Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.ClCCl.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[C:3]([NH2:4])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccccc1-c1ccc(Cl)cc1
Yield: 78.9 %

Procedure:
The title compound was prepared from 2-iodoaniline (5.0 g, 22.83 mmol), 4-chlorophenylboronic acid (3.57 g, 22.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (0.373 g, 0.46 mmol), and a 5.0 M sodium hydroxide solution (9.1 mL, 45.65 mmol) according to the procedure and in the same manner as described in Example 60, step a. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:12) to yield 4′-chloro-1,1′-biphenyl-2-amine (3.67 g, 18.0 mmol, 79%) as an orange oil;
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:27])=O>>[CH2:1]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([Cl:27])=[O:21])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Product: CCCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Nonylpyrimidine-2-yl)benzoic acid (1.63 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-nonylpyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:21]([CH3:23])[CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=2)=[CH:4][N:3]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>CN(C)C=O>[CH3:26][N:27]([CH3:29])[CH:28]=[CH:17][C:16]([C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:11]([CH:21]([CH3:23])[CH3:22])=[C:10]([CH:15]=1)[O:9][C:5]1[C:6]([N:8]=[CH:26][N:27]([CH3:29])[CH3:28])=[N:7][C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])=[N:3][CH:4]=1)=[O:18]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(Oc2cnc(N=CN(C)C)nc2N=CN(C)C)cc1C(=O)C=CN(C)C
Temperature: 114 °C

Procedure:
To 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanone (100 mg, 0.32 mmol, from Example 16) dissolved in anhydrous N,N-dimethylformamide (0.6 mL) was added N,N-dimethylformamide dimethyl acetal (0.17 mL, 1.26 mmol) and the reaction was heated at 114° C. overnight. Concentration of the reaction mixture yielded N′-[5-[5-(3-Dimethylamino-acryloyl)-2-isopropyl-4-methoxy-phenoxy]-4-(dimethylamino-methyleneamino)-pyrimidin-2-yl]-N,N-dimethyl-formamidine.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([NH:11][CH:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14](C)[C:13]2=S)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][OH:33].C(N(CC)CC)C.C1COCC1>CO>[CH:1]1([CH2:7][CH2:8][C:9]([NH:11][CH:12]2[C:13](=[N:32][OH:33])[NH:14][C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:18]2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1C(=S)C(NC(=O)CCC2CCCCC2)N=C(c2ccccc2)c2ccccc21
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CCC1CCCCC1)NC1N=C(c2ccccc2)c2ccccc2NC1=NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide (740 mg, 1.83 mmol), hydroxylamine hydrochloride (140 mg, 2 mmol) and triethylamine (280 μL, 203 mg, 2 mmol) in methanol (15 mL)/THF (15 mL) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (98:2). The residue recrystallized from ethyl acetate. The first isomer to crystallize was recrystallized from ethyl acetate to give (E)-3-cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5-phenyl-1H-1,4-benzodiazepin-3-yl)propanamide as a solid, m.p. 196° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 59F (0.020 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The reaction was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The residue was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.006 g, 14% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.26 (m, 1 H), 1.52 (m, 2 H), 2.32 (m, 1 H), 2.70 (m, 4 H), 2.98 (m, 1 H), 3.09 (m, 2 H), 3.46 (s, 1 H), 3.50 (s, 3 H), 3.81 (s, 3 H), 4.15 (m, 3 H), 4.53 (dd, J=11.40, 3.68 Hz, 2 H), 4.70 (d, J=15.44 Hz, 1 H), 6.63 (d, J=9.56 Hz, 1 H), 6.93 (m, 3 H), 7.07 (d, J=6.62 Hz, 2 H), 7.24 (m, 6 H), 7.59 (m, 3 H), 7.88 (m, 4 H), 8.63 (d, J=3.31 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](C=O)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:27]#[N:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(/[CH:43]=[C:44]2/[C:45]([NH:47][C:48]([S:50]/2)=[NH:49])=[O:46])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](/[CH:43]=[C:44]4/[C:45](=[O:46])[N:47]=[C:48]([NH2:49])[S:50]/4)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:27]#[N:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(C=O)cc23)CC1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(/C=C4\SC(N)=NC4=O)cc23)CC1

Procedure:
Similar procedure as described in example 28c was used, starting from 4-(3-cyano-6-formyl-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester, pseudothiohydantoin, sodium acetate and acetic acid to give 4-{6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-3-cyano-quinolin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester. LC-MS m/e 480 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][NH:25][CH:22]([CH3:24])[CH3:23])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(CCl)N1CCCc2cc(Br)ccc21
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)NCCN1CCCc2cc(Br)ccc21
Temperature: 75 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (compound 1, 0.400 g, 1.093 mmol) in acetonitrile (19 mL) and water (1 mL) in a 50 mL pressure vessel fitted with a stir-bar was treated with potassium carbonate (0.755 g, 5.46 mmol) and isopropylamine (0.646 g, 10.93 mmol) and the sealed vessel stirred at 75° C. overnight. After 24 hours the mixture was partitioned between CH2Cl2 (50 mL) and water (10 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer (pH=12); extracted further with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to a yellow oil. Purification on silica gel eluting with 5% 2M NH3 in methanol/95% dichloromethane yielded a pale yellow oil, 2 (270 mg, 83%). 1H-NMR (DMSO-d6) δ 7.06 (dd, 1H, J=8.8, 2.5 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.52 (d, 1H, J=8.8), 3.31-3.20 (m, 4H), 2.78-2.67 (m, 1H), 2.67-2.59 (m, 4H), 1.84-1.76 (m, 2H), 0.96 (d, 6H, J=6.2 Hz). MS (ESI+): 297/299 (MH+, 10), 238/240 (20), 159 (100).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][C:26]([OH:28])=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:38]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH:47][S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])=[O:28])[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)COCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(COCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer was introduced (2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-ethoxy)-acetic acid (compound 235 prepared at example 1.4.2; 2.7 g, 4.54 mmoles) dissolved in CH2Cl2 (25 ml). Benzenesulphonamide (1.07 g, 6.8 mmoles), DMAP (10 mg, 0.45 mmoles) and EDCI (0.96 g, 5 mmoles) were added to the solution and the reaction mixture was stirred at room temperature for 48 hours. The organic solution was washed with HCl 0.1N and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/NH3: 95/5/0.2 v/v/v) to afford the monohydrate of N-[(2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-ethoxy)-acetyl]-benzenesulfonamide (compound 306; 1.5 g, 50%) as a beige solid.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:15]=[N:14][CH:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12.[CH3:19][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[C:31]3[C:35]([CH:36]=[C:37](B4OC(C)(C)CC(C)(C)O4)[CH:38]=2)=[N:34][N:33](C2CCCCO2)[CH:32]=3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:21].O>O1CCOCC1>[CH3:21][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([C:10]3[CH:15]=[N:14][CH:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:19]
Reactant: Brc1cncc2[nH]ccc12
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cncc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A microwave vial was charged with Solvias catalyst (7 mg), tripotassium phosphate (84 mg) and 4-bromo-1H-pyrrolo[2,3-c]pyridine (from prep such as in US2005/0090529, 29 mg). 1-(1-methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (65 mg) in 1,4-dioxane (0.5 ml) was added, followed by water (0.1 ml) and the reaction was heated under microwave irradiation for a total of 30 min at 120° C. The reaction was washed through a silica cartridge preconditioned with methanol, with methanol. The solvent was removed under a stream of nitrogen, then washed with DCM and water. The resultant solution was evaporated under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). Appropriate fractions were dried under a stream of nitrogen. The residue was dissolved in methanol, 2M HCl (aq) (3 drops) was added and the solution was left to stand for 60 min. The solvent was removed under a stream of nitrogen and the residue was dissolved in methanol, washed with methanol through an aminopropyl cartridge preconditioned with methanol and dried under a stream of nitrogen to give title compound, 5 mg.
Reaction SMILES: C(O)CO.[OH-].[K+].NC1[S:9][C:10]2[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:11]=2[N:12]=1.C1(C)C=CC=CC=1>O.C(O)(=O)C>[NH2:12][C:11]1[CH:13]=[CH:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:10]=1[SH:9]
Reactant: Nc1nc2ccc(Oc3ccccc3)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: OCCO
Product: Nc1ccc(Oc2ccccc2)cc1S
Reaction time: 2 h
Yield: 101.3 %

Procedure:
14 ml of ethylene glycol were added to a solution of 42.3 g of caustic potash dissolved in 49 ml of water, and after the air in the reaction vessel had been replaced by nitrogen, 10.57 g of 2-amino-6-phenoxybenzothiazole were added. While blowing nitrogen through the reaction mixture, the reaction was carried out on an oil bath at 135° C. for 2 hours. At the end of this time, the reaction mixture was cooled, 105 ml of toluene were added, and the mixture was ,neutralized by the addition of 42.3 mI of acetic acid. The toluene layer was separated, and the aqueous layer was once again extracted with toluene. The combined toluene extracts were washed with an aqueous solution of sodium bicarbonate, with water, and with an aqueous solution of sodium chloride, in that order, after which they were dried over anhydrous magnesium sulfate. The resulting solution was then concentrated by evaporation under reduced pressure, and the residue Was dried, to give 9.6 g of the title compound as a solid. This compound was used for the next reaction without further purification.
Reaction SMILES: Cl[Si](C)(C)C.[NH2:6][C:7]1[C:8]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH:35]([CH2:38][OH:39])[CH2:36][OH:37])[C:18](=[O:34])[O:19][CH2:20][CH:21]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>N1C=CC=CC=1>[C:40]([NH:6][C:7]1[C:8]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH:35]([CH2:36][OH:37])[CH2:38][OH:39])[C:18](=[O:34])[O:19][CH2:20][CH:21]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:28]4[C:33]3=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:9]=2[N:10]=[CH:11][N:12]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c(CN(C(=O)OCC3c4ccccc4-c4ccccc43)C(CO)CO)c[nH]c12
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c(CN(C(=O)OCC3c4ccccc4-c4ccccc43)C(CO)CO)c[nH]c12)c1ccccc1
Reaction time: 8 h

Procedure:
Chlorotrimethylsilane (810 μL, 6.3 mmol) was added to a solution of 7 (194 mg, 0.42 mmol) in dry pyridine. After 30 min benzoyl chloride (172 μL, 1.48 mmol) was added and the solution was stirred overnight. The reaction was quenched by the addition of water and concentrated to dryness. The residue was taken up in dichloromethane (10 mL), washed with water, concentrated, stirred for 5 min in methanolic ammonia (7N) and concentrated again. Chromatography of the residue on silica gel eluted with 4% methanol in dichloromethane gave the title compound as a colourless, amorphous solid (160 mg, 2.84 mmol, 67%). ESI-MS+, found 564.2245, calc. for C32H30N5O5 [M+H]+ 564.2245.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15].CCOCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1COCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:22])=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)c1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cc1cnc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a sealed tube were added 5-bromo-2-chloro-3-(trifluoromethyl)pyridine 189-1 (170 mg, 0.65 mmol), 0.5 M (2-tert-butoxy-2-oxoethyl) zinc(II) chloride 86-5 in ether (1.57 mL, 0.78 mmol), Pd(dba)2 (19 mg, 0.03 mmol), Q-phos (46 mg, 0.06 mmol) and THF (3 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 100° C. for 1 hour. After cooling to room temperature, all the solvents were evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give tert-butyl 2-(6-chloro-5-(trifluoromethyl)pyridin-3-yl)acetate 189-3. MS m/z 296.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([NH2:29])[CH:25]=2)[CH:20]=1)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([NH:29][C:12]([C:10]3[O:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)=[O:14])[CH:25]=2)[CH:20]=1)=[O:18]
Reactant: COC(=O)c1ccc2cc(N)ccc2c1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: COC(=O)c1ccc2cc(NC(=O)c3ccc(-c4ccccc4)o3)ccc2c1

Procedure:
5-Phenyl-furan-2-carboxylic acid (56) (50 mg, 0.26 mmol) was coupled to 6-amino-naphthalene-2-carboxylic acid methyl ester (53 mg, 0.26 mmol) using Method C to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[NH4+].[NH4+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]3[N:32]=[C:31]([CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4([C:45]([OH:47])=O)[CH2:44][CH2:43][CH2:42]4)[C:30]([C:48]([F:51])([F:50])[F:49])=[CH:29][N:28]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C1C=CC2N(O)N=[N:58]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl>CCN(CC)CC.CN(C=O)C>[C:45]([C:41]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH2:34][CH2:33][C:31]2[C:30]([C:48]([F:49])([F:51])[F:50])=[CH:29][N:28]=[C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([CH:17]4[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:13])[CH2:15][CH2:16]4)=[CH:21][CH:22]=3)[N:32]=2)[CH2:42][CH2:43][CH2:44]1)(=[O:47])[NH2:58]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(=O)O)CCC4)n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CCC4)n3)cc2)CC1

Procedure:
Ammonium carbonate (92 mg 0.96 mmol) was added to a suspension of 1-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclobutanecarboxylic acid A56 (30 mg, 0.048 mmol), HOBt (32 mg, 0.24 mmol) and EDCl.HCl (46 mg, 0.24 mmol) in Et3N (0.2 mL) and DMF (10 mL) and the resulting mixture was stirred at 40° C. overnight. The volatiles were removed in vacuo and the resulting residue was dissolved in DCM (50 mL), washed with water (50 mL), separated and adsorbed onto silica gel. Purification by column chromatography (Biotage Isolera, 12 g SiO2 cartridge, 0-100% EtOAc in peteroleum benzine 40-60° C.) gave the title compound A57 as a yellow solid (6 mg, 20%). LCMS-A: rt 8.604 min; m/z 624.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH:11]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[CH:22]=2)[CH:20]=1)[CH:12]1[CH2:14][CH2:13]1)[S:6]([CH2:9][CH3:10])(=[O:8])=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:29][C:23]1[CH:22]=[C:21]([C:19]2[CH:20]=[C:15]([CH:11]([N:5]([CH2:4][CH2:3][OH:2])[S:6]([CH2:9][CH3:10])(=[O:7])=[O:8])[CH:12]3[CH2:14][CH2:13]3)[CH:16]=[N:17][CH:18]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CCS(=O)(=O)N(CC(=O)OC)C(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(CCO)C(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 40 mL scintillation vial was charged with ({[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-ethanesulfonyl-amino)-acetic acid methyl ester (130 mg, 0.290 mmol) in THF (5 mL). The reaction mixture was cooled to −78° C. and lithium aluminium hydride (1M in THF, 0.726 mL, 0.726 mmol) was added. The reaction was left to stir at −78° C. for 1 h. The reaction was quenched with water (1 mL), warmed to room temperature and concentrated in vacuo. The crude was dissolved in DMSO (4 mL) and purified using Xbridge C18 eluting with a 10 to 100% AGN-water to afford ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-(2-hydroxy-ethyl)-amide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH2:8][C:9]([NH:11][OH:12])=[O:10])=[CH:4][CH:3]=1.[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([CH2:8][C:9]([NH:11][OH:12])=[O:10])=[O:15])=[CH:13][CH:14]=1
Reactant: O=C(CSCc1ccc(Cl)cc1)NO
Reactant: OO
Solvent: CC(=O)O
Product: O=C(CS(=O)Cc1ccc(Cl)cc1)NO
Temperature: 50 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
31.7 g (0.091 mol) of p-chlorobenzylmercaptoacetohydroxamic acid are mixed with 100 ml of anhydrous acetic acid and 9.1 ml of hydrogen peroxide of 110 volumes strength are added. The temperature, which is 20° C. at the start, rises and solution of the precipitate formed is also observed. The temperature is maintained at 50° C. and after several minutes it is found that the sulphinyl derivative sets solid. 50 ml of acetic acid are now added and the temperature is kept at 50° C. for 1 hour whilst stirring vigorously. The mixture is cooled and the p-chlorobenzylsulphinyl-acetohydroxamic acid is filtered off. This acid is recrystallised from acetic acid and filtered off, the precipitate is washed with water and with ethanol, and dried, and 31.9 g of CRL 40,411 are collected. Yield 85%; instantaneous melting point 210° C. (with decomposition).