Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)CN
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), methyl 2-aminoacetate hydrochloride (5.49 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=449.3 [M+H]+.
Reaction SMILES: C(N1C2C(=CC(C)=CC=2)C(O)([CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17](OC)=[C:16]([O:24][CH3:25])[CH:15]=2)C1=O)C.C([O:36][CH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([Cl:46])[CH:44]=2)[N:39]([CH2:47][CH2:48][CH2:49][CH3:50])[C:38]1=[O:51])(=O)C1C=CC=CC=1.COC1C=C(C=C(OC)C=1)CBr>>[CH2:47]([N:39]1[C:40]2[C:45](=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[C:37]([CH2:13][C:14]2[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=2)([OH:36])[C:38]1=[O:51])[CH2:48][CH2:49][CH3:50]
Reactant: CCCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Reactant: CCN1C(=O)C(O)(Cc2cc(OC)c(OC)c(OC)c2)c2cc(C)ccc21
Agent: COc1cc(CBr)cc(OC)c1
Product: CCCCN1C(=O)C(O)(Cc2cc(OC)cc(OC)c2)c2cc(Cl)ccc21

Procedure:
This compound was made in an analogous fashion to 1-ethyl-3-hydroxy-5-methyl-3-(3,4,5-trimethoxybenzyl)indolin-2-one using 1-butyl-5-chloro-2-oxoindolin-3-yl benzoate and 3,5-dimethoxy benzyl bromide (purchased from Fisher Scientific). 1H NMR δ 7.25 (m, 2H) 6.61 (d, 1H), 6.24 (s, 1H), 6.06 (s, 2H), 3.66 (m, 7H), 3.23 (m, 2H), 3.16 (d, 1H), 1.63 (bs, OH), 1.35 (m, 2H), 1.17 (m, 2H), 0.96 (t, 3H). Calculated mass for C21H24ClNO4, 389.14. Observed 412.2 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)=[N:7][C:6]=2[CH:16]=1.[C:17](Cl)(Cl)=[S:18].C(=O)([O-])[O-].[Ca+2].O>C(Cl)(Cl)Cl>[CH3:15][N:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:17]=[S:18])=[CH:16][C:6]=2[N:7]=1
Reactant: Cn1cccc1-c1nc2cc(N)ccc2o1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1cccc1-c1nc2cc(N=C=S)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of 5-amino-2-(1-methyl-2-pyrrolyl)benzoxazole (0.0047 mole) is dissolved in 50 ml of chloroform and slowly added to the following cold mixture: 0.54 g of thiophosgene (0.0047 mole), 0.47 g of calcium carbonate (0.0047 mole), 100 ml of chloroform and 25 ml of water. After the addition is complete the reaction is stirred at room temperature for 2 hr. The chloroform layer is separated, dried over anhyd. MgSO4 and evaporated under vacuum yielding a light brown solid. This material is crystallized from petroleum ether yielding 0.650 g of tan crystals, mp 105°-106° (54%).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([C:30]#[N:31])[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[N:28][CH:27]=[C:26]([CH:25]=2)[C:30]#[N:31])=[CH:7][CH:6]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cncc(C#N)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 40.8 %

Procedure:
Prepared according to the method described in Example 21b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 21a)), 5-bromopyridine-3-carbonitrile (0.18 g), aqueous sodium carbonate (2M, 0.57 ml) and tetrakis(triphenylphosphine)palladium(0) (0.014 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.073 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH:6]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:3](=[O:4])[CH2:2][Br:1])[CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][C:7]=1[C:3](=[O:4])[CH2:2][Br:1]
Reactant: O=C(Cl)CBr
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)Cc1cc(C(=O)CBr)ccc1O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
Referring to Scheme 5, bromoacetyl chloride (4.59 ml, 54.9 mmol) was added dropwise to a solution of 9H-xanthene (5 g, 27.4 mmol) and AlCl3 (8.05 g, 60.4 mmol), DCM (100 mL) at 0° C. The reaction mixture was allowed to warm up to rt and left to stir for 72 h. The reaction mixture was poured onto ice (400 mL), extracted with DCM (2×200 mL). The combined organic phase was washed with brine (400 mL), dried over MgSO4, filtered and evaporated to dryness. The crude material was precipitated in EtOAc and filtered to give 1,1′-(9H-xanthene-2,7-diyl)bis(2-bromoethanone) (5-2) as a white solid (4.27 g, 36.7% yield). LC-MS (ESI): m/z 425.9 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:7]2[C:2](=[O:1])[N:3]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:4]3[N:5]([N:26]=[CH:27][N:28]=3)[C:6]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)#[N:22]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)OC(C)(C)C)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (9 g), tert-butyl bromoacetate (3.8 mL), potassium carbonate (6 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.6 g, 25%).
Reaction SMILES: [N:1]([C:4]1([CH3:11])[CH:9]([OH:10])[CH2:8][CH:7]=[CH:6][CH2:5]1)=[N+:2]=[N-:3].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH3-]C#N.[Na+]>CO.C(Cl)Cl.CO>[N:1]([C:4]1([CH3:11])[CH2:5][CH2:6][N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:8][CH:9]1[OH:10])=[N+:2]=[N-:3]
Reactant: NCc1ccccc1
Reactant: CC1(N=[N+]=[N-])CC=CCC1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1(N=[N+]=[N-])CCN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A solution of 6-azido-6-methylcyclohex-3-enol (3.9 g, 25 mmol) in MeOH/DCM (100 mL/20 mL) cooled to −78° C. was degassed by bubbling nitrogen through it for 5 min. Ozone was then bubbled through the reaction mixture until a greyish-blue colour persisted. Nitrogen was again bubbled through the cold reaction mixture until only a pale colour persisted. A solution of benzylamine (2.7 g, 25 mmol) dissolved in MeOH (5 mL) was added followed by NaCNBH3 (6.4 g, 101.5 mmol) in MeOH (10 mL). The mixture was allowed to warm to room temperature and stirred for 16 hr. The solvents were removed under reduced pressure and the residue partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was further extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (40 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (1-10% 7 M NH3 in MeOH/DCM) gave 5-azido-1-benzyl-5-methylazepan-4-ol as a viscous yellow oil (4.8 g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.25-7.34 (m, 5H), 3.69-3.62 (m, 2H), 3.51-3.47 (m, 2H), 2.96-2.89 (m, 1H), 2.69-2.62 (m, 3H), 2.19-2.11 (m, 1H), 1.99-1.85 (m, 1H), 1.78-1.68 (m, 1H), 1.61-1.57 (m, 1H), 1.43 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:18]I>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[I:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: CN1Cc2cncn2-c2cccc(Br)c2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(I)ncn2-c2cccc(Br)c2C1=O

Procedure:
12.80 g (44 mmol) of 7-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at 95° for 3.5 hours with 39 g (154 mmol) of iodine in 80 ml of N,N-dimethylformamide. The reaction mixture was evaporated, the residue was taken up in methylene chloride and water and decolorized by the addition of sodium thiosulphate. The mixture was filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate there was obtained 7-bromo-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 203°-204°.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH2:5][CH:4]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)[CH2:3]1.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[F:30][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][CH:4]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][CH2:10][NH:9]2)[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](c2ccccc2)C[C@H]1C1CCCC(F)(F)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: FC1(F)CCCC([C@@H]2C[C@H](c3ccccc3)CCN2)C1
Yield: 98.4 %

Procedure:
A suspension of 11 (500 mg, 1.2 mmol) and Pd(OH)2 (0.2 g) in 10 ml of EtOH was hydrogenated under 1 atmosphere of hydrogen at room temperature overnight. Filtration and concentration afforded (2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine as a colorless oil (330 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:12]=1[C:13]([OH:15])=[O:14]>>[Cl:23][C:16]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Reaction time: 2 h

Procedure:
To 74 g (0.60 mol) of p-anisidine, stirred mechanically at 75 degrees, was added 35.4 g (0.15 mol) of 2,6-dichloro-3-nitrobenzoic acid [Lehmstedt and Schrader, Berichte 70B, 1526 (1937)]in small portions over one-half hour. The mixture was heated at 75 degrees for 24 hours, with stirring during the first two hours. The reaction mixture was cooled, the solid mass shattered, and triturated in a mechanical blender with 300 ml of 2.4N hydrochloric acid. The solid was collected, washed with 3N hydrochloric acid, stirred in 400 ml of 0.5N sodium carbonate, and filtered. The filtrate, diluted with 250 ml of water, was gradually acidified with 4N hydrochloric acid. The precipitate was collected, washed with water, and dried to 38.5 g (79%) of the red title compound, mp 205-213 degrees. A purified sample, from toluene, melts at 212-215 degrees.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC=C(Oc1ccccc1C)C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(Oc1ccccc1CBr)C(=O)OC

Procedure:
A mixture of 1.1 g of methyl 2-(2-methylphenoxy)-3-methoxyacrylate, 0.95 g of N-bromosuccinimide, and a catalytic amount of azobisisobutyronitrile was heated at reflux in carbon tetrachloride for 4 hours. The solid was filtered, and the solvent evaporated to give a crude sample of methyl 2-(2-bromomethylphenoxy)-3-methoxyacrylate. A mixture of this crude sample together with 0.6 g of o-cresol, and 1.0 g of potassium carbonate was heated at reflux in acetonitrile for 20 hours. The solid was filtered, the solvent evaporated, and the residue purified by silica gel chromatography to give methyl 2-[2-(2-methylphenoxy)methylphenoxy]-3-methoxyacrylate (0.47 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[NH2:6].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:21][NH:6][C:5]1[CH:7]=[CH:8][C:9]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:3]([CH3:2])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccc(N2C(=O)c3ccccc3C2=O)c(C)c1

Procedure:
To a mixture of the product aniline of Example 31 (15 g) and 18 g of anhydrous potassium carbonate suspended in 400 ml of dimethylformamide was added 11 g of methyl iodide in 30 ml of dimethylformamide. After 16 hours the mixture was concentrated to an oily residue which solidified upon trituration with water. The crude solid was purified by chromatography as in Example 34 to give the title compound. Samples prepared by the methods of Examples 34 and 36 were identical.
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)=[O:9].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Se:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:14]([C:13]1[CH:12]=[CH:11][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: c1cc[se]c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(=O)c2ccc[se]2)cc1
Yield: 43 %

Procedure:
Selenophene (61) (5.0 g, 0.038 mole) and 4-methoxycarbonyl benzoyl chloride (62) (8.34 g, 0.042 mole) were dissolved in 50 ml of 1, 2-dichloroethane, and then anhydrous aluminum chloride (AlCl3) (10.19 g, 0.076 mole) was added. The mixture was heated under refluxing for 30 min, cooled, and quenched with 250 ml of icewater to stop the reaction. The organic layer was sequentially washed with water, 5% sodium carbonate solution, and water till neutral, then dried over MgSO4 and filtered. The solvent of the filtrate was evaporated under a reduced pressure, and the residue was subjected to a column chromatography (silica gel, chloroform), and then recrystallized from n-hexane to afford compound 63 in yellow crystals (4.78 g).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:4]=[N:3][CH:2]=1.[OH-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>O.CCOCC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1
Reactant: OCCCCCCc1cncnc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCOCCCCCCc1cncnc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 5-pyrimidinehexanol (1.82 g), 50% sodium hydroxide (6 ml), 1,6-dibromohexane (6 ml) and TAB (150 mg) was vigorously stirred at room temperature for 30 h then diluted with water (20 ml) and ether (25 ml). The organic phase was dried and evaporated in vacuo. The residue was purified by FCC eluting with hexane followed by hexane-ether (1:1) and ether, to give the title compound as a colourless liquid (2.21 g), t.l.c. (ether) Rf 0.35.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.[C:38]1([C:44]2[S:45][CH:46]=[C:47]([C:49]([N:51]3[CH2:56][C:55]4([CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)[O:54][CH2:53][CH2:52]3)=[O:50])[N:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:59]2[CH2:60][CH2:61][C:55]3([O:54][CH2:53][CH2:52][N:51]([C:49]([C:47]4[N:48]=[C:44]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[S:45][CH:46]=4)=[O:50])[CH2:56]3)[CH2:57][CH2:58]2)=[CH:10][CH:11]=1)[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)c2csc(-c4ccccc4)n2)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.619 g) in MeCN (3 mL) was added dropwise to a solution of (2-phenylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 112, step b) (0.274 g) and triethylamine (0.22 mL) in MeCN (7.3 mL) at RT under argon. The resulting mixture was stirred at 80° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine and water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-70% EtOAc in petroleum ether (40-60° C.) to give the subtitled compound as a yellow solid. Yield 0.42 g.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:13]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)#[N:12]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(CNc2cnccc2C(=O)O)cc1
Temperature: 166 °C
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol), 4-(aminomethyl)-benzonitrile hydrochloride (240 mg, 1.42 mmol), and DIEA (250 μL, 1.42 mmol) were combined in DMA (2 mL) and the reaction mixture was stirred at 166° C. in a microwave for 90 min. The solution was concentrated in vacuo and purified by silica gel chromatography (10-20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a pale yellow precipitate, which was collected by filtration and dried under vacuum to give 32 mg (18%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.10 (br s, 1H), 8.04 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 4.69 (s, 2H). [M+H] calc'd for C14H11N3O2, 254; found 254.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([NH2:14])=[CH:7]2.Cl[C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CC(O)C>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([NH:14][C:16]1[N:21]=[C:20]([NH:14][C:8]3[CH:9]=[N:10][C:11]4[C:6]([CH:7]=3)=[CH:5][C:4]([OH:3])=[CH:13][CH:12]=4)[CH:19]=[CH:18][N:17]=1)=[CH:7]2
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cnc2ccc(O)cc2c1
Agent: Br
Solvent: CC(C)O
Product: Oc1ccc2ncc(Nc3ccnc(Nc4cnc5ccc(O)cc5c4)n3)cc2c1
Temperature: 25 °C

Procedure:
A mixture of 6-hydroxy-3-aminoquinoline di-hydrobromide (0.064 g, 0.2 mmol) and 2,4-dichloropyrimidine (0.148 g, 1 mmol) in IPA (1 mL) was heated at reflux overnight. The reaction was cooled to RT and a yellow solid was filtered off and washed with IPA. The solid was purified by flash chromatography in CH2Cl2/MeOH/NH4OH (90/10/1). The fractions containing the compound were combined and the solvents were removed under vacuum. The residue was purified by reverse-phase preparative HPLC (CH3CN/water/TFA) to give the bis-trifluoroacetate of the title compound as a yellow solid. MS (MH+)=397.2, Calc'd for: C22H16N6O2—396.4.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14](OC)=[O:15])[N+:10]([O-:18])=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH-].[Na+]>O>[N:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[N:10]3[O:18][C:14](=[O:15])[N:13]=[C:11]3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Nc1cc(N2CCCCC2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CCCCC2)nc2nc(=O)on12

Procedure:
5 G. of dimethyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide are dissolved in 200 ml. of methylene chloride and mixed with 100 ml. of water. While stirring vigorously, the mixture is adjusted with concentrated sodium hydroxide to pH 12.5 and stirred at this pH for 3 hours. The two phases are separated and the aqueous phase is adjusted to pH 4 with concentrated hydrochloric acid. The resulting white precipitate is filtered off, washed with water, pre-dried slightly and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure methyl 5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 210°-214° C. (decomposition).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1)[CH3:8].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=1)[CH3:8]
Reactant: CCOC(=O)Cc1cccc(CN)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CNS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Methanesulfonyl chloride (2.6 mL, 34 mmol) was slowly added to a solution of (3-aminomethyl-phenyl)-acetic acid ethyl ester hydrochloride (7.31 g, 34 mmol) and triethylamine (9.8 mL, 70 mmol) in CH2Cl2 (100 mL) at 0° C. The mixture was stirred for 1 h and 1N aqueous HCl solution was added. The aqueous solution was extracted with CH2Cl2 (3×) and the combined organic extracts were washed with brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1:1 hexanes:EtOAc) provided the title sulfonamide (8.56 g) as a clear and colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.21 (m, 4H), 4.70 (broad, 1H), 4.29 (d, 2H), 4.12 (q, 2H), 3.60 (s, 2H), 2.86 (s, 3H), 1.24 (t, 3H).