Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1.FC(F)(F)C([O-])=O.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)=[O:33].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[N:9][CH:10]=3)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=2)[CH2:37][CH2:36]1)=[O:33]
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Reactant: CCOC(=O)c1cc2ccncc2c(Cl)n1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cc2ccncc2c(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Temperature: 170 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
In a sealed high pressure container with a Teflon lining was combined ethyl 1-chloro-2,7-naphthyridine-3-carboxylate (280 mg, 1.18 mmol), 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86; 957 mg), and K2CO3 (1.25 g) in 15 ml tert-butanol. The container was heated at 170° C. with stirring for 8 hours. The solution was concentrated by rotary evaporation and reconstituted with EtOAc. The organic layer was washed 4× with H2O, and dried over MgSO4. Product was purified on reverse phase Si to yield 36 mg white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](OCC)=[O:11])=[C:6](Cl)[N:5]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.[NH4+:24].[OH-]>O1CCOCC1>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10](=[O:11])[NH:24][C:6]=2[N:5]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCc1c(Cl)nc(/C=C/c2ccccc2)nc1Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CCc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Temperature: 75 °C
Yield: 21 %

Procedure:
To a solution of ethyl 3-{4,6-dichloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate (0.42 g, 1.19 mmol) in 1,4-dioxane (5 mL) was added conc. NH4OH (3.5 mL). The reaction was heated at 75° C. in a sealed tube for 16 h. The solution was concentrated under vacuum, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) to yield the desired compound as a yellow solid (0.072 g, 21%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:14]2[C:15]3[CH2:16][CH2:17][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][C:10]=3[N:11]=[C:12]([CH2:19][O:20][CH3:21])[N:13]=2)=[CH:30][CH:31]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COCc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC#N
Product: COCc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(Cc1ccccc1)C2
Yield: 65.5 %

Procedure:
The title compound was prepared using the general procedure set forth in Example 2, above, using 7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidine (0.583 g, 1.92 mmol), 4-tert-butylbenzenamine (0.33 mL, 2.11 mmol) and acetonitrile (3 mL) to give 0.524 g (66%) of the title compound as an off-white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:17]([F:20])([F:19])[F:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C>C(O)C.[Li+].[OH-].O>[C:11]1([C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=2[C:17]([F:19])([F:20])[F:18])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid ethyl ester (750 mg, 2.50 mmol) in ethanol (12 mL) and 2 N aq. LiOH (6 mL) is stirred at 65° C. for 2 h. The reaction mixture is cooled to rt, diluted with water (60 mL) and extracted with DCM (50 mL). The aq. phase is acidified by adding 2 N aq. HCl (7 mL) and extracted twice with DCM (2×50 mL). These organic extracts are combined, washed with sat. aq. NaHCO3, dried over Na2SO4, evaporated and dried under high vacuum to give 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid (670 mg) as a brown solid, LC-MS: tR=0.97 min, 1H NMR (D6-DMSO): δ 7.57-7.54 (m, 1H), 7.46-7.42 (m, 5H).
Reaction SMILES: B.O1CCC[CH2:3]1.[CH3:7][C:8]([O:11][C:12]([NH:14][CH:15]([C:26]([OH:28])=O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:13])([CH3:10])[CH3:9].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.Cl>O1CCOCC1>[OH:28][CH2:26][CH:15]([N:14]([CH3:3])[C:12](=[O:13])[O:11][C:8]([CH3:7])([CH3:9])[CH3:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(C(F)(F)F)c1
Agent: B
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)C(CO)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A quantity of 438 ml of borane-tetrahydrofuran complex (1M solution in THF, 438 mmol) was introduced with ice cooling. Then 35 g (110 mmol) of N-Boc-2-(3-trifluoromethylphenyl)-DL-glycine were added in portions. The reaction mixture was stirred at RT for 2 h and then cautiously admixed with pieces of ice. After the end of the evolution of gas, the solvent was removed on a rotary evaporator. The aqueous residue was admixed with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was taken up in acetonitrile and 2.5% strength aqueous sodium hydrogen carbonate solution. Then 25.18 ml (109.62 mmol) of di-tert-butyl dicarbonate were added and the mixture was stirred at RT for 3 h. The acetonitrile was removed on a rotary evaporator. The residue was extracted three times with ethyl acetate, dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue was again admixed with 438 ml of borane-tetrahydrofuran complex (1M solution in THF, 438 mmol) and stirred at 70° C. for 3 h. It was worked up again, and an excess of a 4N solution of hydrogen chloride in dioxane was added to the complete work-up mixture, which was stirred overnight. Thereafter the solvent was removed on a rotary evaporator. The residue was dried in an HV and then admixed once again with 400 ml of borane-tetrahydrofuran complex (1M solution in THF, 400 mmol) and stirred overnight. It was then worked up and again, as described above, reacted with 25.18 ml (109.62 mmol) of di-tert-butyl dicarbonate. The crude product obtained after work-up was purified by preparative HPLC. Drying in an HV gave 10.2 g (29% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: NCc1ccc(F)c(F)c1
Product: CCOc1cc2ncc(C#N)c(NCc3ccc(F)c(F)c3)c2cc1OCC

Procedure:
In the manner of Example 61 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3,4-difluorobenzylamine gave the title compound as a tan solid, mp167-169° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[NH:15])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][O:20][CH:21]([C:26](OC)=[O:27])[C:22](OC)=[O:23].C(O)C.C[O-].[Na+]>C(O)(=O)C>[OH:23][C:22]1[C:21]([O:20][CH3:19])=[C:26]([OH:27])[N:16]=[C:14]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:18][CH:17]=2)[N:15]=1
Reactant: N=C(N)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1c(O)nc(-c2ccc(OCc3ccccc3)cc2)nc1O
Temperature: 80 °C
Yield: 61.2 %

Procedure:
A mixture of 85 g of 4-benzyloxybenzamidine hydrochloride, 78.6 g of dimethyl methoxymalonate, 1700 ml of ethanol, and 187 g of sodium methylate (28% methanol solution) was heated at 80° C. for 4 hours with stirring. After cooling, 1000 ml of acetic acid was slowly added to the reaction mixture, whereupon a yellow crystal precipitated. The precipitated crystals were collected by filtration, washed twice with water until the washing became neutral, and dried at 80° C. for 3 hours in high vacuo to obtain 64.2 g (percent yield: 60.7% ) of 4,6-dihydroxy-5-methoxy-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: [NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][C:19](Br)=[O:20].O>C(Cl)Cl>[Br:17][CH2:18][C:19]([N:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1)=[O:20]
Reactant: O=C(Br)CBr
Reactant: C1CCC2NCCCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)N1CCCC2CCCCC21
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.6 %

Procedure:
To an ice cooled suspension of 2.15 g (15 mmol) of decahydroquinoline, 5.20 g (37.5 mmol) of potassium carbonate in 30 ml of methylene chloride was added 3.10 g (15 mmol) of bromoacetylbromide. Then the reaction mixture was stirred at RT for 20 h, Water was added, the mixture extracted by methylene chloride, the organic phase washed by water, dried over sodium sulphate and evaporated to dryness. Flash chromatography using methylene chloride as eluant afforded 2.6 g of compound as uncolorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][NH:16][CH2:15]1>>[Cl:1][C:2]1[C:3]([N:16]2[CH2:15][C@H:14]([CH3:13])[O:19][C@H:18]([CH3:20])[CH2:17]2)=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Product: C[C@@H]1CN(c2c(C(=O)O)ccc(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: 3-chloro-2,4-difluorobenzoic acid and cis-2,6-dimethylmorpholine.
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)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:27]=[C:26](S(C)(=O)=O)[N:25]=1.[NH2:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]1>CN1C(=O)CCC1.O>[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)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:27]=[C:26]([NH:44][C@@H:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[N:25]=1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)nc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)cc1
Temperature: 125 °C
Yield: 47.9 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 0.330 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (198 mg, 0.989 mmol) in NMP (2.0 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 125° C. for 2 h. The mixture was diluted with water and the resulting suspension was filtered. The solid was washed with water and dried to give 115 mg of the crude product, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 727.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:16]O>>[CH3:16][O:13][C:12]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:14]
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(c2ccccc2)CCCC1
Yield: 88 %

Procedure:
A solution of 1-phenyl-1-cyclopentanecarboxylic acid (2.00 g, 10.51 mmol) in 30 mL methanol saturated with HCl was stirred at reflux for two hours. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was dissolved in 50 mL dichloromethane and washed with 2N sodium hydroxide (3×25 mL). The organic layer was washed with water (2×25 mL) and dried (Na2SO4). Evaporation of the solvent gave 1.89 g (88%) of methyl-1-phenyl-1-cyclopentanecarboxylate as a pale yellow liquid and was used in the next step without further purification. CIMS 205 m/z (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1.CO[CH:14]=[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=2)[C:18](=[O:30])[NH:17][C:16]1=[O:31]>CN(C)C=O>[CH3:11][O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][CH:14]=[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N:25]4[CH:29]=[CH:28][CH:27]=[CH:26]4)[CH:23]=3)[C:18](=[O:30])[NH:17][C:16]2=[O:31])[O:4][CH:5]=1
Reactant: COc1coc(CN)cc1=O
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Solvent: CN(C)C=O
Product: COc1coc(CNC=C2C(=O)NC(=O)c3ccc(-n4cccc4)cc32)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-methoxy-pyran-4-one (116 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (201 mg, 0.80 mmole) is stirred for one hour at ambient temperature. The reaction mixture is evaporated to dryness, dissolved in 7.5% methanol in chloroform passed through Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated, treated with acetonitrile, the resulting solid filtered and dried to give a beige solid, 106 mg, (36%), mp 251-4° C. dec; MS (ES−): m/z 390.1 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1)#[N:2]>CO.ClCCl.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[C:10]([CH3:18])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-c1ccc(C#N)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N)ccc1-c1ccc(C#N)cc1
Yield: 29.5 %

Procedure:
1-(4-Cyanophenyl)-2-methyl-4-nitrobenzene (9.7 gm, 40.76 mmol) was dissolved in a mixture of methanol and dichloromethane (1:1, 400 mL) and hydrogenated over 10% palladium on charcoal (970 mg) at 3 bar and 20° C. for 18 h. The mixture was filtered through Arbocel filter aid and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate 20:1 to 1:1) to give 4-amino-1-(4-cyanophenyl)-2-methylbenzene (2.5 gm, 30%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.CC(N(C)C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37]([O:44][C:45]([N:47]1[CH2:51][CH:50]2[CH2:52][CH:53]([CH2:55]OS(C)(=O)=O)[CH2:54][CH:49]2[CH2:48]1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:37]([O:44][C:45]([N:47]1[CH2:48][CH:49]2[CH2:54][CH:53]([CH2:55][O:17][C:11]3[CH:10]=[C:9]4[C:14]([C:5]([O:4][C:3]5[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=5[F:1])=[CH:6][CH:7]=[N:8]4)=[CH:13][C:12]=3[O:15][CH3:16])[CH2:52][CH:50]2[CH2:51]1)=[O:46])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Reactant: CS(=O)(=O)OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (2.74 g, 6.7 mmol, 1.0 eq.), DMA (30 ml) and cesium carbonate (6.6 g, 20.2 mmol, 3.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 5-methanesulfonyloxymethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (2.6 g, 7.3 mmol, 1.1 eq) was added. The reaction was heated to 75° C. and allowed to stir overnight. After allowing the reaction to cool to room temperature the reaction was poured into water. The solid was filtered and was then dissolved in EtOAc and washed 2× water, 1× brine and dried over NaSO4. The solvent was removed to yield 5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester as a cream solid (3.7 g, 94% yield). 1H NMR (400 MHz), CDCl3): 8.55 (d, 1H), 8.15 (d, 1H), 8.09 (d, 1H), 7.32 (m, 8H), 6.52 (d, 1H), 5.11 (d, 2H), 4.13 (d, 2H), 3.95 (s, 3H), 3.57 (m, 2H), 3.43 (m, 2H), 2.93 (m, 3M, 2.16 (m, 2H), 1.39 (m, 2H); MS (EI) for C32H30FN3O7: 588 (M+H+).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:20].[Na+].Cl[CH2:23][C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH3:36]>O1CCCC1>[I-:20].[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[S:28][C:24]([CH2:23][P+:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:25]([CH3:36])[N:26]=2)=[CH:34][CH:33]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
Triphenylphosphine (1.15 g, 4.26 mmol) and sodium iodide (580 mg, 3.87 mmol) were added to 5-chloromethyl-2-(4-chlorophenyl)-4-methylthiazole (1.00 g, 3.87 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred for 5 hours while being stirred. Subsequently, the crystallized powdery product was collected by filtration and washed with hexane to give 2.43 g (quant.) of the desired compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[C:6]([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)=[O:19])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH2:4][CH2:3][O:2][CH3:1])[CH:25]=[CH:24]3)=[O:19])=[CH:14][CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3[nH]ccc3c2)cc1
Reactant: COCCBr
Product: COCCn1ccc2cc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)ccc21

Procedure:
Analogous to the procedure used to prepare Example 70, 2-bromoethyl methyl ether (140 mg, 1.0 mmol, Aldrich) and (2E)-3-[4-(tert-butyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 161, (320 mg, 0.01 mmol) provided, after purification by silica gel chromatography (65:35 hexane:EtOAc), the title compound as a pale yellow solid. MP 138° C. MS (ESI, pos. ion) m/z: 377 (M+1).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5](Cl)[N:4]=1.[Na+].[Cl-].[CH2:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][O:18][C:5]1[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([NH2:9])[CH:6]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CC(C)CCO
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: CC(C)CCOc1cc(N)nc(N)n1
Reaction time: 11 h
Yield: 88 %

Procedure:
To a solution of 6.9 g (0.30 mol) sodium in 200 ml isopentyl alcohol were added 43.4 g (0.30 mol) 2,4-diamino-6-chloropyrimidine. The mixture was heated under reflux with stirring for 11 h. The reaction mixture was then stirred at 80° C. for a further 36 h. After the reaction was ended the precipitated NaCl was separated off and the solution was concentrated to dryness. The residue was repeatedly taken up in ethanol and again concentrated in order to remove residual isopentyl alcohol. After drying, 6-(3-Methylbutoxy)-2,4-diaminopyrimidine (51.8 g, 88%) was obtained as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([B-](F)(F)F)=[CH2:19].[K+].C(N(CC)CC)C>C(O)CC>[C:1]([N:5]1[C:9]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([CH:18]=[CH2:19])[N:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[B-](F)(F)F
Reactant: CC(C)(C)n1nccc1Nc1cncc(Cl)n1
Agent: [K+]
Solvent: CCCO
Solvent: CCN(CC)CC
Product: C=Cc1cncc(Nc2ccnn2C(C)(C)C)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 65.04 g of N-(1-tert-butyl-1H-pyrazol-5-yl)-6-chloropyrazin-2-amine, 41.6 g of potassium vinyltrifluoroborate, 4.22 g of (1,1′-bis (diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane complex, 72 ml of triethylamine and 685 ml of 1-propanol was stirred at 110° C. overnight, followed by cooling down to room temperature and concentrated in vacuo. The obtained residue was diluted with ethyl acetate, and an insoluble matter was filtered off using Celite. The resulting ethyl acetate solution was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was suspended in 100 ml of ethyl acetate, and 400 ml of diisopropylether was added to the mixture. The obtained precipitate was collected to give the title compound as a pale brown solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]C)=[O:27])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(CC(=O)O)cc1
Reaction time: 8 h

Procedure:
Methyl 2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetate (Intermediate #33) (210 mg, 0.51 mmol) was dissolved in methanol (10 mL) and treated at ambient temperature with a 2M solution of sodium hydroxide (1.27 mL, 2.53 mmol). The mixture was stirred overnight and then methanol was removed by evaporation under reduced pressure. The clear aqueous solution was diluted with water (20 mL) and acidified to pH3 with 2M HCl. The resulting white precipitate was extracted into ethyl acetate (2×20 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to give the crude product. The crude product was purified by to preparative HPLC using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetic acid. (84 mg, 41%).