Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH3:9][CH:10](O)[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH:10]([CH3:11])[CH3:9])[CH:3]=1
Reactant: CC(C)O
Reactant: O=c1cc(I)cc[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)Oc1cc(I)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 2.30 g (10.4 mmol) 4-iodo-1H-pyridin-2-one in 130 mL DCM are added 0.88 mL (11.4 mmol) 2-propanol and 3.00 (11.4 mmol) triphenylphosphine. After cooling down to 0° C. 2.23 mL (11.4 mmol) DIAD are added dropwise. After 5 min the cooling is removed and the mixture is stirred at r.t. for 2 h. The reaction mixture is washed with water and brine, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 90/10).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[S:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[N:6]=[C:7]([S:19][CH3:23])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncccc2C(=S)Nc2c(C)cc(C)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1c2ncccc2C(SC)=Nc2c(C)cc(C)nc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 5,11-dihydro-2,4-dimethyl-11-ethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-thione (0.2 g, 0.7 mmol) in dimethylformamide (10 mL) was added NaH (50% in mineral oil, 0.04 g, 0.8 mmol). The mixture was stirred under argon at 40° C. for 1 hr. After cooling to 30° C. methyl iodide (0.12 g, 0.8 mmol) was added, and the mix was stirred for 1 hr. The reaction was quenched with water, and the mixture was concentrated in vacuo. The residue was treated with ethyl acetate, washed, dried, and concentrated. Chromatography over silica gel (eluted with 20% EtOAc/Hex) gave 0.2 g of the title compound, m.p. 130°-132° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2N=C(C)S[CH:19]=2)[N:3]=1.[CH3:21][C:22]1[S:23]C(C(OCC)=O)=C[N:26]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[I:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[S:23][C:22]([CH3:21])=[N:26][CH:19]=2)[N:3]=1
Reactant: Cc1nc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)cs1
Reactant: CCOC(=O)c1cnc(C)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Temperature: 85 °C

Procedure:
To a solution 4-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-2-methylthiazole (prepared according the method of Example 15, Steps A-D, using ethyl 2-methylthiazole-5-carboxylate) in EtOH/H2O (8 mL/2 mL) was added iron (463 mg, 8.30 mmol) and NH4Cl (44.4 mg, 0.830 mmol). The reaction mixture was heated at 85° C. for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. EtOAc/Et3N (40 mL/10 mL) was added to the residue. The mixture was heated at 85° C. for 20 minutes, cooled to 45° C., and filtered through Celite. The Celite pad was washed with MeOH (30 mL). The combined filtrate was concentrated under reduced pressure to remove EtOAc and MeOH. The aqueous suspension was extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give the product (156 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH:3]1[C:12]([O:14][CH3:15])=[O:13].C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]1[CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH:3]([C:12]([O:14][CH3:15])=[O:13])[C:2]1=[O:1]
Reactant: COC(=O)C1CC2(CCC1=O)OCCO2
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: COC(=O)C1CC2(CC(=CN(C)C)C1=O)OCCO2

Procedure:
Methyl 8-oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylate (64 mg, 0.3 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (80 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 270.3 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[O:30]C(=O)[O:28][C:27]2=O)=[CH:22][CH:21]=1>C1COCC1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:1][C:27](=[O:28])[CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[OH:30])[CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1N
Reactant: O=C1OC(=O)C(c2ccc(F)cc2)O1
Solvent: C1CCOC1
Product: NC(=O)c1ccc(OCc2ccccc2)cc1NC(=O)C(O)c1ccc(F)cc1
Temperature: 63 °C
Yield: 63 %

Procedure:
To a solution of 2-amino-4-(benzyloxy)benzamide (4.0 g, 16.5 mmol) in THF (60 mL) was added a solution of 5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione (3.65 g, 18.6 mmol) from Example 16 in THF (20 mL) portionwise at rt. After heating to 63° C. for 18 h, the solution was cooled and concentrated. After addition of H2O, the solution was extracted twice with DCM. The combined organic phases were washed with brine and dried over sodium sulfate. Chromatography on silica gel eluting with 10 to 80% EtOAc/DCM afforded 4-(benzyloxy)-2-(2-(4-fluorophenyl)-2-hydroxyacetamido)benzamide as a foamy solid (4.1 g, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.06 (m, 1H), 5.12 (s, 2H) 6.68-6.74 (m, 1H) 7.14-7.20 (m, 2H) 7.32-7.51 (m, 6H) 7.77 (d, J=8.85 Hz, 1H) 8.05 (br. s., 1H) 8.30 (d, J=2.64 Hz, 1H) 12.73 (s, 1H). LC-MS (ESI) m/z 392 (M−2).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11].O>CCOCC>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]([CH3:1])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][CH:16]=1
Reactant: [Li]C
Reactant: COC(=O)C=Cc1cccc(OC)c1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CC(C)c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Under a N2 blanket, a solution of lithium dimethylcuprate was prepared at 0° C. from cuprous iodide (7.6 g, 0.04 mol) and a solution of methyl-lithium in ether (80 ml, 1 M, 0.08 mol). A solution of methyl m-methoxycinnamate (4.8 g, 0.025 mol) in ether (20 ml) was then added dropwise and the reaction mixture was stirred for 1 hour at 0° C. A large volume of water was cautiously added, after which the ether layer was separated, dried (anhydrous Na2SO4) and evaporated to dryness. The residue was chromatographed on silica gel (100 g) with hexane/ethyl acetate (80:20) as eluent, giving 3.65 g methyl β-(m-methoxyphenyl)-butyrate (68% yield by weight).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[O:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
Trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine was prepared from trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) and N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine (0.151 g, 0.425 mmol) in a manner similar to that used for the cis-isomer. The compound was formed as a white powder (0.053 g, 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:23]=[C:22]([O:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)[CH:21]=[N:20][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(-c3cncc(O[C@@H]4CCCNC4)n3)c2c1
Temperature: 80 °C

Procedure:
A glass microwave reaction vessel was charged with (R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (1.91 g, 3.77 mmol) in DCM (10 mL)/TFA (4 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 80° C. for 15 min, and then the solvent was removed. The residue was purified with RP-HPLC to give (R)-5-(2,6-difluorophenyl)-3-(6-(piperidin-3-yloxy)pyrazin-2-yl)-1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].Br[CH2:15][C:16]([O:18]C)=[O:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:10][S:7]([NH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:13]=[CH:12][CH:11]=1)[O:1][CH2:15][C:16]([OH:18])=[O:17])(=[O:9])=[O:8]
Reactant: COC(=O)CBr
Reactant: CS(=O)(=O)NCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)NCc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 72.9 %

Procedure:
A mixture of N-(3-hydroxy-benzyl)-methanesulfonamide (6.000 g, 29.82 mmol), methyl bromoacetate (4.562 g, 29.82 mmol), K2CO3 (4.121 g, 29.82 mmol), and acetone (250 mL) was stirred at room temperature for 68 h. The solids were removed by filtration and the solution was concentrated in vacuo. Purification by flash chromatography (1:1 hexanes:EtOAc) provided the title compound (5.637 g). 1H NMR (400 MHz, CDCl3) δ7.25 (m, 1H), 6.96 (m, 1H), 6.89 (s, 1H), 6.82 (m, 1H), 4.63 (m, 3H), 4.28 (m, 2H), 3.80 (s, 3H), 2.86 (s, 3H); MS 274 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4](=[S:6])[NH2:5])#[N:2].[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29])=O>N1CCCCC1.C(O)C>[NH2:5][C:4](=[S:6])[C:3]([C:1]#[N:2])=[CH:7][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]
Reactant: N#CCC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=C(C#N)C(N)=S)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
1.5 g (15 mmol) of 2-cyanoethanethioamide, 60 ml of ethanol and one drop of piperidine are added respectively to 5 g (15 mmol) of tert-butyl 4-(4-formyl-3-nitrophenyl)piperazine-1-carboxylate. The reaction mixture is stirred at room temperature for 12 hours. The precipitate obtained is filtered to yield 5.2 g (83%) of tert-butyl 4-(4-(3-amino-2-cyano-3-thioxoprop-1-enyl)-3-nitrophenyl)piperazine-1-carboxylate in the form of a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:15][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1
Reactant: Cc1c(I)cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(I)c(C)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of 3-iodo-4-methyl-5-nitro-benzoic acid (16.06 g, 52.3 mmol) in acetone (300 mL) was added K2CO3 (14.46 g, 104.6 mmol) followed by methyl iodide ((3.91 mL, 62.76 mmol). The reaction mixture was stirred at 40° C. overnight, then cooled to room temperature and partitioned between ethyl acetate and brine. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to provide 16.5 g (98%) of 3-iodo-4-methyl-5-nitro-benzoic acid methyl ester.
Reaction SMILES: [C:1]12([C:11]3[CH:31]=[CH:30][C:14]([O:15]/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24]([OH:26])=[O:25])=[O:19])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl.Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][O:25][C:24](=[O:26])[C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([NH:20][C:18](=[O:19])/[CH:17]=[CH:16]/[O:15][C:14]2[CH:30]=[CH:31][C:11]([C:1]34[CH2:2][CH:3]5[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]5)[CH2:8]3)[CH2:10]4)=[CH:12][CH:13]=2)[CH:22]=1
Reactant: O=C(/C=C/Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)O)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)c1cccc(NC(=O)/C=C/Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 10.6 %

Procedure:
(E)-3-(3-(4-Adamantan-1-yl-phenoxy)acrylamido)benzoic acid (60 mg, 0.144 mmol) and 2-(dimethylamino)ethylchloride.HCl (31.1 mg, 0.216 mmol) were dissolved in DMF (3 ml), to which K2CO3 (39.8 mg, 0.288 mmol) was added, followed by stirring at 60° C. for 12 hours. The reaction mixture was extracted with ethylacetate and NaHCO3 solution, thereafter the organic layer was washed with NaCl solution and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-TLC (n-Hexane:EtOAc=10:1) to give the target compound as a white solid (21.5 mg, yield: 10.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[H-].[Na+].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]=1[C:26]([F:29])([F:28])[F:27].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]=1[C:26]([F:27])([F:29])[F:28]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2c(Cl)cc(Cl)cc2Cl)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
2,4,6-trichloroaniline (3.9 g.) was dissolved in dimethylformamide (20 ml.) and carefully added to sodium hydride (obtained by washing sodium hydride in mineral oil (2.0 g; 50%) with petrol) suspended in dimethylformamide (10 ml.) at 10° C. When the addition was complete the temperature of the mixture was allowed to rise to the ambient temperature over a period of 30 minutes, before being cooled to 10° C. A solution of 2-chloro-3,5-dinitrobenzotrifluoride (5.4 g.) in dimethylformamide (20 ml.) was slowly added, and the mixture stirred at the ambient temperature for 5 hours, and allowed to stand for further 16 hours. The mixture was poured into iced water and the resultant mixture acidified with concentrated hydrochloric acid. The precipitate was collected by decanting off the supernatant liquid and recrystallised from methylated spirit to yield 2(2,4,6-trichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 105° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)[CH:5]=O.[C:13]([NH:17][C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:5][C:4]2[CH:3]=[C:2]([Br:1])[CH:9]=[C:8]([NH2:10])[CH:7]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Reactant: O=Cc1cc(Br)cc([N+](=O)[O-])c1
Product: CC(C)(C)NC(=O)C1CCN(Cc2cc(N)cc(Br)c2)CC1

Procedure:
The title compound is prepared according to the reactions described above starting from 3-bromo-5-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination BB-10a; LC-MS A: tR=0.65 min; [M+H]+=398.00 followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.60 min; [M+H]+=369.67.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:32])[NH:33][CH2:34][CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCCCN1CCOCC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCCCN1CCOCC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 63.9 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with N-(3-aminopropyl)morpholine (available from Aldrich Chemical Company, Inc.; 89 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-morpholin-4-yl-propylcarbamoyl)-biphenyl-2-carboxylic acid (80 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br s, 1H), 9.60 (br s, 1H), 8.67 (br t, 1H), 8.47 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 6H), 3.60-4.00 (m, 4H), 3.34-3.42 (m, 3H), 2.93-3.21 (m, 4H), 1.87-1.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: NCc1cccnc1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCc3cccnc3)nc21

Procedure:
This compound was prepared by a procedure similar to that described in Example 33 starting with 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 1.08 g (10.0 mmol) of 3-(aminomethyl)-pyridine yielding 0.053 g of pure product; mp 224-226° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[O:27][CH3:28].OS(O)(=O)=O.O>CN1C(=O)CCC1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[N:3]=[C:4]([NH:17][CH3:18])[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=2)=[CH:22][C:21]=1[O:27][CH3:28]
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Reactant: COc1cc(N)ccc1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1nc(Nc2ccc(Br)c(OC)c2)nc2c1CCC2c1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Ga) (0.24 g, 0.924 mmol), 4-bromo-3-methoxyaniline (0.187 g, 0.924 mmol) and H2SO4 (0.064 mL, 1.201 mmol) in NMP (Volume: 2 mL) was stirred in a sealed microwave tube at 90° C. overnight. The reaction was poured into 20 mL of water. The precipitate was collected by filtering. The cake was air dried. The cake was triturated with a minimum amount of cold MeOH to get 0.36 g (84%) of product as an off-white solid. LC-MS (M+H)+=425.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.39 (1 H, br. s.), 7.68 (1 H, d, J=1.51 Hz), 7.53 (1 H, d, J=8.53 Hz), 7.34-7.42 (2 H, m), 7.24-7.34 (3 H, m), 6.94 (1 H, dd, J=8.66, 2.38 Hz), 4.36-4.51 (1 H, m), 3.83 (3 H, s), 3.05 (3 H, d, J=4.52 Hz), 2.79-2.95 (1 H, m), 2.59-2.77 (2 H, m), 1.93-2.12 (1 H, m).
Reaction SMILES: C(N(CC)CC)C.C1(O[C:15](=[O:27])[NH:16][C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)C=CC=CC=1.[NH2:28][C@H:29]([CH2:33][OH:34])[CH:30]([CH3:32])[CH3:31]>C(Cl)(Cl)Cl>[OH:34][CH2:33][C@@H:29]([NH:28][C:15]([NH:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1)=[O:27])[CH:30]([CH3:32])[CH3:31]
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1)Oc1ccccc1
Reactant: CC(C)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H](CO)NC(=O)Nc1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 113.3 %

Procedure:
Triethylamine (0.54 mL) and phenyl[6-(trifluoromethyl)pyridin-3-yl]carbamate (600 mg) were added to a solution of L-valinol (200 mg) in chloroform, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford 1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea (640 mg).