Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32]C)=[C:6]([C:8]2([CH2:11][C:12]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:13][NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH2:25][OH:26])=[N:20]4)[CH2:10][CH2:9]2)[CH:7]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]([C:8]2([CH2:11][C:12]([C:28]([F:29])([F:30])[F:31])([OH:27])[CH2:13][NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH2:25][OH:26])=[N:20]4)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(CNc2cccc3nc(CO)ccc23)C(F)(F)F)CC1
Agent: BrB(Br)Br
Product: OCc1ccc2c(NCC(O)(CC3(c4cc(F)ccc4O)CC3)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 38, 100 mg (0.22 mmol) of 3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-(hydroxymethyl)quinolin-5-ylamino)-2-(trifluoromethyl)propan-2-ol is reacted with 4.40 ml (4.40 mmol) of a 1 M boron tribromide solution. After working-up and purification on silica gel with hexane-ethyl acetate (0-100%) as well as with ethyl acetate-methanol (0-20%), 50 mg (50% of theory) of the product is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[O:12][CH3:13].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=2[O:12][CH3:13])[CH2:25][CH2:26]1)([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20]
Reactant: COc1c(F)cc([N+](=O)[O-])cc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1c(F)cc([N+](=O)[O-])cc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The compound was prepared by analogy to Example 7, starting from commercially available 1-bromo-3-fluoro-2-methoxy-5-nitrobenzene, which was reacted with tert.butyloxycarbonyl-piperazine by analogy to preparation example 3.1 top yield 1-(N-boc-piperazin-4-yl)-3-fluoro-2-methoxy-5-nitrobenzene. Reduction of the nitro group to the corresponding aniline by analogy to preparation example 3.2, subsequent coupling with commercially available 3-difluoromethoxybenzenesulfonylchloride by analogy to preparation example 1.4, and final deprotection of the tert.-butoxycarbonyl group under acidic conditions by analogy to example 1 yielded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH2:13]([O:20][N:21]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(=NOCc1ccccc1)C(=O)OCC
Temperature: 75 °C
Yield: 99 %

Procedure:
Di-ethylketomalonate (60 g) was added at 20° C. to a stirred suspension of O-benzylhydroxylamine (57.8 g) in IMS (500 ml) containing pyridine (30 ml). The reaction was heated at 75° C. for 4 hr. The reaction was cooled and solvents removed under reduced pressure. The residue was partitioned between EtOAc (500 ml) and water (300 ml) and the organic layer separated, washed with water (250 ml) and dried over MgSO4. Solvents were evaporated to give the title compound 95.3 g, as a colourless oil (99% th, ca 3% w/w residual EtOAc) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.I[CH:22]([CH3:24])[CH3:23]>>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH:22]([CH3:24])[CH3:23])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CC(C)I
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Product: CCOC(=O)c1c(OC(C)C)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 74 %

Procedure:
Following the procedure of Example 4, this material was prepared in 74% yield from product of Example 2 and 2-iodopropane as a liquid, nD25 1.4210.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cccn1Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccn1Cc1ccccc1N
Reaction time: 2 h

Procedure:
A mixture of 1117 g methyl 1-(2-nitrobenzyl)-pyrrole-2-carboxylate in 1117 mL of tetrahydrofuran, 458 g of potassium carbonate in 840 mL of water and 19 g of 5% palladium on carbon is stirred and heated to a temperature of 60°. The heat is removed and a solution of 1876 g of sodium hypophosphite hydrate in 3725 mL of water is added slowly over a period of one hour. The refluxing is controlled by the rate of the addition. When the addition is complete the mixture is refluxed, with stirring, for 2 hours. After stirring at room temperature for 5 hours, the reaction mixture is allowed to stand overnight. Methylene chloride (4 L) is added, the mixture is stirred for 3 hours and then filtered through filter-cel. The methylene chloride layer is separated and dried over magnesium sulfate. The magnesium sulfate is filtered off and the filtrate is concentrated to dryness to give a residue which is dried at 40°-50° and high vacuum to yield methyl 1-(2-aminobenzyl)-pyrrole-2-carboxylate, m.p. 95°-97°.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH2:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH:24][CH2:25][C:26](=[CH2:31])[C:27]([O:29][CH3:30])=[O:28]>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:31][CH:26]([CH2:25][OH:24])[C:27]([O:29][CH3:30])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(CO)C(=O)OC
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN)ccc3c2)CC1
Solvent: CO
Product: COC(=O)C(CO)CNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compounds (6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanamine (311 mg, 1.0 mmol, 1.0 eq.) and methyl 2-(hydroxymethyl)acrylate (116 mg, 1.0 mmol, 1.0 eq.) was dissolved in MeOH (5 mL). The mixture was stirred at r.t. for 2 h. Then the mixture was concentrated and purified by silica gel column chromatography using DCM/CH3OH (10/1) to give product (250 mg, 58%) as a slight yellow oil. ESI-MS (M+H)+: 428.3. HPLC: 90.18%. 1H NMR (400 MHz, CDCl3) δ 7.68 (t, 2H), 7.63 (s, 1H), 7.37 (dd, 1H), 7.14-7.11 (m, 2H), 4.27-4.25 (m, 1H), 4.01-3.96 (m, 2H), 3.91 (s, 2H), 3.71 (s, 3H), 3.18-2.93 (AB, 2H), 2.73-2.71 (m, 1H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.40 (m, 2H), 1.25-1.09 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12])=[O:5])C.[OH-].[Na+].Cl>CO.O>[CH3:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1CCCCN1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCCCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 g) was dissolved in a mixture of 100 ml methanol and 10 ml water. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was then neutralized with hydrochloric acid, evaporated to dryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step.
Reaction SMILES: [F-].C([N+:6](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2([CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:29][C:28]2([C:34]([O:36][CH3:37])=[O:35])[C:30](OC)=[O:31])[CH:23]=[CH:24][C:25]=1[Cl:26].[NH4+].[OH-]>C1COCC1.CO>[NH2:6][C:30]([C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:29][C:27]1([C:22]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=1)[CH2:38][CH2:39][OH:40])=[O:31]
Reactant: COC(=O)C1(C(=O)OC)CC1(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1(C(N)=O)CC1(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrabutylammonium fluoride (TBAF) (5.6 mL, 1.1M/TFH) was added dropwise to a stirred solution of dimethyl 2-(3,4-dichlorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate (P14, 2.38 g) in THF (27 mL), at 0° C. After 4 h the ice-bath was removed and the reaction mixture was stirred for 3 h at RT. The solvent was removed under reduced pressure, the residue was treated with ether and water, the organic phase washed with brine, dried over Na2SO4 and the solvent evaporated under vacuum to give the crude lactone intermediate (2.08 g). This product was dissolved in a mixture of THF (15 mL) and methanol (10 mL), at RT, aqueous NH4OH (28%, 16 mL) was added dropwise and the reaction mixture was stirred for 4 h. The mixture was concentrated under reduced pressure, the residue was taken up with DCM and water, the organic phase was washed with brine, dried over Na2SO4 and the solvent evaporated under vacuum. The crude product was purified by FC (eluting with DCM/methanol from 1/0 to 9/1) to give the title compound (0.89 g) as a white foam.
Reaction SMILES: [OH:1][C@@H:2]1[C@:10]2([CH3:11])[C@H:5]([CH2:6][C@@H:7]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)=[CH:37][CH:36]=3)[C@@H:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=3)[CH2:9]2)[CH2:4][CH2:3]1.[C:48](OC(=O)C)(=[O:50])[CH3:49].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:48]([O:1][C@@H:2]1[C@:10]2([CH3:11])[C@H:5]([CH2:6][C@@H:7]([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)=[CH:39][CH:40]=3)[C@@H:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:14][CH:13]=3)[CH2:9]2)[CH2:4][CH2:3]1)(=[O:50])[CH3:49]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCSCCCC(F)(F)C(F)(F)F)cc3)[C@H](c3ccc(OC4CCCCO4)cc3)C[C@@H]1CC[C@@H]2O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H]2C[C@@H](c3ccc(OC4CCCCO4)cc3)[C@@H](c3ccc(OCCCCCSCCCC(F)(F)C(F)(F)F)cc3)C[C@@]21C
Yield: 86 %

Procedure:
The solution of 1.43 g (2.51 mmol) of the compound that is presented in Example 2c is reacted analogously to Example 1, and after working-up, a mixture that consists of the title compound is isolated, and (1S,3S,4R,6S,9S)-9-hydroxy-4-[4-(tetrahydropyran-2-yloxy)phenyl]-1-methyl-3-[4-(10,10,11,11,11-pentafluoro-6-thia-undecyloxy)phenyl]-bicyclo[4.3.0]nonane, which is dissolved in 25 ml of anhydrous pyridine, is mixed with 3 ml of acetic anhydride and a spatula tip full of 4-dimethylaminopyridine, and it is stirred for 2 hours at 23° C. It is poured into saturated sodium bicarbonate solution, extracted several times with dichloromethane, the combined organic extracts are washed with saturated sodium chloride solution and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on about 400 ml of fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 1.57 g (2.16 mmol, 86%) of the title compound is isolated as a colorless foam.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31].[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:18][CH2:19]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenylmethyl 4-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)-1-piperazinecarboxylate from previous step was dissolved in DCM (60 mL) and cooled to 0° C. TFA (20 mL) was added. Reaction was stirred for 1 h. TLC showed no starting material remaining. Removed DCM and TFA on rotovap to give title compound of step B (presumed to be the bis-TFA salt) (14.0 g, 53% over 2 steps) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.03-7.40 (m, 5H), 5.02 (s, 2H), 2.93-4.16 (m, 7H), 2.11-2.82 (m, 7H), 1.06-1.88 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([CH:13]([C:16]([C:18]1[CH:32]=[CH:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C:20]=2[CH:19]=1)=[O:17])[CH2:14][CH3:15])(C(OCC)=O)[C:3]([O:5]CC)=[O:4].O1CCOCC1.[OH-].[Li+].Cl>O>[CH3:1][CH:2]([CH:13]([C:16]([C:18]1[CH:32]=[CH:31][C:21]2[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:20]=2[CH:19]=1)=[O:17])[CH2:14][CH3:15])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C(=O)OCC)C(CC)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C(=O)c1ccc2nc(-c3ccccc3)oc2c1)C(C)C(=O)O
Reaction time: 8 h

Procedure:
850 mg (1.94 mmol) diethyl 2-methyl-2-[1-(2-phenyl-benzoxazole-6-carbonyl)-propyl]-malonate are mixed with 10 ml dioxane, then a solution of 300 mg (12.53 mmol) lithium hydroxide in 10 ml of water is added and the mixture is left overnight at RT with stirring. The next day the reaction mixture is acidified with 4N hydrochloric acid and extracted with DCM. The org. phase is dried on magnesium sulphate and concentrated by rotary evaporation i. V., the residue is stirred with 5 ml DMSO and 500 mg lithium chloride for 1.5 h at 150° C., the reaction mixture is purified by RP-HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=1)=[O:9]
Reactant: CC(C)c1cccc(N)c1
Reactant: O=C(O)c1cncc(Br)c1
Product: CC(C)c1cccc(NC(=O)c2cncc(Br)c2)c1

Procedure:
In a manner similar to that described in Preparation 17, 5-bromonicotinic acid and 3-isopropylaniline were converted to the title compound
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)on1
Yield: 32.5 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (151 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H14) (190 mg, 0.63 mmol) according to the general procedure K. Obtained as an off-white solid (86 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[NH2:35][C@@H:36]([C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1)[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:35][C@@H:36]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=3)[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11]([F:14])([F:15])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)c1cccc(Cl)c1
Reactant: Nc1ncc(C2CCC(F)(F)CC2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCC(F)(F)CC3)cnc2N)cc1F)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To 4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (48 mg, 0.124 mmol) were added DMSO (1 mL), Hünig's base (0.108 mL, 0.619 mmol), (S)-tert-butyl (2-amino-2-(3-chlorophenyl)ethyl)carbamate (50.3 mg, 0.186 mmol) and then HATU (94 mg, 0.248 mmol). The reaction was stirred for 1 h at room temperature. To the reaction was added 0.5 mL of DMSO, filtered, purified by prep HPLC, and lyophilized to give 11 mg of the desired product used as is (12% yield). LCMS (m/z): 604.2 (MH+), 1.05 min.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([Cl:32])=[CH:34][CH:35]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Reactant: Clc1ccc(CBr)cc1
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc(Cl)cc2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 4-chlorobenzylbromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.27-7.34 (m, 2H) 7.19-7.26 (m, 2H) 6.95-7.03 (m, 1H) 6.68-6.80 (m, 1H) 5.69-5.89 (m, 2H) 5.16-5.48 (m, 1H) 4.15-4.27 (m, 2H) 3.64-3.71 (m, 3H) 2.63-2.77 (m, 2H) 2.05-2.16 (m, 2H) 1.93-2.04 (m, 3H) 1.01-1.19 (m, 9H); LCMS (m/z) ES+=549 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:8]([OH:11])[CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[CH:7]([C@H:8]1[CH2:9][O:11]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@@H](O)C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: c1ccc(C(c2ccccc2)[C@H]2CO2)cc1
Yield: 77.5 %

Procedure:
A solution of (2S)-3,3-diphenyl-propane-1,2-diol (3.5 g, 15.35 mmol), Ph3P (8.05 g, 30.7 mmol), and DEAD (5.4 g, 30.7 mmol) in benzene (50 ml) was refluxed for 24 h. Solvent was removed and the residue was diluted with ethyl ether (200 ml) to precipitate Ph2PO. The filtrate was concentrated and the residue was chromatographed on silica gel (hexane/ether=9:1) to give (2S)-2-benzhydryl-oxirane 23b 2.5 g (78%, ([α]D=(−)9.6, c=1, MeOH). The 1HNMR and 13CNMR were identical with (R)-isomer.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[NH:5][N:4]([CH2:14][CH2:15][CH2:16][OH:17])[N:3]=1.[NH2:18][NH2:19]>O1CCOCC1>[NH:18]([C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[NH:5][N:4]([CH2:14][CH2:15][CH2:16][OH:17])[N:3]=1)[NH2:19]
Reactant: NN
Reactant: OCCCN1N=C(Cl)C=C(N2CCOCC2)N1
Solvent: C1COCCO1
Product: NNC1=NN(CCCO)NC(N2CCOCC2)=C1
Yield: 87.6 %

Procedure:
3-(4-Chloro-6-morpholin-4-yl-triazin-2-yl)-propan-1-ol (19.4 mmol) is dissolved in dioxane (30 mL). To the reaction mixture is added anhydrous hydrazine (10 mL, 300 mmol). The reaction is then heated at reflux for five hours. The solvent is removed under reduced pressure, and the crude solid is dissolved in a mixture of dichloromethane (800 mL) and 10% potassium carbonate (40 mL). The organic layer is isolated, dried with sodium sulfate, and evaporated to yield crude 3-(4-hydrazino-6-morpholin-4-yl-triazin-2-yl)-propan-1-ol (4.3 g., 17 mmol).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]CC3C=CC=CC=3)[N:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br>C(O)(=O)C>[N:1]1([S:7]([C:10]2[NH:11][C:12](=[O:16])[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(c1cccc(OCc2ccccc2)n1)N1CCOCC1
Agent: Br
Solvent: CC(=O)O
Product: O=c1cccc(S(=O)(=O)N2CCOCC2)[nH]1
Temperature: 45 °C

Procedure:
To a solution of 2-(morpholine-4-sulphonyl)-6-benzyloxypyridine (0.6 g) in acetic acid (10 cm3) was added 48% hydrobromic acid (10 cm3). The mixture was heated to 45° C., then stirred until the reaction was complete. The mixture was cooled, quenched in water (50 cm3) and the product extracted into ethyl acetate (4×20 cm3). The combined organic layers were washed with water, dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure. The crude product was purified by silica chromatography eluting with hexane containing a gradually increased proportion of ethyl acetate (from 50%-60%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C=O)C.CN(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[CH3:27][S:28]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1)(=[O:30])=[O:29]
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (1.0 g) was added to a mixture of 10 ml of DMF and 0.85 ml of trimethylamine and the mixture was stirred at room temperature while slowly adding dropwise 5 ml of DMF solution containing 440 mg of methanesulfonyl chloride. After completion of addition, the reaction mixture was stirred at the same temperature as above for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 0.17 g of 6-(4-methanesulfonyl-1-piperazinyl)-3,4-dihydrocarbostyril, m.p. 241.5°-243° C., colorless granules.