Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10](B4OC(C)(C)C(C)(C)O4)=[CH:11][CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[C:14]=3[NH:15]2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Br[C:31]1[C:32]([CH3:49])=[C:33]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([F:48])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:48][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]2[C:42]=1[N:41]=[CH:40][N:39]=[C:38]2[NH:37][C:33]1[C:32]([CH3:49])=[C:31]([C:10]2[C:9]3[C:8]4[C:16](=[CH:17][C:5]([C:2]([OH:1])([CH3:4])[CH3:3])=[CH:6][CH:7]=4)[NH:15][C:14]=3[C:13]([C:18]([NH2:20])=[O:19])=[CH:12][CH:11]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(B3OC(C)(C)C(C)(C)O3)c12
Reactant: Cc1c(Br)cccc1Nc1ncnc2c(F)cccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1c(Nc2ncnc3c(F)cccc23)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(C)(C)O)ccc3c12
Temperature: 90 °C
Yield: 65.4 %

Procedure:
Step 2 A mixture of 7-(2-hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide (ca. 60% purity, 35 mg, 0.053 mmol), N-(3-bromo-2-methylphenyl)-8-fluoroquinazolin-4-amine (Intermediate 32-7, 17.69 mg, 0.053 mmol), and 2 M aqueous sodium carbonate (0.067 mL, 0.133 mmol) in toluene (0.8 mL) and ethanol (0.200 mL) was purged with argon, treated with tetrakis(triphenylphosphine)palladium (3.1 mg, 0.003 mmol) and heated at 90° C. in a sealed tube for 16.5 h. The mixture was cooled to rt and concentrated. The residue was purified by preparative HPLC and the appropriate effluent fractions were treated with NaHCO3 (aq) and partially concentrated at rt. The resulting aqueous suspension was filtered and the precipitate was washed with water and dried to provide 4-(3-(8-fluoroquinazolin-4-ylamino)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (18.0 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (1H, s), 10.08 (1H, s), 8.56 (1H, s), 8.35 (1H, d, J=8.4 Hz), 8.16 (1H, br. s.), 7.99 (1H, d, J=7.9 Hz), 7.87 (1H, s), 7.70 (1H, dd, J=10.2, 8.3 Hz), 7.60 (1H, td, J=8.1, 5.2 Hz), 7.42-7.54 (3H, m), 7.28 (1H, dd, J=7.3, 1.3 Hz), 7.11 (2H, s), 7.01 (1H, d, J=7.7 Hz), 5.00 (1H, s), 1.85 (3H, s), 1.49 (6H, s). Mass spectrum m/z 520.1 (M+H)+.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CCCCCCCCCCCC)C(=O)C1C=CC(C(O)=O)=CC=1)CCCCCCCCCCC>CO>[CH2:15]([NH:27][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:13][CH3:14])=[O:12])=[CH:11][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCCCCCCCCCCCN
Agent: CCCCCCCCCCCCN(CCCCCCCCCCCC)C(=O)c1ccc(C(=O)O)cc1
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)c1ccc(C(=O)OC)cc1
Reaction time: 8 h
Yield: 91.2 %

Procedure:
19.4 g (0.1 mole) of dimethyl terephthalate and 18.5 g (0.1 mole) of dodecylamine are refluxed in 100 ml of methanol. After addition of 9 g (0.05 mole) of sodim methylate (30% strength in methanol) refluxing is continued for 8 hours, and the reaction batch is then worked up as described in Example 1, affording 31.7 g (91.2%) of 4-carbomethoxybenzoic acid dodecylamide having a 14% terephthalic acid bisdodecylamide content.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][N:14]=2)=[C:9]([CH3:22])[C:8]=1[CH3:23])C.[OH-].[Na+]>C(O)C>[O:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])=[C:8]([CH3:23])[C:9]=2[CH3:22])=[N:14]1
Reactant: CCOC(=O)COc1ccc(-c2noc3ccccc23)c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCC(=O)O)ccc(-c2noc3ccccc23)c1C
Yield: 83.2 %

Procedure:
A solution of 5 g (0.015 m) of ethyl-4-(1,2-benzisoxazol-3-yl)-2,3-dimethylphenoxyacetate of Example 1D, 25 ml 10% NaOH and 25 ml of ethanol is refluxed 3 hours. Ethanol is evaporated in vacuo and 5% HCl is added to the residue until the mixture is acidic. The mixture is extracted with ethyl acetate, dried (Na2SO4) and evaporated to give 3.8 g (83%) of 4-(1,2-benzisoxazol-3-yl)-2,3-dimethylphenoxyacetic acid, m.p. 146°-152° C. An analytical sample is recrystallized from ethanol/H2O, m.p. 147°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[N:9]2)=[CH:4][CH:3]=1.[C:28](Cl)([Cl:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:28]([Cl:30])=[O:29])[C:10]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
Using the procedure as described in example 1, cis-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The enantiomers of cis-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride were separated by chiral chromatography using a Modcol spring column (50 mm×70 cm) packed with R,R-Whelk-O1 spherical Kromasil silica gel (Regis Technologies, eluent: 30% methylene chloride in hexane, flowrate: 85 mL/min) to give the desired 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[C:4]([O:17][CH3:18])[CH:3]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(F)ccc1-c1ccc(N)cc1

Procedure:
A mixture of 10 grams of 4'-fluoro-2'-methoxy-4-nitrobiphenyl in 250 ml. of ethanol is reduced by hydrogen at atmospheric pressure and at room temperature using 5% palladium-on-charcoal (0.5 gram) catalyst. After the required uptake of hydrogen, the mixture is filtered and the catalyst washed with fresh ethanol. The ethanol solution is then concentrated in vacuo, and the residue recrystallized from aqueous ethanol to yield 4-(4'-fluoro-2'-methoxyphenyl)-aniline.
Reaction SMILES: C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:11][C@H:12]([C:18]([O:20][CH3:21])=[O:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>ClCCl.O>[N:11]1([C@@H:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:18]([O:20][CH3:21])=[O:19])[CH:24]=[CH:28][CH:27]=[CH:26]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C[C@@H](C(=O)OC)n1cccc1
Temperature: 80 °C
Yield: 69 %

Procedure:
Acetic acid (2.5 ml) and sodium acetate (32.5 mmol, 2.6 g) were added to a solution of dimethyl L-aspartate hydrochloride (29.5 mmol, 5.830 g) in dichloromethane (60 ml) and water (30 ml). Tetrahydro-2,5-dimethoxyfuran (29.5 mmol, 3.8 ml) was added to the resulting mixture heated at 80° C. After 90 min. the solution was cooled and the acqueous layer was washed with DCM. The combined organic layers were washed with brine and then dried, filtered and evaporated. The crude residue was purified by chromatograpgy on silica gel (eluent:Hex/AcOEt:7/3) to give the wanted compound as a colorless viscous oil (4.3 g, 68% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].C(#N)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([N:13]=[C:12]=[S:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Cc1ccccc1)N=C=S
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 2-phenylacetyl chloride (36.6 mg) was added potassium thiocyanate (53.8 mg) and acetonitrile (3 ml) under a nitrogen atmosphere, followed by stirring at 60° C. for 2 hrs. The reaction mixture was cooled down to room temperature, and then ethyl acetate (20 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml) were added thereto, followed by stirring for 30 min. After partitioning the solution, the separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to provide phenylacetyl isothiocyanate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:25])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)CC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CC(C)CC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-5-methyl-hexanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless oil, MS (ESI+): m/z=376.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[CH2:15]([O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=1)[CH3:16].[NH4+].[Cl-]>CN(C)C=O.O>[OH:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:22]1[CH:23]=[CH:24][C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:26])=[CH:20][N:21]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2c(O)[nH]c3ccc(C#N)cc23)nc1
Temperature: 110 °C
Yield: 34.4 %

Procedure:
To a solution of 5-cyanooxindole (360 mg, 2.27 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (106 mg, 4.41 mmol). The greenish reaction mixture was stirred for 50 min whereafter 6-chloronicotinic acid ethyl ester (350 mg, 1.89 mmol) dissolved in N,N-dimethylformamide (5 mL) was added. The reaction mixture was heated at 110° C. for 30 min and water (50 mL) and saturated NH4Cl(aq) (20 mL) was added, followed by extraction with ethyl acetate. The phases were separated and the organic phase contained the title compound as a precipitation that was filtered off. The solvent was concentrated in vacuo and additional product precipitated that was filtered to give 200 mg (34% yield) of the title compound in total: 1H NMR (DMSO-d6, 300 MHz) δ 14.50 (br s, 1 H), 11.00 (s, 1 H), 8.73 (s, 1 H), 7.95 (s, 2 H), 7.80 (s, 1 H), 7.48 (s, 1 H), 6.95 (d, J=7 Hz, 1 H), 4.50-4.15 (m, 2 H), 1.32 (t, J=7 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]#[C:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1.Cl.[CH:23]([NH2:25])=[NH:24]>C(#N)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:25]=[CH:23][N:24]=2)=[CH:4][CH:3]=1
Reactant: O=C(C#CCCCOC1CCCCO1)c1ccc(Cl)cc1
Reactant: N=CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Clc1ccc(-c2cc(CCCOC3CCCCO3)ncn2)cc1
Yield: 82.4 %

Procedure:
A mixture of 3.60 g (11.73 mmol) of 1-(4-chlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hex-2-yn-1-one, prepared in stage 5.2., of 9.45 g (117 mmol) of formamidine hydrochloride and of 25 g (234 mmol) of sodium carbonate in suspension in 108 ml of acetonitrile and 0.1 ml of water is stirred at 40° C. for 5 hours. The mixture is subsequently taken up in 600 ml of water and 400 ml of a saturated aqueous sodium carbonate solution. The organic phase is separated by settling, washed with 200 ml of water and 200 ml of a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 70/30 mixture of n-hexane and of ethyl acetate, to produce 3.22 g (9.67 mmol) of product in the form of a yellowish oil.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:14]([N:9]1[CH2:10][CH2:11][CH2:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: c1ccc(C2=NNCCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1cccnc1)N1CCCC(c2ccccc2)=N1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
3-Phenyl-1,4,5,6-tetrahydropyridazine (2.4 g) synthesized in Reference Example 1 was dissolved in chloroform (50 ml). Thereto were added nicotinic acid chloride hydrochloride (2.6 g) and triethylamine (3.2 g) with ice-cooling. Stirring was conducted for 30 minutes. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain 1.8 g of a title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH:20]([OH:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>N1CCCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C(C)O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C(C)=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from ethyl 2-(R/S)-(1-tert-butoxycarbonyl-piperidin-4-yl)-3-(R/S)-hydroxy-butanoate (from Step A) using a procedure analogous to that described in Piperdine 8, Step D. 1H-NMR (500 MHz) δ 1.11–1.22 (m, 2H), 1.27 (t, J=7.0, 3H), 1.41 (s, 9H), 1.57–1.68 (m, 2H), 2.23 (s, 3H), 2.23–2.30 (m, 1H), 2.72 (br s, 2H), 3.27 (d, J=9.5, 1H), 4.09 (br s, 2H), 4.21 (q, J=7.0, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:17]2[CH:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:67]([O:69]CC)=[CH2:68])CCC>O1CCOCC1.O.[Cu]I.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([C:67](=[O:69])[CH3:68])=[N:3][C:4]=2[C:17]2[CH:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(Nc2ncc(Cl)nc2-c2cc(SC)nc(C)n2)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncc(C(C)=O)nc2-c2cc(SC)nc(C)n2)cn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
A mixture of 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (30 mg, 0.080 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl (7.63 mg, 0.016 mmol, Aldrich), copper (I) iodide (17 mg, 0.016 mmol, Aldrich), palladium diacetate (1.8 mg, 8.00 μmol, Aldrich), cesium fluoride (15 mg, 0.160 mmol, Alfa Aesar) and tributyl(1-ethoxyvinyl)tin (0.041 mL, 0.120 mmol, Aldrich) in dioxane (2 mL) was stirred at 100° C. for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography, eluting with 10% EtOAc/CH2Cl2 to give 1-(5-(6-methoxypyridin-3-ylamino)-6-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)ethanone (19 mg, 0.050 mmol, 62.1% yield). 1H NMR (300 MHz, CDCl3) δ 2.66 (s, 3H) 2.71 (s, 3H) 2.80 (s, 3H) 3.96 (s, 3H) 6.82 (d, J=8.92 Hz, 1H) 8.14 (dd, J=8.92, 2.78 Hz, 1H) 8.25 (s, 1H) 8.45 (d, J=2.63 Hz, 1H) 8.91 (s, 1H) 12.79 (s, 1H). m/z (ESI, +ve ion) 383.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[O:12])[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)Cl.CN([CH:30]=[O:31])C>[Au]>[C:19]([N:16]1[CH2:15][CH2:14][CH:13]([C:11]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[NH:1][C:2]([CH:30]=[O:31])=[CH:3][C:4]2=3)=[O:12])[CH2:18][CH2:17]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]ccc32)CC1
Reactant: CN(C)C=O
Agent: [Au]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]c(C=O)cc32)CC1

Procedure:
1-[4-(5,6,7,8-Tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-piperidin-1-yl]-ethanone (1.1 g) was formylated with POCl3 (186 μL, 1.2 eq.) and DMF using standard Vilsmierer condition to give 240 mg of 4-(1-acetyl-piperidine-4-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde as a gold colored solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CC1CCCCC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Br)CCCCC1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 15 g (0.134 mol) of 2-methyl-1-cyclohexanone (7) and 23.84 g (0.134 mol) of N-bromosuccinimide in 150 mL of carbon tetrachloride was stirred and heated to reflux for 12 h under argon. The mixture was cooled to room temperature, filtered through Celite to remove succinimide and the filter cake was washed with 150 mL of ether. The filtrate was concentrated to give 25.6 g (100% yield) of 2-bromo-2-methyl-1-cyclohexanone. 1H NMR δ 3.21 (td, J=16 Hz, 8 Hz, 1 H, CH--CO), 2.36 (m, 2 H), 2.06 (m, 2 H), 1.82 (s, 3 H, Me), 1.77 (m, 2 H), 1.62 (m, 1 H).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
415 mg of methyl 4-mercaptobenzoate were dissolved in 3 ml of dry dimethylformamide, and 108 mg of a 55% w/w suspension of sodium hydride in mineral oil were then added to the resulting solution, whilst ice-cooling, after which the mixture was stirred at room temperature for 30 minutes. 567 mg of a solution of 1-[2-chloro-2-(2,4-dichlorophenyl)ethyl]imidazole dissolved in 3 ml of dry dimethylformamide were then added to the resulting solution, and the mixture was heated at 60° to 70° C. for 7 hours. At the end of this time, the resulting mixture was treated and purified similarly to the procedure described in Example 1, to give 317 mg of the title compound as colorless crystals, melting at 121°-124° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([O:45]C)=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[NH2:63][CH2:64][CH2:65][CH2:66][NH:67]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>CN(C=O)C.C(Cl)Cl>[NH2:63][CH2:64][CH2:65][CH2:66][NH:67][C:43]([C:40]1[S:39][C:35]2[N:36]=[CH:37][N:38]=[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[O:47][CH:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[C:34]=2[C:41]=1[CH3:42])=[O:45]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCN)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
HATU (0.073 g, 0.193 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.07 g, 0.175 mmol) and Hünig's base (30 μL, 0.175 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. tert-Butyl 3-aminopropylcarbamate (0.152 g, 0.875 mmol) was added, the coolant removed and the reaction stirred at ambient temperature overnight. The product was recrystallised from EtOAc to yield colourless solid. The solid was dissolved in DCM (2.0 mL), treated with trifluoroacetic acid (0.50 mL) and the reaction stirred at ambient temperature for 2 hours. The reaction mixture was applied to an SCX cartridge and eluted with MeOH (30 mL) followed by ammonia in MeOH to elute the product. Evaporation of appropriate fractions gave the product as a colourless solid (0.049 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)N3CCOCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, morpholine (10 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-morpholin-4-yl-3-oxo-propyl)-1H-pyrazol-3-yl]-propionamide (17 mg, 30%) as a white solid: ESI-LRMS m/e calcd for C25H33ClN4O5S [M+] 536.2, found 537.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.22 (m, 2H, CH2), 1.44-1.93 (m, 8H, 4×CH2), 2.12-2.30 (m, 1H, CH), 2.79 (t, J=6.6 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.31-3.41 (m, 2H, CH2), 3.53 (t, J=7.6 Hz, 1H, CH), 3.55-3.66 (m, 6H, 3×CH2), 4.35 (t, J=6.6 Hz, 2H, NCH2), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.35 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.75 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).