Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:21])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
6-Amino-9-benzyl-2-ethoxypurine (143 mg, 0.53 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated and dried on sodium sulfate, filtered and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (42 mg, yield 23%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>C1COCC1.C(O)C.O.[Fe]>[NH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[C:5]1[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cccc(CN(Cc2cccc([N+](=O)[O-])c2)c2ccc(F)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1cccc(CN(Cc2cccc(N)c2)c2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a slurry of the product from Example 143A (0.450 g, 1.180 mmol) in THF (4 mL), ethanol (1.00 mL) and water (4.00 mL) at rt was added ammonium chloride (0.189 g, 3.54 mmol) followed by iron (0.329 g, 5.90 mmol) and the mixture heated to 80° C. After 3 h, the mixture was filtered through Celite, concentrated and the residue partitioned between water and 25% isopropyl alcohol-CHCl3. The organic phase was dried (Na2SO4) and concentrated. The solid was dried in a vacuum oven to provide 321 mg (85%) of the title compound. MS (ESI; M+H) m/z=322.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:43]([O:47][C@H:48]([CH3:58])[C@H:49]([NH:56][CH3:57])[CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl>[C:43]([O:47][C@H:48]([CH3:58])[C@H:49]([N:56]([CH3:57])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=1)[CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CN[C@H](CN1CCCC1)[C@@H](C)OC(C)(C)C
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCCC2)[C@@H](C)OC(C)(C)C)ccc1F
Yield: 17.9 %

Procedure:
4-Fluoro-3-methylbenzoic acid (101 mg, 0.66 mmol), TBTU (232 mg, 0.72 mmol) and DIPEA (0.172 mL, 0.99 mmol) was stirred in DCM (2 mL) for 1 h. (2R,3R)-3-tert-butoxy-N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M7) (150 mg, 0.66 mmol) was added and the resultant mixture was stirred at rt overnight. The reaction mixture was washed with NaHCO3 (8% aq., 2 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (43 mg, 18%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.94, 1.05-1.15, 1.55-1.72, 2.20, 2.21-2.28, 2.31-2.45, 2.60-2.66, 2.77, 2.83, 2.90, 3.27, 3.44-3.50, 3.70-3.77, 3.87-3.93, 4.51-4.58, 7.08-7.22, 7.23-7.28, 7.37.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:12]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=3)=[N:11][C:10]=2[N:9]([CH3:37])[C:8]1=[O:38].[NH3:39]>CO>[NH2:39][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:12]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=3)=[N:11][C:10]=2[N:9]([CH3:37])[C:8]1=[O:38]
Reactant: Cn1c(=O)n(CCOCCBr)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: N
Solvent: CO
Product: Cn1c(=O)n(CCOCCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 39 %

Procedure:
1-(2-(2-bromoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.16 mmol) was dissolved in a preformed solution of ammonia in methanol (15 mL). The reaction was heated at 60° C. overnight in a sealed tube. The reaction was cooled to room temperature and the solvent was evaporated. The residue was purified by preparative HPLC to give 1-(2-(2-aminoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (35 mg, 39% yield) as white solid.
Reaction SMILES: [NH:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:12]([C:19]([N:21]=[C:22]=[S:23])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4]([CH:3]([C:2](=[NH:1])[CH2:9][CH2:10][CH3:11])[C:22]([NH:21][C:19]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:20])=[S:23])=[O:5])[CH3:8]
Reactant: CCCC(=N)CC(=O)OCC
Reactant: O=C(N=C=S)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCCC(=N)C(C(=O)OCC)C(=S)NC(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of ethyl 3-iminohexanoate (31.4 g.) in toluene (25 ml.) was added to a stirred solution of phenoxycarbonyl isothiocyanate (36 g.) in toluene (75 ml.) at 20° C. The temperature rose to 54° C. The mixture was allowed to cool to room temperature, filtered, and the solid washed with light petroleum (b.p. 40°-60° C.) to give 2-ethoxycarbonyl-3-imino-N-phenoxycarbonylthiohexanamide (62 g.) in the form of a yellow powder. This powder was suspended in ethyl acetate (150 ml.) and treated at 0°-5° C. with a solution of bromine (10.5 ml.) in ethyl acetate (50 ml.) during 20 minutes. The mixture was stirred for a further hour and then filtered, and the solid washed with light petroleum (b.p. 40°-60° C.) to give 4-ethoxycarbonyl-5-phenoxycarbonylamino-3-n-propylisothiazole hydrobromide (69 g.) m.p. 135°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][NH:7][CH2:6][CH2:5]2.[Br-].[K+].I(C1C=CC=CC=1)=[O:16]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8](=[O:16])[NH:7][CH2:6][CH2:5]2
Reactant: O=Ic1ccccc1
Reactant: Fc1cc2c(cc1Cl)CCNC2
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C1NCCc2cc(Cl)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of 6-chloro-7-fluoro-1,2,3,4-tetrahydro-isoquinoline (130 mg, 0.7 mmol), potassium bromide (83.5 mg, 0.7 mmol) and iodoso benzene (0.46 g, 2.1 mmol) in water (4 mL) was stirred at room temperature overnight. The mixture was then extracted with EtOAc and the organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product. Flash column chromatography separation (silica gel, 12 g, 30% EtOAc in hexane) then afforded the tile compound (58 mg, 41%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.OCCS(C1C=C(C=CC=1)[NH2:36])(=O)=O.[N+:40]([C:43]1[CH:44]=[C:45]([CH2:49][S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=1)([O-])=O>>[S:50]([CH2:49][C:45]1[CH:44]=[C:43]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:48]=[CH:47][CH:46]=1)(=[O:52])(=[O:51])[NH2:36]
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Product: NS(=O)(=O)Cc1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-(2-hydroxy-ethanesulfonyl)-aniline [CAS-Nr. 344750-15-8; prepared from commercially available 3-nitro-phenylmethane-sulfonyl chloride] according to general procedure II. Yellow solid. MS (ISP) 542.0 [(M−H)−]; mp 298° C.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:14])[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:3][CH:2]=1.[SH:21][CH2:22][CH2:23]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)CCC>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=[CH:3][C:4]([C:7]2([CH2:8][N:9]3[CH:13]=[N:12][CH:11]=[N:10]3)[S:21][CH2:22][CH2:23][O:14]2)=[CH:5][CH:6]=1
Reactant: O=C(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(C3(Cn4cncn4)OCCS3)cc2)cc1
Yield: 41.6 %

Procedure:
To a slurry of 13.1 g of 1-[1,1'biphenyl]-4-yl-2-(1H-1,2,4-triazol-1-yl)ethanone in 175 ml dry toluene and 70 ml 1-butanol was added, with stirring, 7.8 g 2-mercaptoethanol and 12.3 g p-toluenesulfonic acid. The resultant thickened slurry was refluxed under a Dean-Stark [trademark] trap for 72 hours. At this point, no further water was collected. After the reaction was allowed to cool, the solid was filtered out, slurried in dichloromethane and shaken with 10% aqueous sodium hydroxide and once with water. The organic layer was dried and evaporated to leave an oil which solidified on high-vacuum pumping. This solid was triturated with petroleum ether to give 6.7 g of 1-[(2-[1,1'-biphenyl]-4-yl-1,3-oxathiolan-2-yl)methyl]-1H-1,2,4-triazole, the product of this reaction. The melting point of this compound was 85°-90° C.
Reaction SMILES: C(O[CH:5]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH:7]=[CH:6]1)(=O)C.[N-:22]=[N+:23]=[N-:24].[Na+].O1CCCC1.O>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.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.[Pd].C(OCC)(=O)C>[C:10]1([C:9]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH:7]([N:22]=[N+:23]=[N-:24])[CH:6]=[CH:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC1C=CCC1(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1C=CC(c2ccccc2)(c2ccccc2)C1
Reaction time: 14.5 h
Yield: 56.8 %

Procedure:
To a mixture of 5,5-diphenyl-2-cyclopentenyl acetate (0.30 g) and sodium azide (84 mg) in a solution of tetrahydrofuran (3 ml) and water (1.5 ml) was added tetrakis(triphenylphosphine)palladium(O) (62 mg) at room temperature under an argon atmosphere. After being stirred for 14.5 hours, ethyl acetate was added. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate as an eluent to give 4,4-diphenyl-2-cyclopentenyl azide (0.16 g).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1CCN(C2C3CNC(C4N=CC=CN=4)CC=3N=C(C3C=CC(N)=CC=3)N=2)C[CH2:32]1.[CH3:60][N:61]1[CH:65]=[C:64]([NH2:66])[CH:63]=[N:62]1.C1(CN)CC1>>[CH3:60][N:61]1[CH:65]=[C:64]([NH:66][C:32]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12]3[N:13]=[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])[C:9]4[CH2:24][CH2:23][N:22]([C:25]5[N:26]=[CH:27][CH:28]=[CH:29][N:30]=5)[CH2:21][C:10]=4[N:11]=3)=[CH:15][CH:16]=2)=[O:31])[CH:63]=[N:62]1
Reactant: Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC(c2ncccn2)C3)cc1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Reactant: Cn1cc(N)cn1
Agent: NCC1CC1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3cnn(C)c3)cc2)nc2c1CCN(c1ncccn1)C2

Procedure:
The title compound lh was prepared by the general procedure of Example 30 substituting (S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline for 4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)aniline and 1-methyl-1H-pyrazol-4-amine for cyclopropylmethylamine. LC-MS: m/z=+527 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[NH2:26][C@H:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([OH:33])[CH2:28]1.O>CN(C=O)C>[C:11]1([C:9]2[O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][C@H:29]([OH:33])[CH2:28]4)[C:3]=3[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncnc2oc(-c3ccccc3)cc12
Reactant: N[C@H]1CCC[C@H](O)C1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CCC[C@@H](Nc2ncnc3oc(-c4ccccc4)cc23)C1
Temperature: 120 °C

Procedure:
Heat a mixture of 4.0 g (17.34 mmol) of 4-chloro-6-phenylfuro[2,3-d]pyrimidine, 4.5 ml (26 mmol) of DIEA and 2.8 g of (+/−)-cis/trans-3-aminocyclohexanol (approx. 85% strength, approx. 20.8 mmol; approx. 3:1 cis/trans mixture; prepared according to J. Chem. Soc. Perkin Trans. I, 1994, 537) in 15 ml of DMF is heated to 120° C. overnight. After cooling, add the reaction mixture to water and extract three times with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution, dry over magnesium sulphate and concentrate under reduced pressure. Repeated stirring of the crude product with a mixture of methyl tert-butyl ether and dichloromethane enriches the product in the mother liquor. After concentrating the mother liquor, filter off the product with suction after crystallization from dichloromethane/methanol (10:1) and dry it under reduced pressure. 1.11 g (20.7% of theory) of the target product are obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[C:7]([C:13]#N)[C:6]1=[O:15])[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)[OH:17].[OH-:21].[Na+]>O>[CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[C:7]([C:13]([OH:17])=[O:21])[C:6]1=[O:15])[CH:2]([CH3:4])[CH3:3]
Reactant: [OH-]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)n(CC(C)C)c(=O)c1C#N
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)n(CC(C)C)c(=O)c1C(=O)O
Yield: 40.6 %

Procedure:
To a mixture of 1-isobutyl-3-cyano-4,6-dimethylpyrid-2-one (99.8 g., 0.489 mole) and 100 ml. of water is slowly added, with stirring, concentrated sulfuric acid (200 ml.) When the addition of complete the reaction mixture is heated on a steam bath for 24 hours. The solution is then poured into a sodium hydroxide solution and filtered. The alkaline filtrate is acidified and the resulting solid is then collected by filtration to give 1-isobutyl-3-carboxy-4,6-dimethylpyrid-2-one, 44.5 g. (40.6% yield), mp 93°-95° C.
Reaction SMILES: [CH:1]1([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10](O)[C:9]=2[C:18]2[C:23]([F:24])=[CH:22][C:21](F)=[CH:20][C:19]=2[F:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32].[H-].[Na+].[Cl-:36].[Na+]>CS(C)=O>[Cl:36][C:10]1[C:9]([C:18]2[C:19]([F:26])=[CH:20][C:21]([O:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])=[CH:22][C:23]=2[F:24])=[C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[N:11]=1
Reactant: Oc1nc2nccn2c(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Reactant: [Cl-]
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCCOc1cc(F)c(-c2c(Cl)nc3nccn3c2C2CCCCCC2)c(F)c1
Temperature: 40 °C

Procedure:
To a solution of the above 5-cycloheptyl-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidin-7-ol and 3-dimethylamino-1-propanol (206 m g, 2.0 mmol) in 3.0 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 80 mg, 2.0 mmol). The mixture is heated at 40° C. for 2 h, and cooled to room temperature. A saturated sodium chloride solution is added, and the product is extracted with ehtyl acetate. The organic solution is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. To the residue is added 5 mL of phosphorous oxychloride and 2 mL of N,N-diethylaniline, and the mixture is heated at 110° C. for 1 h. The excess phosphorous oxychloride is removed in vaccuo, and the resulting residue is partitioned between ethyl acetate and 5% sodium carbonate solution. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 20% methyl alcohol in ethyl acetate. Concentration provides 3-[4-(7-chloro-5-cycloheptylimidazo[1,2-a]pyrimidin-6-yl)-3,5-difluorophenoxy]-N,N-dimethylpropan-1-amine as a brown oil (24 mg). MS: m/z 463.3 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[CH2:4][C@H:3]1[OH:14].C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[CH2:4][C@H:3]1[OH:14])=[O:25]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2c1C[C@@H](N)[C@H](O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1C[C@@H](NC(=O)CCl)[C@H](O)C2
Reaction time: 2 h

Procedure:
1.01 g (0.005M) of trans-3-amino-1,2,3,4-tetrahydro-5-methoxy-2-naphthalinol are dissolved in 50 ml of absolute methylene chloride. 0.81 g (0.008M) of triethylamine are added, and the mixture left to cool to 0°. At this temperature, 0.68 g (0.006M) of chloroacetyl chloride (dissolved in 5 ml of absolute methylene chloride) are then added in drops over the course of 5 minutes. Stirring is effected for 2 hours at room temperature. The reaction mixture is subsequently washed once with 1N hydrochloric acid and once with ice water. It is extracted three times, each with 20 ml of methylene chloride, the combined organic phases are dried, and the solvent is concentrated by evaporation. Trans-2-chloro-N-(1,2,3,4-tetrahydro-2-hydroxy-5-methoxy-3-naphthalinyl)-acetamide is obtained (m.p. 176°-178°, recrystallisation from methylene chloride/ether).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.Cl.[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH2:16].C(N(CC)CC)C.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:15][C:14]([O:13][CH3:12])=[O:17])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: COC(=O)CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)CNCc1ccc(Br)cc1Cl
Temperature: 50 °C
Yield: 31.5 %

Procedure:
4-bromo-2-chlorobenzaldehyde (2B1) (4.56 mmol, 1.0 g) and glycine methyl ester hydrochloride (2C2) (4.56 mmol, 572 mg) were dissolved in ethanol (15 ml) under nitrogen with stirring and triethylamine (135 mmol, 19.0 ml, 13.7 g) was added. The reaction mixture was heated to 50° C. for 1 hour, then evaporated to dryness and the residue taken up in methanol (15 ml) and cooled in an ice bath. Sodium borohydride (5.01 mmol, 0.190 g) was added portionwise and stirring continued until no starting material remained as determined by TLC. The reaction mixture was concentrated to dryness and partitioned between DCM and water and the phases separated. The organic layer was dried over sodium sulphate, filtered and concentrated before purification on silica eluting with 15% EtOAc/heptane to yield methyl 2-(4-bromo-2-chlorobenzylamino)acetate (2C3) 420 mg (31%); 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H) 7.38 (d, 1H) 7.31 (d, 1H) 3.86 (s, 2H) 3.73 (s, 3H) 3.43 (s, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.NCC([N:55]1[CH2:60][CH2:59][CH:58]([NH:61][C:62]2[CH:67]=[C:66]([Br:68])[CH:65]=[CH:64][C:63]=2[O:69][CH3:70])[CH2:57][CH2:56]1)=O>CN(C=O)C.O>[Br:68][C:66]1[CH:65]=[CH:64][C:63]([O:69][CH3:70])=[C:62]([NH:61][CH:58]2[CH2:57][CH2:56][N:55]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:60][CH2:59]2)[CH:67]=1
Reactant: COc1ccc(Br)cc1NC1CCN(C(=O)CN)CC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1NC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 0.03 h
Yield: 35 %

Procedure:
DIPEA (45 mg, 0.35 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (26 mg, 0.1 mmol) in DMF (1 mL) followed by HOBt (20 mg, 0.15 mmol) and EDCI.HCl (28 mg, 0.15 mmol). After 2 minutes of stirring, 2-amino-1-[4-(5-bromo-2-methoxy-phenylamino)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 2 and 5 of the General Scheme) (0.03 g, 0.0001 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure Purification by column chromatography (using neutral alumina and 5% MeOH in CHCl3 as eluent) to afford 60 mg (35% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-bromo-2-methoxy-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 512.4, 91%, 1H NMR (300 MHz, DMSO-d6): δ10.2 (m, 1H), 7.9 (m, 1H), 7.7 (m, 7H), 7.4 (m, 2H), 7.2 (m, 1H), 3.6 (m, 5H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:38])=[O:30])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7]>C(O)C.O.C(OCC)C>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C@@H:4]([C:3]([OH:39])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[S:7])=[CH:23][CH:24]=1)=[O:30]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)CCCCC1(C(=S)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 52.5 °C
Reaction time: 22 h
Yield: 70.2 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl] cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (25.86 mmol, 15.87 g) in ethanol (75 mL) was added aqueous 1. ON sodium hydroxide (60 mL) at 50° C. The mixture was heated to 50-55° C. and the resulting clear light brown solution was stirred for 22 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water and allowed to cool to room temperature and was filtered to remove a small amount of solids. The filtrate was concentrated and the residual aqueous solution was washed with diethyl ether (2×75 mL). The basic aqueous layer was acidified with 3.ON HCl to form a cloudy suspension and was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (200 mL) then the dried (MgSO4) solution was filtered and evaporated to dryness. The residue was taken up in dichloromethane and diluted with diethyl ether:hexane (1:1) to obtain a solid which was collected by filtration. Trituration of the solid with hot ethyl acetate (˜100 mL) resulted in a suspension that was then diluted with diethyl ether (˜50 mL) and the solid was collected by filtration. The above Trituration was repeated to afford 10.89 g (70%) of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine as a colorless solid. HR MS: Obs. mass, 599.1193. Calcd. mass, 599.1208 (M+H).