Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12](=[O:14])[CH3:13])[N:4]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:26][C:27]([N:10]1[CH2:9][CH2:8][N:7]2[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][C:5]([C:12](=[O:14])[CH3:13])=[C:6]2[CH2:11]1)=[O:28])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2

Procedure:
1-(3-Trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl)-ethanone 27g (192 mg, 0.72 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid if (0.24 g, 0.72 mmol) were dissolved in 20 mL of dichloromethane under stirring, and triethylamine (0.4 mL, 2.88 mmol) was then added to the solution. After stirring to mix well, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.275 g, 1.08 mmol) was then added. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-acetyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 27h (0.3 g) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].Cl[C:23]([O:25][CH:26]1[CH:33]2[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2)=[O:24].CO>[OH-].[Na+].O1CCOCC1.ClCCl>[CH:33]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:35][CH:27]([CH2:28]3)[CH:26]1[O:25][C:23]([NH:1][CH:2]([CH:6]([C:8]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4])=[O:24])[CH2:32]2
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: CC(c1c[nH]c2ccccc12)C(N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CC(c1c[nH]c2ccccc12)C(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Yield: 62.8 %

Procedure:
Percent amino acid (75) (449 mg, 2.29 mmol) in 1N sodium hydroxide (2.29 mL) was added to sodium hydrogen carbonate (211 mg, 2.5 mmol). This mixture was cooled to 0° C. (ice bath), dioxan. (2.29 mL) was added, followed by dropwise addition with stirring of a solution of the chloroformate (76) (742 mg, 34.46 mmol) in dioxan (2.29 mL). When all the amino acid had gone (TLC SiO2 :4% methanol in dichloromethane), the dioxan was removed in vacuo and the residue partitioned between 10% citric acid and ethyl acetate. The aqueous phase was extracted further with ethyl acetate. The organic extracts were combined, dried (MgSO4), and evaporated to dryness. The crude acid was purified by column chromatography on normal silica [hexane:ethyl acetate (3:20+0.5% acetic acid as eluant] to give 2-(2-adamantyloxy-carbonyl)amino-3-(3-indolyl) butanoic acid (77) (570 mg, 63%); δ H (300 M Hz, d6 -DMSO), 1.34 (3H, d, J 8Jz. CH3), 1.68-2.00 (14H, m, adamantyl), 3.40-3.53 (1H, m, indCH(CH3)), 4.36 (1H, brt, CH(CO2H)), 4.59 (1H, s, adamantyl 2-H), 6.73 (1H, d, J 9 Hz, urethane NH), 6.96 (1H, t, J 7 Hz, indole 5-H), 7.06m (1H, t, J 7 Hz, indole 6-H), 7.17 (1H, brs, indole 2-H), 7.33 (1H, d, J 8 Hz, indole 7-H), 7.60 (1H, d, J 8 Hz, indole 4-H), 10.83 (1H, s, indole NH)m, ca 12.6 (vbrs, CO2H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:15].[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH:11]=[CH:12][CH:13]=[CH:14][C:7]5=[N:6][C:5]=4[CH3:15])[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1nc2ccccn2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 19 %

Procedure:
A mixture of 3.3 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 3.3 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 1 part of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 3 hours. The reaction mixture was cooled, water was added and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 1.2 parts (19%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170.4° C. (compound 11).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[CH:16](=[O:18])[CH3:17].[Cl-].[NH4+]>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.O>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:16]([OH:18])[CH3:17]
Reactant: CC=O
Reactant: Fc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: O
Product: CC(O)c1ccncc1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
Into a stirred solution of 3-fluoropyridine (14 g, 144.2 mmol) in anhydrous THF (150 mL), cooled to −78° C. and under argon, 79.2 mL (158.6 mmol) of a 2N solution of lithiumdiisopropylamide (LDA) in n-heptane, THF, ethylbenzene, were slowly dropped in about 1 h. After stirring for 2.5 h a cooled solution (ca. 0° C.) of acetaldehyde (8.9 mL, 158.5 mmol) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred at −78° C. for 1.5 h. The solution was warmed to −30° C. and a solution of ammonium chloride (150 g) in 700 mL of water was added. The mixture was extracted with ethylacetate (3×400 mL) and the organic layers were washed with brine (4×200 mL) and dried over sodium sulfate. After concentration, the oil was crystallized with n-hexane (40 mL) and 15.6 g (76% yield) of 1-(3-fluoropyridin-4-yl)ethanol were obtained. A mixture of 1-(3-fluoropyridin-4-yl)ethanol (10 g, 70.3 mmol) and commercial activated MnO2 (8 g, 92.1 mmol) in toluene (100 mL) were refluxed until disappearance of starting material. After cooling, the mixture was filtered on a bed of celite, the cake washed with toluene and the organic phases concentrated to give 3-fluoro-4-acetyl pyridine (6.9 g, 70%) that was used directly in the next step. To a stirred solution of 3-fluoro-4-acetylpyridine (5.3 g, 38.1 mmol) in glacial acetic acid (14 mL) and 48% hydrobromic acid (5.3 mL), bromine (2 mL, 38 mmol) in glacial acetic acid (5.3 mL) was added slowly and dropwise. After addition, the solution was stirred at 60° C. for 2.5 hour. This solution was cooled down and ethylacetate (70 mL) was added. After 30 minutes of stirring, the mixture was filtered and the solid was washed thoroughly with ethylacetate and dried. The title compound was obtained in 82% yield (9.4 g).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:9]([NH:11]N)=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl.CCOCC.N(OC(C)(C)C)=O.N[C@H:37]([C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:66]([NH:68][CH2:69][C:70]([O:72][CH3:73])=[O:71])=[O:67])[CH2:60][O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:44])[NH2:43]>CN(C)C=O.C(N(CC)CC)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:9]([NH:11][C@H:37]([C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:66]([NH:68][CH2:69][C:70]([O:72][CH3:73])=[O:71])=[O:67])[CH2:60][O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:57])[CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:44])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCCNC(=N)N
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
7.6 g of Z-His-NH-NH2 (25 mmols) are suspended in 60 ml of dimethylformamide, 31 ml of hydrogen chloride in ether (2.43 N,. 75.3 mmols) are added at -16°C and the clear yellowish solution thereby obtained is mixed, at -18°C, with 3.2 ml of t-butyl nitrite (95 % strength, 26.5 mmols) in 10 ml of dimethylformamide. After 10 minutes 10.4 ml of triethylamine (75 mmols) in 25 ml of pre-cooled dimethylformamide, and 8.5 g of H-Arg-Phe-Ser(tBu)-Gly-OCH3. 2 HCl (14 mmols) in 50 ml of pre-cooled dimethylformamide are added. The mixture is diluted with 40 ml of dimethylformamide and four portions each of 1.0 ml of triethylamine (a total of 28.7 mmols) are added in intervals of 5 minutes. The mixture is allowed to stand for a further 3 hours at 0°C and for 20 hours at room temperature, the precipitated salts are then filtered off, and the reaction solution is concentrated in vacuo to about three-fourths of its volume. On repeatedly stirring the product into a large amount of ethyl acetate a crude product is obtained which is purified by counter-current distibution in the system methanol-buffer-chloroform-carbon tetrachloride (9:3.5:8:2) through 130 stages (buffer as under 18); rmax = 54; K = 0.7. The pure fractions are combined, evaporated, freed of ammonium acetate in a high vacuum at 40°C, and lyophilised after solution in water.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:38]=[C:23]4[C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=5)=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH2:13]1[C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:38]=[C:23]4[C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=5)=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9][NH:8][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cccc(C(F)(F)F)c5)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cccc(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1

Procedure:
(2,3,4,5-Tetrahydro-1H-3-benzazepin-7yl)-[8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 7-[8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.203 g, 388 mmol) and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.072 g, 44%). MP=88-91° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.83 (d, 1H), 8.65 (s, 1H), 8.40 (d, 1H), 7.95 (d, 1H), 7.82 (m, 2H), 7.50 (m, 2H), 7.15 (t, 1H), 7.05 (d, 1H), 2.75 (br m, 9H). MS=424 (MH)+.
Reaction SMILES: C([O:8][C:9](=[O:35])[C:10]1[CH:15]=[C:14]([C:16]([CH3:18])=[CH2:17])[C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][C:11]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C1C=CC=CC=1.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[CH2:28]([O:27][C:11]1[CH:12]=[C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:16]([CH3:18])=[CH2:17])=[CH:15][C:10]=1[C:9]([OH:35])=[O:8])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=C(C)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid benzyl ester (40.8 g, 87.9 mmol) in THF-MeOH-water (3:1:1, 300 mL total) was added lithium hydroxide (8.42 g, 352 mmol). The mixture was heated at 50° C. for 16 h, allowed to cool to ambient and then diluted with water (300 mL). The mixture was taken to pH˜1 using conc. HCl (˜30 mL) and then extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and reduced in vacuo. The solid residue was taken up in P.E-MeOH (9:1, 300 mL total), the slurry stirred for 1 h at ambient and the solid collected by filtration. The solid was dried in vacuo to give the title compound (26.8 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 12.30 (s, 1H), 7.61 (s, 1H), 7.53 (d, J=7.0 Hz, 2H), 7.47-7.31 (m, 8H), 6.94 (s, 1H), 5.23 (d, J=14.0 Hz, 4H), 5.08 (d, J=9.0 Hz, 2H), 2.04 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[N:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][CH2:8][CH2:7]2
Reactant: Cc1c2c(cc3c1NCCC3)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCCc2cc3c(c(C)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 201 mg of t-butyl 11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2 ml of pyridine was added 0.1 ml of ethyl chloroformate, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 261 mg of 8-t-butyl 1-ethyl 11-methyl-3,4,6,7,9,10-hexahydro-1H-azepino[4,5-g]quinoline-1,8(2H)-dicarboxylate as a colorless viscous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][CH:9]2[CH2:15][CH2:14][C:13]3[C:16]([O:26]C)=[C:17]([O:24][CH3:25])[C:18]([O:22][CH3:23])=[C:19]([O:20]C)[C:12]=3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH:9]2[CH2:15][CH2:14][C:13]3[C:16](=[O:26])[C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19](=[O:20])[C:12]=3[CH2:11][CH2:10]2)=[CH:28][CH:29]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc(Cl)cc1)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(Cl)cc3)CC2)C1=O
Reaction time: 0.25 h
Yield: 79.6 %

Procedure:
To a mixture of 7-[2-(4-chlorophenoxy)ethyl]-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.38 g), 2,6-pyridinedicarboxylic acid (1.64 g), THF (52 ml), and water (13 ml) was dropwise added a solution of CAN (7.18 g) in water (13 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography(ethyl acetate) and then with recrystallization from hexane-ethyl acetate to yield the entitled compound (1.02 g) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO>[OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1O
Yield: 83.2 %

Procedure:
A solution of methyl 2-hydroxy-4-[2-(phenethyl)phenethyl]benzoate (0.25 g) in THF (5 ml) and methanol (5 ml) containing aqueous 2N sodium hydroxide (5 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated to small volume and acidified with aqueous 2N hydrochloric acid. The mixture was extracted three times with ethyl acetate (25 ml each time) and the combined extracts were washed with brine and dried over anhydrous magnesium sulphate. The solid obtained on removal of the solvent was crystallised from a mixture of diethyl ether and hexane to give 2-hydroxy-4-[(2-phenethyl)phenethyl]benzoic acid (0.2 g), m.p. 134-7° C.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[N:6]1[C:7]2[N:8]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:9]=[CH:10][C:11]=1O>ClCCCl.CN(C=O)C>[Br:3][C:11]1[CH:10]=[CH:9][N:8]2[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=[C:7]2[N:6]=1
Reactant: Oc1ccn2c(n1)nc1ccccc12
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Brc1ccn2c(n1)nc1ccccc12
Temperature: 100 °C
Yield: 100 %

Procedure:
Phosphorus oxybromide (25 g, 87 mmol) was added to a suspension of benzo[4,5]imidazo[1,2-a]pyrimidin-2-ol (5.2 g, 28.1 mmol) in DCE (Ratio: 1.000, Volume: 93 ml) and DMF (Ratio: 0.01, Volume: 0.927 ml). Heated the reaction mixture to 100° C. for 3 hours. Cooled the reaction to room temperature and concentrated. Diluted with ice water and quenched to pH ˜8 with concentrated ammonium hydroxide. The resulting residue was filtered and washed with water followed by ethyl ether. Dried under vacuum to afford crude 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (6.97 g, 28.1 mmol, 100% yield).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[CH:14][C:13]3[CH:16]=[N:17][N:18]([C:19]4[N:24]=[C:23]([N:25]5[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.N>C(Cl)Cl.CO>[N:25]1([C:23]2[N:24]=[C:19]([N:18]3[C:12]4[CH:11]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=5)[N:15]=[CH:14][C:13]=4[CH:16]=[N:17]3)[CH:20]=[CH:21][CH:22]=2)[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cnn(C(C)(C)C)c5)cc43)n2)CC1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)n1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 56.9 %

Procedure:
A solution of tert-butyl 4-(6-(6-(1-tert-butyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (100 mg, 0.19 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to afford a residue. The residue was diluted with MeOH (10 mL), neutralized with 28% ammonia solution, concentrated, and purified by preparative HPLC to afford 145 as a white solid (45 mg, 56%). 1H-NMR (500 MHz, CD3OD) δ (ppm) 9.03 (s, 1H), 8.71 (d, J=6.5 Hz, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.65-7.68 (m, 1H), 7.25 (d, J=7.5 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 3.90-3.94 (m, 4H), 3.14-3.16 (m, 2H), 2.91-2.94 (m, 2H), 2.05-2.10 (m, 2H), 1.68 (s, 9H); MS (ESI) m/z: 417 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14](F)[CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:31][S-:32].[Na+].O>CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:32][CH3:31])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[S-]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(SC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 657.5 %

Procedure:
To a solution of 50 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-benzonitrile (prepared according to the method described in example 1) in 10 ml of dimethylformamide was added 121 mg of sodium thiomethoxide. The resulting mixture was stirred at room temperature overnight, then poured into water, extracted with diisopropyl ether. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by crystallization from diisopropyl ether/heptane to give 350 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfanyl-benzonitrile, which was transformed into 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfanyl-phenyl}-4H-[1,2,4]oxadiazol-5-one according to the method described in example 1.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C:19]3=[O:24])=[CH:14][CH:13]=2)=[N:4][CH:3]=1.C(O)(=O)C.CC([O-])=O.[Na+].[CH3:34][C:35]([CH3:37])=O.[BH3-]C#N.[Na+].Cl>CO>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:35]([CH3:37])[CH3:34])[CH2:20][C:19]3=[O:24])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C1CNCCN1c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a solution of 1-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-piperazin-2-one (example 31, step 2) (180 mg, 0.47 mmol) in MeOH (4 mL) are added acetic acid (0.03 mL, 0.47 mmol), NaOAc (38 mg, 0.47 mmol) and acetone (0.2 mL, 1.18 mmol). The reaction mixture is stirred at room temperature for 1 hour then NaCNBH3 (60 mg, 0.94 mmol) is added and the mixture is stirred at 40° C. overnight. After cooling to room temperature, the reaction mixture is acidified with conc. HCl (pH 1) and concentrated in vacuo. The residue is partitioned between 6N NaOH and DCM. The aqueous layer is extracted with DCM (3×) and the combined organic layers are dried over MgSO4 and concentrated in vacuo to afford a crude compound which is purified by silica gel column chromatography. Elution with DCM and 98:2 DCM:MeOH affords the title compound as a yellow solid (45 mg, 25%).
Reaction SMILES: [Br:1][C:2]1[O:19][CH:5]2[CH2:6][N:7](CC3C=CC(OC)=CC=3)[C:8](=[O:9])[CH:4]2[CH:3]=1>C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[O:19][CH:5]2[CH2:6][NH:7][C:8](=[O:9])[CH:4]2[CH:3]=1
Reactant: COc1ccc(CN2CC3OC(Br)=CC3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC2OC(Br)=CC12
Yield: 77.8 %

Procedure:
A solution of 2-bromo-5-(4-methoxy-benzyl)-3a,5,6,6a-tetrahydro-furo[2,3-c]pyrrol-4-one (0.16 g, 0.498 mmol) in TFA (1.8 mL) and anisole (0.2 mL) is stirred at 80° C. for 2.5 hours. The reaction mixture is then diluted with ethyl acetate and neutralised with sat. NaHCO3. The aqueous layer is extracted with ethyl acetate (3×) and the combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. The crude compound is purified by silica gel column chromatography eluting with 1:1 petroleum ether:ethyl acetate followed by 1:4 petroleum ether:ethyl acetate, to afford the title compound (79 mg, 78%).