)(=O)=O>>[CH2:3]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:21]4[CH2:24][N:23]([C:25]([C:27]5[O:28][C:29]([C:32]6[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=6)=[N:30][N:31]=5)=[O:26])[CH2:22]4)=[CH:11][CH:10]=3)[CH2:5]2)[CH2:1][O:2]1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccc(Cl)cc3)o2)C1
Reactant: Oc1ccc(CN2CC3(COC3)C2)cc1
Product: O=C(c1nnc(-c2ccc(Cl)cc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Yield: 12 %

Procedure:
The title compound was prepared using a similar protocol as described in Example 1 employing 2A and 2C as starting materials. There was obtained 70 mg (12%) of 2 as an oil. The oil gradually solidified on standing in room temperature. 1H NMR (500 MHz, CDCl3): δ 3.41 (s, 4H), 3.53 (s, 2H), 4.34 (d, 1H), 4.65 (m, 1H), 4.74 (s, 5H), 5.09 (m, 1H), 5.14 (m, 1H), 6.73 (d, 2H), 7.21 (d, 2H), 7.52 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 467 [M+H]−, LC purity: 92%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]3[N:29]=[C:28]4[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]4)=[CH:22][CH:21]=3)[CH2:11][CH2:10]2)[CH:3]=1>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[N:29]=[C:28]4[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]4)=[CH:22][CH:21]=3)[CH2:13][CH2:14]2)[CH:3]=1
Reactant: Cc1cc(C)nc(N2CCN(CCCC=Cc3ccc4c(n3)NC(=O)CC4)CC2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)nc(N2CCN(CCCCCc3ccc4c(n3)NC(=O)CC4)CC2)c1
Yield: 57.2 %

Procedure:
7-{5-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.54 g, 1.33 mmol) was hydrogenated using 20% Pd/C in EtOH for 58 h. The reaction was filtered and concentrated. Purification by liquid chromatography (Biotage 12 SiO2 column, CHCl3 to 1% MeOH/CHCl3) followed by recrystallization from Et2O/hexanes gave the title compound as an off-white solid (313 mg, 0.761 mmol, 57%). MS: APCI: M+1: 408.2 (Exact Mass: 407.27).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([F:13])([F:12])[CH:9]([F:11])[O:10][C:5]=2[CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.[OH2:27]>>[CH:2]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([F:13])([F:12])[CH:9]([F:11])[O:10][C:5]=2[CH:4]=1)=[O:27]
Reactant: O
Reactant: FC1Oc2cc(CBr)ccc2OC1(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1ccc2c(c1)OC(F)C(F)(F)O2

Procedure:
318 g of 6-bromomethyl-2,2,3-trifluoro-1,4-benzodioxane are added to 318 g of urotropin in 630 ml of water, the reaction mixture is heated under reflux for 2 hours, 318 ml of hydrochloric acid and 470 ml of water are then added and the mixture is heated for a further 3 hours. The product is driven over with steam and is separated off and, after drying, distilled. 158 g of distillate are obtained (boiling point: 112-115° C. (under 18 mbar)) and partly crystallize on standing. The crystal sludge is filtered off with suction and the crystals are washed with cold petroleum ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.[CH3:15][CH:16]([O:18][C:19](=[O:44])[NH:20][C@H:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[N:24]([C:40](=[O:42])[CH3:41])[C@@H:23]([CH3:43])[CH2:22]1)[CH3:17].CC(OC(=O)NC1C2C(=CC=C(B3OC(C)(C)C(C)(C)O3)C=2)N(C(=O)C)C(C)C1)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.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.C1(C)C=CC=CC=1>[C:40]([N:24]1[C:25]2[C:30](=[CH:29][C:28]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][N:3]=3)=[CH:27][CH:26]=2)[C@H:21]([NH:20][C:19](=[O:44])[O:18][CH:16]([CH3:15])[CH3:17])[CH2:22][C@@H:23]1[CH3:43])(=[O:42])[CH3:41]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: Brc1ccc(CN2CCCCC2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C(NC(=O)OC(C)C)CC1C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C

Procedure:
2-bromo-5-(1-piperidinylmethyl)pyridine (for a preparation see Intermediate 24) (98 mg, 0.384 mmol) was mixed with 1-methylethyl[(cis)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 12) (100 mg, 0.240 mmol), potassium carbonate (66.4 mg, 0.480 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.88 mg, 0.012 mmol), dissolved in ethanol (1 mL) and toluene (1 mL) and stirred under nitrogen at 90° C. The reaction mixture was loaded onto a 5 g SCX column, eluting with MeOH (30 mL) followed by 2M MeOH/NH3 (30 mL). Product-containing fractions were evaporated to dryness to give a yellow solid (155 mg). This was purified by MDAP. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (55 mg). LCMS (Method C): Rt=0.67, MH+=465
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CO>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 107.3 %

Procedure:
A cooled (0° C.) solution of compound 55A (510.1 mg, 1.51 mmol) and imidazole (516 mg, 7.58 mmol) in dry DMF (2.6 mL) was treated with 97% tert-butyldimethylsilyl chloride (572 mg, 3.68 mmol), stirred at 0° C. for 5 min then at rt for 24 h. Methanol (3.5 mL) was added and the solution stirred at rt for another 24 h. The mixture was partitioned between 10% citric acid (5.3 mL) and EtOAc (3×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting syrup was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (732.3 mg, 100%) as a white solid, mp 123-125° C. HPLC: 3.38 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=9.30 min (98.6%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 452 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][C:12]#[CH:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].C(O)(=O)C>C(O)C>[CH3:13][C:12]1[O:9][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=2)=[N:10][CH:11]=1
Reactant: C#CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cnc(-c2ccc([N+](=O)[O-])cc2)o1
Temperature: 52.5 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
To a stirred solution of 4-nitro-N-prop-2-ynyl-benzamide (7.5 g, 36.7 mmol) in ethanol (150 mL) was added a solution of potassium hydroxide (4.1 g, 73.4 mmol) in ethanol (100 mL) and the mixture was stirred at 50-55° C. for 12 h. The mixture was acidified with acetic acid and concentrated to dryness in vacuo at 45-50° C. The resultant residue was extracted into ethyl acetate and the separated organic phase was washed with water; aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford 5-methyl-2-(4-nitrophenyl)oxazole (3.47 g, 46%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Br:11]Br.C(OCC)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(O)c(Br)c1
Yield: 54.7 %

Procedure:
2-Hydroxy-5-nitropyridine (10.0 g, 71 mmol) in chloroform (200 ml) and acetic acid (10 ml) was treated with bromine (3.7 ml, 72 mmol) and then refluxed for 24 hrs. More bromine (3.7 ml, 72 mmol) was added and the mixture refluxed for a further 48 hrs, then cooled. Ethyl acetate (150 ml) was added and the solid formed removed by filtration, washed with ethyl acetate (50 ml) and dried to give the product as an off-white powder (8.5 g).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.I[CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14]>>[CH3:14][O:13][Si:12]([O:17][CH3:18])([O:15][CH3:16])[CH2:11][CH2:10][CH2:9][S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ncccn1
Reactant: CO[Si](CCCI)(OC)OC
Product: CO[Si](CCCSc1ncccn1)(OC)OC
Yield: 74 %

Procedure:
2-(3-(trimethoxysilyl)propylthio)pyrimidine was synthesized from 2-mercaptopyrimidine and iodopropyltrimethoxysilane in the similar method as described above. 1H NMR (CD3Cl): δ(ppm) 8.62 (2H, m, Pyr.-H), 7.11 (1H, m, Pyr.-H), 3.57 (9H, s, —CH3), 3.25 (2H, m, —CH2—), 1.88 (2H, m, —CH2—), 0.83 (2H, t, JH-H=8.25, —CH2—). Yield: 74%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C>C(OCC)C.C1(C)C=CC=CC=1>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:18])=[CH:12][CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: NCCCO
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(NC(=O)NCCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.5 %

Procedure:
A solution of 3-amino-1-propanol (0.180 mL, 2.36 mmol) in diethylether (15 mL) was cooled at 0° C. and treated dropwise with 1-tert-butyl-4-isocyanatobenzene (0.400 mL, 2.25 mmol). The reaction mixture was allowed to slowly warm to room temperature. After 16 h the reaction was found to be complete by TLC (100% ethyl acetate) The reaction mixture was diluted with 10 mL portions of Cl2Cl2 and Et2O and washed with 15 mL portions of H2O, 0.5N HCl and brine and dried over Na2SO4. The organic phase was filtered and concentrated to yield a colorless viscous oil which was dissolved in PhCH3, concentrated and placed under high vac overnight to yield the title compound (600 mg, 110%) as a colorless viscous oil: MS (ESI+) for C14H22N2O2 m/z 251.0 (M+H)+; (ESI−) for O14H22N2O2 m/z 249.3 (M−H)−; HPLC purity 98% (ret. time, 3.43 min).