Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@:4]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:42])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][C@H:29]([C:32]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)CC1.[CH:49]([N:52]([CH2:56][CH3:57])[CH:53]([CH3:55])[CH3:54])([CH3:51])C.C1C[O:61]CC1>>[C@H:51]12[CH2:54][C@H:53]([N:52]([CH2:56][CH2:57][NH:1][C@:4]34[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:5]3[C@@H:6]3[C@@:19]([CH3:22])([CH2:20][CH2:21]4)[C@@:18]4([CH3:23])[C@@H:9]([C@:10]5([CH3:42])[C@@H:15]([CH2:16][CH2:17]4)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]4[CH2:31][CH2:30][C@H:29]([C:32]([O:34][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[O:33])[CH2:28][CH:27]=4)=[CH:12][CH2:11]5)[CH2:8][CH2:7]3)[CH2:49]1)[CH2:55][O:61]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C1CCOC1
Reactant: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Reaction time: 70 h
Yield: 37.1 %

Procedure:
To a mixture of (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (50 mg, 0.077 mmol), 4° A mol. sieves (100 mg, 0.077 mmol) and N,N-diisopropylethylamine (0.094 mL, 0.538 mmol) in THF (2 mL) was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, HCl (52.2 mg, 0.385 mmol). The reaction mixture was stirred at 100° C. After 70 h, the reaction was cooled to rt, purified by prep-HPLC using prep-HPLC method 15 and dried under vacuum at 50° C. to give the title compound (27.9 mg, 0.029 mmol, 37.1% yield) as a white solid. LC/MS: m/e 749.6 (M+H)+, 4.65 min (method 9). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.90 (br. s., 3H), 7.44-7.29 (m, 5H), 5.35 (br. s., 1H), 5.20-5.09 (m, 3H), 4.78 (br. s., 1H), 4.67 (d, J=18.1 Hz, 2H), 4.27 (br. s., 1H), 4.18 (d, J=10.0 Hz, 1H), 3.81 (d, J=9.8 Hz, 1H), 3.71 (d, J=19.8 Hz, 2H), 3.53-3.26 (m, 4H), 2.87-2.67 (m, 1H), 2.64-2.51 (m, 1H), 2.34 (br. s., 2H), 2.15 (br. s., 5H), 2.07-1.89 (m, 5H), 1.88-1.72 (m, 3H), 1.69 (s, 3H), 1.63-1.21 (m, 13H), 1.07 (br. s., 3H), 1.01 (s, 3H), 0.96 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H).
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH2:19].CCCCCC>C(O)C>[C:1]([C:3](=[CH:12][NH:19][C:18]1[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:17]=1[CH3:16])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Cc1cccc(C)c1N
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1c(C)cccc1C
Yield: 73.2 %

Procedure:
A solution of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.05 mol) and 2,6-dimethylaniline (0.05 mol) in 75 ml ethanol is refluxed for several hours until the 2,6-dimethylaniline disappears as checked by thin layer chromatography. On cooling, (precipitate not formed) hexane (about 400 ml) is added and the mixture is filtered to yield 10.52 g of α-cyano-β-(2,6-dimethylanilino)-N-ethoxycarbonylacrylamide, m.p. 138°-140°, which is cyclized by heating in ortho-dichlorobenzene for about 4 hours to yield 5-cyano-1-(2,6-dimethylphenyl)uracil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CO>[F:14][C:2]([F:13])([F:1])[C:3]([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:8]1)=[O:4]
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCOC(CNC(=O)C(F)(F)F)C1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 1 (6.37 g) in methanol (250 ml) under nitrogen was added benzylchloroformate (4.7 ml) and triethylamine (6.3 ml). The mixture was stirred at 22° C. for 1 h before the volatiles were removed in vacuo. The residue was purified by Biotage flash chromatography on a 90 g silica cartridge eluting with 33% ethyl acetate in cyclohexane, to give the title compound as a white solid (4.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a solution of N-(3-aminophenyl)-3-nitrobenzenesulfonamide (1.00 g, 3.41 mmol) and 2,4,5-trichloropyrimidine (0.57 g, 3.1 mmol) in DMF (10 mL) was added potassium carbonate (0.52 g, 3.7 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The crude was purified by combi-flash column chromatography to give the desired product (1.2 g, 88%). LCMS for C16H11Cl2N5O4S (M+H)+: m/z=439.9, 441.9. 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 9.51 (s, 1H), 8.54 (t, J=2.1 Hz, 1H), 8.43 (ddd, J=8.2, 2.0, 1.0 Hz, 1H), 8.37 (s, 1H), 8.18 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.50 (t, J=2.0 Hz, 1H), 7.29 (ddd, J=8.2, 2.0, 1.2 Hz, 1H), 7.24 (m, 1H), 6.88 (ddd, J=8.0, 2.0, 1.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:19]=[CH:20][C:21]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:22]([CH:32]=1)[C:23]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:24]>O.COCCOC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:22]([CH:32]=2)[C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(-c2ccnc(F)c2)ccc1OCc1ccccc1

Procedure:
(2-Fluoro-4-pyridinyl)boronic acid (425 mg, 3.02 mmol), bis(triphenylphosphine)palladium(II) chloride (70.6 mg, 0.10 mmol) and sodium carbonate (1066 mg, 10.06 mmol) as a solution in 2 ml of water was added to a solution of 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 771 mg, 2.01 mmol) in 1,2-dimethoxyethane (20 ml). The mixture was heated to reflux for 2 hours. The mixture was diluted with ethyl acetate (50 ml) and water (50 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The organics were combined and evaporated. The residue was purified by chromatography on silica eluting with 0-10% methanol/dichloromethane 1% ammonia to yield the title compound as an off-white solid. 500 mg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>CN(C=O)C.C(OCC)C>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1cccc(F)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A solution of 1,3-difluoro-2-nitrobenzen (5.0 g, 31.4 mmol) in 50 mL of dry DMF was added K2CO3 (4.41 g, 32 mmol) and diethyl malonate (3.6 mL, 31.4 mmol). The reaction mixture was heated to 65° C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with 2 N HCl and extrated with diethyl ether. The ether layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified via column chromatograph to afford diethyl (3-fluoro-2-nitrophenyl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ 7.50˜7.55 (m, 1H), 7.38˜7.40 (rn, 1H), 7.23˜7.28 (m, 1H), 4.82 (s, 1H), 3.77 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].Cl[C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1.C(Cl)Cl.CO>CS(C)=O>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[N:9][C:8]([N:1]3[CH2:5][CH2:4][NH:3][C:2]3=[O:6])=[CH:13][CH:12]=2)=[CH:15][CH:16]=1)#[N:21]
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: O=C1NCCN1
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCNC3=O)nn2)cc1

Procedure:
Prepared from imidazolidin-2-one and 3-chloro-6-(4-cyano-phenyl)-pyridazine in dimethylsulphoxide Rf value: 0.30 (silica gel; methylene chloride/methanol=19:1)
Reaction SMILES: [C:1]([O-:5])([CH3:4])([CH3:3])C.[K+].FCP(C1C=CC=CC=1)(C1C=CC=CC=1)[C:10]1[CH:15]=CC=C[CH:11]=1.F[B-](F)(F)F.C(N(CC)[C:36](N[C@H]1C[C@H]2[C@@H](CC3C4C(=CC=CC2=4)NC=3C=O)N(CCC)C1)=[O:37])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH:1]([O:5][CH:10]([CH3:15])[CH3:11])([CH3:4])[CH3:3].[CH3:36][OH:37]
Reactant: FC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]21
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)OC(C)C
Product: CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.58 g (14 mmol) of potassium tert-butanolate was added in three portions in 2-3 minute intervals to a suspension of 5.35 g (14 mmol) of fluoromethyl-triphenyl- phosphine-tetrafluoroborate (Burton, D. J., Wiemers, D. M., J. Fluor. Chem. 27, 85 (1984)) in 120 ml of dry dioxane was instilled. It was allowed to stir for 30 minutes at room temperature and then a solution of 560 mg (1.4 mmol) of 1,1-diethyl-3-(2-formyl-6-n-propyl-8α-ergolinyl)-urea in 15 ml of dioxane was instilled. After 30 minutes (TLC), the batch was poured onto ice and a pH of 3 was padjusted with solid citric acid. It was extracted with ethyl acetate and the organic phase was washed with 2N citric acid. The combined aqueous phases were made alkaline with 25% NH3 solution with cooling and extracted with dichloromethane. These organic phases were washed with water, dried on MgSO4 and the solvent was removed in a vacuum. After chromatography (prepacked columns C; Merck company, diisopropyl ether/methanol 95:5) a total yield of 279 mg (48%) of fluorovinyl compound was obtained. By crystallization of the individual fractions, both isomers were obtained pure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[C:8]([OH:13])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:14][C@@:15]1(S([O-])(=O)=O)C=CC(C)=C(CC=O)[CH:16]1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-:36].[K+].[K+].O>CN(C)C=O>[CH3:14][C@H:15]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][OH:1])[C:16]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:36]
Reactant: O=C([O-])[O-]
Reactant: OCCc1c[nH]c2c(O)cccc12
Reactant: CC1=C(CC=O)C(N2CCOCC2)[C@](C)(S(=O)(=O)[O-])C=C1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Oc1cccc2c(CCO)c[nH]c12)C(=O)N1CCOCC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 68.3 %

Procedure:
To a solution of 3-(2-hydroxyethyl)-1H-indol-7-ol (1.05 g, 5.93 mmol) in N,N-dimethylformamide (20 mL) are added (1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl-4-methylbenzenesulfonate (2.79 g, 8.90 mmol) and potassium carbonate (1.3 g, 9.41 mmol), and the mixture is stirred at 60° C. for 5 hours. The reaction solution is cooled to room temperature, and the mixture is poured into water. The mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent is removed by distillation, and the obtained crude product is purified by silica gel column chromatography (chloroform→chloroform:methanol=50:1→30:1) to give the title compound (1.29 g, yield: 68%).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:17][C@@H:18]([C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:10](=O)[O:11]C(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(OC(=O)C)(=O)C>>[CH2:1]([O:8][N:9]([CH2:17][C@@H:18]([C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](CN(OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc(-c3ccccc3)cc2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)C[C@@H](CN(C=O)OCc1ccccc1)C(=O)N1CCN(c2ccc(-c3ccccc3)cc2)CC1
Yield: 52.2 %

Procedure:
The title product was obtained following the protocol of Example 1 (step c), but starting from tert-butyl (benzyloxy){(2S)-2-[(4-biphenyl-4-ylpiperazin-1-yl)carbonyl]-4-methyl pentyl}carbamate (219 mg, 0.46 mmol) and a preformed mixture of formic acid (875 μL; 23.2 mmol; 50 eq.) and acetic anhydride (220 μl; 2.32 mmol; 5.0 eq.) (mixture formed at 0° C. for 30 min). Purification by column chromatography (Silicagel, gradient from 33% EtOAc up to 50% EtOAc in c-Hex) gave the title product as a white solid (120 mg, 52%). HPLC, Rt: 4.60 min (purity: 99.7%). M+ (LC-MS (ESI)): 500.4.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]([F:17])([F:16])[F:15])[C:8]([C:18]([O:20]CC)=[O:19])=[CH:7]2.[OH-].[Na+]>CO.O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]([F:15])([F:16])[F:17])[C:8]([C:18]([OH:20])=[O:19])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)ccc2NC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2cc(OC(F)(F)F)ccc2NC1C(F)(F)F
Temperature: 25 °C
Yield: 88.9 %

Procedure:
The ethyl 1,2-dihydro-6-(trifluoromethoxy)-2(trifluoromethyl)-3-quinolinecarboxylate from Step 4 (880 mg, 2.5 mmol) and 2.5 N aqueous sodium hydroxide (2 mL) were mixed in methanol (15 mL) and water (15 mL). The solution was heated on a steam bath for 2 hours. The reaction was allowed to cool to room temperature and was extracted with diethyl ether (50 mL). The aqueous layer was acidified (pH=1) with 3 N HCl and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extracts were dried over MgSO4 and concentrated in vacuo leaving an oil. The oil was crystallized from cold dichloromethane-hexanes to afford the 1,2-dihydro-6-(trifluoromethoxy)-2(trifluoromethyl)-3-quinolinecarboxylic acid as yellow needles (0.727 g, 89%): mp 127.7-128.9° C. 1H NMR (CDCl3, 300 MHz) 7.80 (s, 1H), 7.05 (m, 2H), 6.62 (d, 1H, J=8.0 Hz), 5.13 (m, 1H), 4.62 (brs, 1H). ESHRMS m/z 326.0252 (M−H, Calc'd 326.0252). Anal. Calc'd for C12H7NO3F6: C, 44.05; H, 2.16; N, 4.28. Found: C, 43.89; H, 2.04; N, 4.24.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH:12]([C:14]([O:16]CC)=[O:15])[CH3:13].CO.[OH-].[Na+]>C1COCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH:12]([C:14]([OH:16])=[O:15])[CH3:13])=[C:4]([CH:9]=1)[C:3]([OH:19])=[O:2]
Reactant: CCOC(=O)C(C)Oc1ccc(Br)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1ccc(Br)cc1C(=O)O)C(=O)O
Temperature: 85 °C
Yield: 87.9 %

Procedure:
A solution of 5-bromo-2-(1-ethoxycarbonyl-ethoxy)-benzoic acid methyl ester (41.1 g, 124 mmol) in a mixture of THF (250 mL), MeOH (250 mL) and a 5 M aqueous NaOH solution (300 mL) is heated under reflux (85° C.) for 16 h. After cooling to room temperature the resulting suspension is concentrated by rotary evaporation. The residue is dissolved in water and acidified with an aqueous concentrated HCl solution under cooling with ice. The aqueous phase is extracted twice with EtOAc and the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a beige solid (31.5 g, 109 mmol, 88%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=13.04 (bs, 2H), 7.72 (d, J=2.7 Hz, 1H), 7.63 (dd, J=8.9, 2.7 Hz, 1H), 6.92 (d, J=8.9 Hz, 1H), 4.90 (q, J=6.6 Hz, 1H), 1.49 (d, J=6.6 Hz, 3H). MS (ES+): 289 (M(C10H979BrO5)+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([N+:16]([O-])=O)=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1CC2CC(C1)c1cc(N)ccc12
Yield: 368.3 %

Procedure:
10-Isopropyl-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (75 mg, 0.30 mmol) in 10 ml EtOH in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-isopropyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (239 mg, 98%). LC/MS (ESI+): 217 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[C:11]#[CH:12].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[CH2:10]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:20][CH:21]=1)[C:11]#[CH:12]
Reactant: C#CCOc1ccc(C=O)cc1
Reactant: NCCCCCC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C#CCOc1ccc(CNCCCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of 6-aminohexanoic acid (2.62 g, 20 mmol), 4-(prop-2-yn-1-yloxy)benzaldehyde (0.80 g, 5.0 mmol) and acetic acid (0.50 mL) in DCE (50 mL) was heated at 80° C. for 60 min. The reaction mixture was cooled to 0° C., and treated with NaBH(OAc)3 (2.11 g, 10 mmol). The reaction was stirred at room temperature for 12 hours and decomposed with water and then extracted with DCM. The organic layer was dried and concentrated under reduced pressure to give a residue, which was purified using a Biotage SP4 and gradient elution of 5-50% methanol in DCM. The yield of the target compound 644-(prop-2-yn-1-yloxy)benzyl)amino)hexanoic acid was 62% (0.856 g). 1H NMR (400 MHz, DMSO-d6): δ 7.19 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.71 (s, 2H), 3.56 (s, 2H), 3.49 (s, 1H), 2.39 (t, J=7.0 Hz, 2H), 2.00 (t, J=7.2 Hz, 2H), 1.41-1.19 (m, 6H); MS (ESI), 276.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:27])[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[CH:21]=2)([OH:19])[C:15]([F:18])([F:17])[F:16])=[C:9]([Cl:28])[CH:8]=1)C.[OH-].[Na+].O.Cl>C1COCC1>[Cl:28][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH:12]=[CH:11][C:10]=1[CH:13]([CH3:27])[C:14]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[CH:21]=1)([OH:19])[C:15]([F:16])([F:18])[F:17]
Reactant: CCOC(=O)CCc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(CCC(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-{3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl}-propionic acid ethyl ester (118 mg) was dissolved in THF (1 mL). To the solution was added 1M aq. NaOH (1 mL) to give a cloudy, light yellow mixture. The reaction was allowed to stir at RT for 2.5 hours; a clear solution was obtained at that time. Water was added and the pH was adjusted to pH=3 with dilute aqueous HCl. A colorless precipitate was formed. The mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried over Na2SO4 and evaporated. The title compound was obtained as a colorless solid (78 mg). MS (neg. ion, m/e)=420.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@@H:27]([S:38]([CH3:41])(=[O:40])=[O:39])[C@@H:26]([CH3:42])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:43].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@H:28]1[C@@H:27]([S:38]([CH3:41])(=[O:40])=[O:39])[C@@H:26]([CH3:42])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:43])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1S(C)(=O)=O
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylsulfonyl)cyclohexylcarbamate in DCM (0.02 M) was added TFA (30.0 equiv.). The solution was capped and left standing at rt for 1 hr. The volatiles were removed in vacuo; the residue was dissolved in DMSO and purified by reverse phase HPLC. The product fractions were lyophilized directly to yield N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 73% yield. LC/MS (m/z)=519.2 (MH+), Rt=0.58 min. 1H NMR (400 MHz, <dmso>) δ ppm 10.52 (s, 1H), 8.51-8.54 (m, 2H), 8.34 (dd, J=8.0, 4.0, 1H), 8.20 (dd, J=8.0, 8.0, 1H), 8.15 (dd, J=16.0, 4.0, 1H), 7.67-7.74 (m, 1H), 7.36 (dd, J=8.0, 8.0, 2H), 7.28 (d, J=4.0, 1H), 3.77-3.79 (m, 1H), 3.18 (s, 3H), 3.02-3.20 (m, 1H), 1.94-2.40 (m, 5H), 1.57-1.62 (m, 1H), 1.24 (d, J=8.0, 3H).