Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:18])=[C:9]([CH:17]=1)[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[N:19]([O-])=O.[Na+]>Cl>[Cl:18][C:8]1[CH:7]=[CH:6][C:5]([NH:4][NH2:19])=[CH:17][C:9]=1[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=N[O-]
Reactant: CCOC(=O)C=Cc1cc(N)ccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: CCOC(=O)C=Cc1cc(NN)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
First. 60 g of tin (11) chloride was dissolved in 60 ml of concentrated hydrochloric acid, and the mixture was cooled to −30° C., to which a diazonium solution prepared from 19 g of ethyl 5-amino-2-chlorocinnamate and 6.3 g of sodium nitrite was added dropwise at 0° C. or lower. The reaction mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration. These crystals were added to ice-water, neutralized with 2N aqueous sodium hydroxide, and extracted with chloroform. The chloroform layer was dried and concentrated, which afforded 7.0 g of ethyl 2-chloro-5-hydrazinocinnamate.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]([C:15]([OH:17])=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:1]([N:8]1[CH:14]([C:15]([NH:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:17])[CH2:13][C:10]2([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)C1CC2(CC2)CN1Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)C1CC2(CC2)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-benzyl-5-azaspiro[2.4]heptane-6-carboxylic acid (62.0 mg, 0.000268 mol) dissolved in DMF (1.0 mL, 0.013 mol) was added cyclohexanamine (30.7 μL, 0.000268 mol), benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (130 mg, 0.00029 mol) and TEA (0.25 mL, 0.0018 mol). After stirring at RT for 1 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The extracts were washed with brine, then dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by prep.-LC/MS to afford the desired product as a white solid. LC/MS: m/e 313.2 (M+1H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.CN(C)C=O.[C:19]([C:23]1[C:24]([CH:30]=[CH2:31])=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:23]1[C:24]([CH:30]=[CH2:31])=[C:25]([NH:29][C:7]([C:5]2[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH:26]=[CH:27][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Reactant: C=Cc1c(N)cccc1C(C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1c(NC(=O)c2cn(C)nc2C(F)(F)F)cccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
197 mg (1,01 mmol) 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and 135 mg (1,07 mmol) oxalylic acid chloride are dissolved in 8 ml methylenechloride. The solution is stirred for 3 hours at room temperature in the presence of a catalytic amount of dimethylformamide (DMF). After this the solution is slowly added to a solution consisting of 180 mg (1,01 mmol) 3-tert-butyl-2-vinyl-phenylamine, 155 mg (1,52 mmol) triethylamine and 7 ml methylenechloride. The resulting reaction mixture is then stirred at room temperature for 16 hours. After removal of the solvent in a water jet vacuum, the residue is purified by flash chromatography over silicagel (eluent: hexane/ethylacetate 2:1). This gives 0,27 g 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-tert-butyl-2-vinylphenyl)amide in the form of a colourless solid (m.p. 118-119° C.; 76% of theory).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:15][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)[CH:9]=[C:10]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]=2[CH:4]([CH2:22][C:23]([O:25]CC)=[O:24])[O:3]1.[OH-].[Li+].Cl>CCO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:15][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)[CH:9]=[C:10]([O:11][CH:12]([CH3:13])[CH3:14])[C:5]=2[CH:4]([CH2:22][C:23]([OH:25])=[O:24])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OC(C)C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of ethyl 2-(1-hydroxy-4-isopropoxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (96 mg, 0.26 mmol) in EtOH (4 mL) was added an aqueous solution of lithium hydroxide (21.8 mg, 0.52 mmol) in water (1 mL). The reaction mixture stirred at room temperature overnight and acidified with 1 N HCl to pH=4. The resulting mixture was extracted with EtOAc (15 mL) and combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (41 mg. Yield: 45%). 1H NMR (400 MHz, DMSO-d6) δ 12.41-12.12 (m, 1H), 9.25 (s, 1H), 8.55 (d, J=0.8 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.23 (t, J=1.2 Hz, 1H), 6.99 (s, 1H), 5.42 (m, 1H), 4.67 (m, 1H), 3.18 (m, 1H), 2.19 (m, 1H), 1.27 (m, 6H). MS (ESI) m/z=345 [M+H]+.
Reaction SMILES: FC1C=CC=C(F)C=1CN.C1([N+]#[C-])CCCCC1.[CH:19]1([NH:25][C:26]([CH:28]2[C:34]3[CH:35]=[C:36]([Br:39])[CH:37]=[CH:38][C:33]=3[O:32][CH:31]([CH:40](C)[CH3:41])[C:30](=[O:43])[N:29]2[CH2:44][C:45]2[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=2[F:52])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CO>[CH:19]1([NH:25][C:26]([CH:28]2[C:34]3[CH:35]=[C:36]([Br:39])[CH:37]=[CH:38][C:33]=3[O:32][CH:31]([CH2:40][CH3:41])[C:30](=[O:43])[N:29]2[CH2:44][C:45]2[C:46]([F:52])=[CH:47][CH:48]=[CH:49][C:50]=2[F:51])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)C1Oc2ccc(Br)cc2C(C(=O)NC2CCCCC2)N(Cc2c(F)cccc2F)C1=O
Agent: NCc1c(F)cccc1F
Agent: [C-]#[N+]C1CCCCC1
Solvent: CO
Product: CCC1Oc2ccc(Br)cc2C(C(=O)NC2CCCCC2)N(Cc2c(F)cccc2F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
2,6-Difluorobenzylamine (51 mg, 0.35 mmol) and cyclohexylisocyanide (39 mg, 0.36 mmol) were added to a solution of 2-(4-bromo-2-formyl-phenoxy)-butyric acid (prepared in analogy to 2-(4-bromo-2-formyl-phenoxy)-3-methyl-butyric acid [example 1] from ethyl 2-bromo-3-methyl butyrat, 100 mg, 0.35 mmol) in methanol (0.5 ml). After stirring for 2 h at r.t., the title compound was isolated (diastereomer 1 [inhibitorially active], retention time 2.09 min: 17.9 mg; diastereomer 2 [inhibitorially active], retention time 2.28 min, 7.3 mg, combined yield 14%, MS: m/e=521.1 [M+H+]) from the reaction mixture by reversed-phase, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5–95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:19]1([C:2]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]2)[CH2:21][CH2:20]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2Br)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C2CC2)CC1
Yield: 96.8 %

Procedure:
A mixture of 1-(2-bromo-4-nitrobenzyl)-4-methylpiperazine (0.94 g, 3.0 mmol), 0.77 g (9.0 mmol) of cyclopropylboronic acid, 0.067 g (0.30 mmol) of Pd(OAc)2, 2.87 g (13.5 mmol) of K3PO4, and 0.168 g (0.60 mmol) of tricyclohexylphosphine in 18 mL of toluene/water (5:1) was heated at reflux under an atmosphere of N2 for 19 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with 5% MeOH/DCM; MeOH was pre-saturated with ammonia gas) to provide 0.80 g of product.
Reaction SMILES: O[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1.S(Cl)([Cl:16])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1ccc(CO)nc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CCl)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A solution of 10.5 g of ethyl 6-hydroxymethylnicotinate in chloroform (100 ml) was cooled to 0° C., and 8.28 g of thionyl chloride was added dropwise to the solution. The mixture was stirred at 0° C. for 2 hours, an aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexene/ethyl acetate=6/1) to obtain 10.52 g of ethyl 6-chloromethylnicotinate.
Reaction SMILES: [C:1]([C:4]1[C:9](/[CH:10]=[CH:11]/[C:12]([O:14]C(C)(C)C)=[O:13])=[C:8]([F:19])[C:7]([Cl:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:4]1[C:9](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[C:8]([F:19])[C:7]([Cl:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)c(F)c1/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)c(F)c1/C=C/C(=O)O
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A solution of Intermediate 12D (25 g, 84 mmol) in DCM (330 mL) and TFA (330 mL) was stirred at rt. After 1.5 h, the solvent was concentrated to give Intermediate 12 (19.5 g, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.69 (bs, 1H), 7.80-7.76 (m, 2H), 7.62 (d, J=12.1 Hz, 1H), 6.30 (dd, J=2.4, 2.0 Hz, 1H), 2.6 (s, 3H) ppm. MS (ESI) m/z: 241 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2cncc(Br)c2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 4-(trifluoromethyl)-phenylboronic acid.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C@:13]([CH3:49])([CH2:47][OH:48])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]1[S:42][C:41]([CH3:43])=[N:40][CH:39]=1)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([CH2:7][S:8]([O:48][CH2:47][C@:13]([OH:12])([CH3:49])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]2[S:42][C:41]([CH3:43])=[N:40][CH:39]=2)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)Cc1ccccc1

Procedure:
Prepared according to procedures described above, by reacting phenylmethanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C32H40N4O10S2 m/z: 705 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][C@@H:19]1[CH2:24][O:23][C@@H](C2C=CC=CC=2)[O:21][CH2:20]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Agent: Cl
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1cc(F)ccc1F

Procedure:
In the same manner as that described in Example 7(vi) above, 5.0 g of crude (2R,3R)-2-(2,5-difluorophenyl)-3-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 8(v) above] were treated with hydrochloric acid and the product obtained was purified by chromatography on a silica gel (50 g) column using a 3:100 mixture of methanol and ethyl acetate as the eluant to afford 3.17 g [overall yield from Step 8(v) 83%] of the of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][O:14][C:15]([CH3:24])([C:20]([F:23])([F:22])[F:21])[C:16]([O:18]C)=[O:17])[CH:7]=[CH:6]2.[OH-].[K+].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][O:14][C:15]([CH3:24])([C:20]([F:21])([F:22])[F:23])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6]2
Reactant: COC(=O)C(C)(OCc1ccc2cc(OC)ccc2c1)C(F)(F)F
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2cc(COC(C)(C(=O)O)C(F)(F)F)ccc2c1

Procedure:
The process of Example 17 is repeated using (±)-methyl 2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate, obtained as an oil in Example 43, as starting material except that the potassium hydroxide is replaced by 4.4 N aqueous sodium hydroxide and the reaction is carried out for 21/2 hours to give (±)-2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid, m.p. 117°-119° C. (from light petroleum b.p. 60°-80° C.).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([C:7]([OH:9])=O)[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]>>[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:7]([C:5]3[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[N:6]=3)=[O:9])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: Cn1nc(C(=O)O)c(C(F)(F)F)n1
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3nn(C)nc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-methyl-5-trifluoromethyl-2H-[1,2,3]triazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (15% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.05, 7.83, 7.00, 4.28, 3.97-3.67, 3.51-3.45, 1.75-1.68, 1.49, 0.92. MS (ES+) m/z 455.2 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>C(O)(=O)C.O1CCOCC1.ClCCl>[CH2:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([N:1]1[C:24]2[CH:4]=[CH:3][CH:2]=[CH:18][C:28]=2[C:27]2[C:26]1=[CH:27][CH:28]=[CH:24][CH:26]=2)[C:18]([O:20][CH3:21])=[O:19])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21
Temperature: 110 °C
Reaction time: 5.5 h
Yield: 49.5 %

Procedure:
A vigorously stiffed solution of L-Lys(Z)—OMe (3.31 g, 10 mmol) in acetic acid (20 mL) and dioxane (40 mL) was heated to 75° C., at this temperature 2,5-dimethoxytetrahydrofuran (DMTHF, ee 97%) (3.97 g, 3.90 mL, 30 mmol) was added dropwise to the reaction mixture. After complete addition of DMTHF, the reaction mixture was refluxed at 110° C. for 3 h followed by 5-6 h stiffing at room temperature. The volatiles were removed under reduced pressure to afford a dark brown residue, which was dissolved in dichloromethane (100 mL) and washed with 10% NaHCO3 solution (15 mL), brine (15 mL) and water (15 mL). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (230-400 mesh) using hexane:ethyl acetate (7:3) as eluent to afford (S)-methyl 6-benzyloxycarbonylamino-2-carbazol-9-yl-hexanoate 3 (1.10 g, 25%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[CH3:17][C:18]1[N:19]([C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[CH:20]=[CH:21][N:22]=1
Reactant: Cc1ncc[nH]1
Reactant: C[C@@H](Nc1cncc(Cl)n1)c1ccccc1
Product: Cc1nccn1-c1cncc(N[C@H](C)c2ccccc2)n1
Yield: 96.2 %

Procedure:
In a procedure analogous to example 2, reaction of 6-chloro-N-[(1R)-1-phenylethyl]pyrazin-2-amine (150 mg, 0.64 mmol) and 2-methylimidazole (58 mg, 0.71 mmol) furnished the product (172 mg, 40%).
Reaction SMILES: [O:1]=[C:2]([NH:17][CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[C:19]([O:21]C)=[O:20])[CH2:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO>[OH-].[Na+].O1CCCC1>[O:1]=[C:2]([NH:17][CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[C:19]([OH:21])=[O:20])[CH2:3][CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(OC)c1)NC(=O)CC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(NC(=O)CC(c2ccccc2)c2ccccc2)C(=O)O)cc1OC
Temperature: 25 °C

Procedure:
α-[(1-Oxo-3,3-diphenylpropyl)amino]-3,4-dimethoxybenzenepropionic acid, methyl ester (6.0 g) in 1N sodium hydroxide, tetrahydrofuran, and methanol was allowed to stir at room temperature for several hours. The mixture was evaporated to 50% volume and poured into ethyl acetate and water. The layers were separated and the aqueous layer was brought to pH 2 using concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (2×50 ml) and the combined extracts were washed with water, brine, dried over magnesium sulfate, filtered and evaporated at reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:18][CH2:19][O:20][CH3:21].[H-].[Na+].[Br-]>CN(C=O)C.CC(=O)OCC>[CH3:21][O:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:7]=1
Reactant: COCCBr
Reactant: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[3-Hydroxy-5-(pentafluorosulfanyl)phenyl]ethanone (O3.050; 592 mg) and 1-bromo-2-methoxyethane (255 μl) were dissolved in DMF (14.8 ml), and sodium hydride (65 mg) was added. After stirring at RT for 2 h, further bromide (80 μl) was added and the mixture was heated to 50° C. for 12 h. Then the DMF was drawn off and the residue was taken up in EA, washed with water, dried, filtered and concentrated. 578 mg of the title compound were obtained. LC-MS rt: 1.58 min [M+H]+: 321.1 (met. a)
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[CH3:54][N:55]1[CH:59]=[CH:58][C:57]([C:60]([OH:62])=O)=[N:56]1>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:53])=[O:2])=[O:22])[N:24]([C:60]([C:57]5[CH:58]=[CH:59][N:55]([CH3:54])[N:56]=5)=[O:62])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cn1ccc(C(=O)O)n1
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3ccn(C)n3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (30 mg) was reacted with 1-methyl-1H-pyrazole-3-carboxylic acid in DCM (3.0 mL) according to General Procedure A and directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 847.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[C:4]1[CH3:26])[CH3:2].[OH-].[Na+]>Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[C:4]1[CH3:26])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C)c(C(=O)c2ccc(N)cc2C(=O)O)c2ccccc21
Temperature: 55 °C
Yield: 54.3 %

Procedure:
To a solution of 7.04 g (0.02 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-5-nitrobenzoic acid, prepared as described in part A of this example, in 70 ml of concentrated hydrochloric acid, there was added 13.5 g (0.06 mole) of stannous chloride dihydrate at such a rate as to allow the reaction to exotherm to 55° C. The temprature was maintained at 55° C. for an additional one-half hour. The reaction was then cooled to room temprature and the pH adjusted to six by the addition of 10 percent aqueous sodium hydroxide solution. The red precipitate thus formed was filtered off and extracted into acetone. The acetone solution was evaporated and the paste-like residue was slurried in diethylether and then the solid was collected by filtration to obtain 3.5 g of 2-[(1-ethyl-2-methyl-3-indolyl)-carbonyl]-5-aminobenzoic acid (Formula VIII: R3 =R2 =R°=Y1 =H; R1 =NH2 ; R5 =CH3 ; R6 =CH2CH3), a red solid which melted at 187°-189° C.