Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[NH:5][CH:4]=1)[CH3:2].[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[CH2:1]([C:3]1[C:11]2[C:10](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[NH:5][CH:4]=1)[CH3:2]
Reactant: CCc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1c[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 31.7 %

Procedure:
A mixture of 3-ethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.5 g), aminoguanidine hydrochloride (0.25 g), concentrated hydrochloric acid (0.1 ml), water (0.1 ml) and ethanol (30 ml) was refluxed for 7 hours, and to the mixture was added 1N hydrochloric acid (0.1 ml). Under reduced pressure, the solvent was evaporated. The resulting crystals were washed with water and recrystallized from ethanol to give 3-ethyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 3) (0.22 g) as colorless crystals.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([NH2:36])[N:27]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][CH:45]([CH3:49])[C:46](O)=[O:47])=[O:43])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:38]([O:41][C:42](=[O:43])[NH:44][CH:45]([CH3:49])[C:46]([NH:36][C:28]1[N:27]=[C:26]([Br:25])[C:35]2[C:30]([CH:29]=1)=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([CH3:40])([CH3:37])[CH3:39]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc2ccccc2c(Br)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(Br)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
HATU (7.5 g, 19.7 mmol) is added to a mixture of 1-bromoisoquinolin-3-amine (2.0 g, 9.0 mmol), 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (1.7 g, 9.0 mmol) and DIPEA (3.4 ml, 200 mmol) in DMA (10 ml). After stirring for 3 days at RT the mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 3.3 g (94%). HPLC-MS: M−H=392/394; tR=1.97 min (*Method—1).
Reaction SMILES: [O:1]1[C@@H:3]2[C@H:4](O)[C@@H:5]3[C@@H:14]([C@@:15]4([CH3:27])[CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19][C@@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[C@@H:7]2[CH2:29][C@@H:8]2[C:9]1=[O:28].[Cl:31]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:31][C@@H:4]1[C@H:3]2[O:1][C@:2]32[C@:15]([CH3:27])([CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19]3)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:28])[C@H:8]2[CH2:29][C@@H:7]12
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Temperature: 1 °C
Reaction time: 1 h

Procedure:
A solution of 5,6β-epoxy-7β-hydroxy-15β,16β-methylen-3β-pivaloyloxy-5β-androstan-17-one (1.66 g, 0.004 mol) in dichloromethane (8 mL) is treated with hexachloroacetone (2 mL, 0.013 mol) and cooled to 0-2° C. Triphenylphosphine (1.53 g, 0.0044 mol) in dichloromethane (4 mL) is added dropwise and the mixture is stirred for one hour at 3-4° C., then for an additional hour at 10-15° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][OH:10])[N:6]=[CH:5]1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[Si:11]([O:10][CH2:9][C:7]1[N:6]=[CH:5][N:4]([CH2:3][O:2][CH3:1])[CH:8]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COCn1cnc(CO)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 24 h

Procedure:
The compound (8.81 g) obtained in (2) was dissolved in dichloromethane (100 mL), followed by addition of tert-butyldiphenylsilyl chloride (hereinafter, also referred to as TBDPSCl) (24.3 mL), DIEA (21.6 mL) and DMAP (0.760 g) under stirring, and the stirring was continued for 1 day. The reaction solution was concentrated, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=50%→100%) using silica gel column (product name: Hi-Flash Column 4 L, manufactured by Yamazen Corporation) to afford the title compound (16.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH:9]([CH3:11])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)c1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of 32 g of 4-bromo-2-isopropylphenol, 25.7 g of benzyl bromide, 23 g of potassium carbonate and 300 ml of N,N-dimethylformamide was stirred at room temperature for 24 hours. The reaction solution was poured into ice-water, acidified by adding 10% hydrochloric acid and then extracted with 500 ml of diethyl ether. Then, the ether layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 30 g of 4-bromo-2-isopropylphenyl benzyl ether (yield, 65%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C2C(=CC=CC=2)N=C(CCl)[N:27]=1.C(OC1C=CC(NC)=CC=1)(C)C>Cl>[NH2:27][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)Oc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: ClCc1nc(Cl)c2ccccc2n1
Agent: CNc1ccc(OC(C)C)cc1
Agent: Cl
Product: CC(C)Oc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine: The title compound was prepared from 4-chloro-2-chloromethyl-quinazoline (300 mg, 1.4 mmol), 4-isopropoxy-N-methylaniline (279 mg, 1.7 mmol) and concd HCl (12 M, 10 drops) by a procedure similar to Example 203c with subsequent MPLC purification. 1H NMR (CDCl3) δ 7.8 (d, 1H), 7.55 (m, 1H), 7.10 (d, 2H), 7.0 (m, 2H), 6.9 (d, 2H), 4.7 (s, 2H), 4.5 (sept, 1H), 3.6 (s, 3H), 1.37 (d, 6H); LC-MS (ESI+; 342 ([M+H]+)).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][NH:30][CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N>[CH3:28][O:29][N:30]([CH3:31])[C:16](=[O:18])[C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
To a 1-liter round bottom flask were added (R)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanoic acid (10 g, 27 mmol), N-methoxy-N-methylamine-HCl (5.3 g, 55 mmol), PyBOP (21 g, 41 mmol), and MeCN (400 mL). DIEA (19 mL, 110 mmol) was added and the reaction was allowed to stir at room temperature for 12 hours. The solvent was removed under reduced pressure and the residue was suspended in EtOAc and washed with 1N NaOH (aq) (×3) then 2N HCl (aq) (×2), then saturated NaHCO3 (aq) (×1), then brine (×1). The product was then purified by column chromatography (EtOAc/hexanes) to give N-methoxy-N-methyl-(R)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanamide (305) (10.9 g, 26.7 mmol, 99% yield) as a clear oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[Si](C)(C)C.C([Li])CCC.[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][CH2:20][C:19](=O)[CH2:18]1>O1CCCC1.C(OCC)C>[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][CH2:20][C:19](=[C:2]2[S:3][CH2:4][CH2:5][CH2:6][S:1]2)[CH2:18]1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: CC1(C)CCCC(=O)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CCCC(=C2SCCCS2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1,3-dithian-2-yl)trimethylsilane (5.0 g) in tetrahydrofuran at −78° C. was added n-butyllithium (1.6M, 16.24 mL). After stirring for 30 minutes, 3,3-dimethylcyclohexanone (3.3 g) was added as a solution in tetrahydrofuran and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with diethyl ether (100 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 0.13% to 2.5% ether/hexanes gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[C:25](O)=[O:26])[CH:22]=[CH:21][S:20]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:25]([C:24]1[N:23]2[C:19]([S:20][CH:21]=[CH:22]2)=[N:18][C:17]=1[CH3:16])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2sccn2c1C(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (A. Andreani et al. Eur. J. Med. Chem. 1982, 17, 271-274).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=O)[CH3:13].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:20][C:17]1[S:16][C:15]([C:12](=[N:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])[CH3:13])=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccc(C)s1
Reactant: Nc1ccccc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1C(F)(F)F)c1ccc(C)s1
Yield: 87.5 %

Procedure:
A solution of 2-(trifluoromethyl)aniline (4.0 q, 25 mmol), 2-acetyl-5-methylthiophene (4.4 g, 31 mmol), and p-toluenesulfonic acid (50 mg) in toluene (30 mL) was heated under reflux with azeotropic removal of water for 10 hours. Then the mixture was concentrated on a rotary evaporator, and the oily residue was distilled under reduced pressure to give 6.2 g (88%) of ketimine 12q as an oil (bp 128°-130° C./0.3 mm Hg).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24]>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(Oc2ccc(F)c(C(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 35.6 %

Procedure:
6-[4-Fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazin-3-amine (198 mg, 36%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 4-fluoro-3-(trifluoromethyl)phenol (0.57 g, 3.18 mmol) according to the general procedure of Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:21]1[CH:22]=[CH:23][N:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][C:25]=12.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:31][CH2:30][C:27]4[CH:28]=[CH:29][N:24]5[CH:23]=[CH:22][N:21]=[C:25]5[CH:26]=4)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Reactant: NCc1ccn2ccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(NCc3ccn4ccnc4c3)c2C1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (250 mg, 0.82 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (270 mg, 1.83 mmol) in acetonitrile (10 mL) and N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) was subjected to microwave irradiation at 185° C. for 4 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][C:23]#[N:24])[C:16](=O)[C:15]12[O:30][CH2:29][CH2:28][CH2:27][O:26]1)(=[O:11])=[O:10].N.C1COCC1.[H][H]>[Ni].CCO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH2:23][N:24]=[C:16]3[C:15]3([O:26][CH2:27][CH2:28][CH2:29][O:30]3)[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2CCC#N
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Temperature: 135 °C
Yield: 14.5 %

Procedure:
A mixture of 3-[5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′ (2′H)-yl]propanenitrile (4.48 g, 10.3 mmol), and wet Raney nickel (4.1 g) in 2M EtOH.NH3 (100 mL) and THF (100 mL) was hydrogenated in a Parr Hydrogenation Bottle (2L) at 45 lb/in2 hydrogen for 24 hours. The Raney nickel was removed by filtration through Sulka Floc. The filtrate was poured into a steel pressure vessel and heated to 135° C. for 51 hours. The reaction was cooled and the solvents were removed. The residue was taken up in CH2Cl2 and combined with silica gel. The solvent was removed and the adsorbate was flash chromatographed (Biotage KP silica gel, and step gradient of CH2Cl2/CH3OH/NH4OH (98.5/1.0/0.5-98/01.5/0.5)) to give the title compound as a white solid (0.63 g, 14.5% yield). Anal: Calc'd. for C20H27N3O5S: C, 56.99; H, 6.46; N, 9.97; Found: C, 56.80, H, 6.45, N, 9.87; NMR (400 MHz, DMSO-d6): consistent. MS: (ES+) m/z 422 [M+H]. Opt. Rotation: 94.1(calculated) at 25° C. in CH3OH (1% concentration), wavelength 589; m.p. 129-130°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH3:27])[CH2:19][C:20]#[CH:21]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]3[O:16][C:20]([CH2:19][CH2:18][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])=[CH:21][C:12]=3[CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccc(F)c1)c1ccc(O)c(I)c1
Reactant: C#CCCN1CCC[C@H]1C
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3cccc(F)c3)ccc2o1

Procedure:
The product from Example 69B and a 0.1 M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.26 (d, 3H, J=6.1 Hz), 1.57 (m, 1H), 1.91 (m, 2H), 2.10-2.63 (m, 2H), 2.87 (m, 2H) 3.18 (m, 2H), 3.42 (m, 2H), 6.76 (s, 1H), 7.37-7.59 (m, 5H), 7.76 (d, 1H, J=8.9 Hz), 7.98 (s, 1H); MS (ESI) m/z 352.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21](O)[CH3:22].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH2:21]([O:12][C:11](=[O:13])[C@H:10]([NH:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:22]
Reactant: CC(C)(C)OC(=O)CN[C@H](Cc1ccccc1)C(=O)O
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
(2R)-2-((tert-Butoxycarbonyl)methylamino)-3-phenylpropionic acid (4.0 g, 14.27 mmol) was dissolved in dichloromethane (5 ml) and ethanol (0.95 ml, 16.27 mmol). 4-Dimethylaminopyridine (0.19 g, 1.57 mmol) was added. The solution was cooled to 0° C. and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.98 g, 15.55 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. for 16 h at room temp. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate/water (30 ml/30 ml). The phases were separated. The organic phase was washed with a saturated solution of sodium hydrogencarbonate and water and dried over magnesium sulfate. The crude product was purified by flash chromatography on silica (180 g) with ethyl acetate/heptane 1:2 to give 1.95 g of (2R)-2-((tert-butoxycarbonyl)methylamino)-3-phenylpropionic acid ethylester.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[OH:13]S(O)(=O)=O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:13])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Br)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-3-trifluoromethylaniline (48 g, 0.2 mol) was treated with water (300 ml) and concentrated H2SO4 (36 ml) at 60° C. for 1 hour. The resulting suspension was cooled in an ice bath and treated with sodium nitrite (16 g, 0.23 mol) in water (30 ml) maintaining the temperature of the reaction mixture below 10° C. The resulting solution was stirred at 0° C. for 1 hour, and then added portionwise, over 1 hour, to a 25% H2SO4 aqueous solution (160 ml) whilst steam distilling. After collecting approximately 1 liter of distillate, the aqueous distillate was extracted with ether and the organic solution dried using MgSO4, filtered and concentrated. The product, 4-bromo-3-trifluoromethylphenol, was obtained by distillation under reduced pressure. Yield 18.0 g (37%); boiling point 68-71/1 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
23 g (105 mmol) of methyl 5-bromonicotinate and 26 g (126 mmol, 1.2 eq.) of 4-trifluoromethoxyphenylboronic acid were reacted according to the General Method 1A. Yield: 14 g (41% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-])=O)[CH:28]=4)[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CO.[Ni]>[NH2:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:22]=[C:21]2[C:19]1[CH:18]=[N:17][CH:16]=[C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]2)[N:20]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc([N+](=O)[O-])cc34)n2)CC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(N)cc34)n2)CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of tert-butyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-nitro-1H-indole-1-carboxylate (200 mg, 0.37 mmol) in MeOH (2 mL) was added Raney Ni (30 mg) and then heated at 50° C. for 5 min. Hydrazine hydrate (0.2 mL) was added and the resulting mixture was stirred at the same temperature for another 10 min. The reaction mixture was cooled to RT and filtered off the Raney Ni through Celite. The filtrate was concentrated to obtain the title compound as a pale brown solid (160 mg, 85%). MS (ESI, pos. ion) m/z: 509.3 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=2[OH:28])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:21]=2[O:28][CH2:17][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(O)cc2O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
241 mg (1.74 mmol, 3 eq) of potassium carbonate (325 mesh) are added to a solution of 181 mg (0.58 mmol, 1 eq) of 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester in 3 ml of acetone. 152 μl (1.28 mmol, 2.2 eq) of benzyl bromide are added dropwise. The reaction medium is heated at 50° C. for 20 hours. The solvent is evaporated off and then the residue is taken up with a water/ethyl acetate mixture. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined, washed with a solution of sodium hydrogen carbonate and then with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel, elution being carried out with 85/15 heptane/ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([NH:12][S:13]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])(=[O:15])=[O:14])[CH:5]=1.Br[CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]2[O:11][CH2:28][CH2:27][N:12]([S:13]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][CH3:24])(=[O:15])=[O:14])[C:6]=2[CH:5]=1)=[O:25]
Reactant: COC(=O)c1cc(C)c(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Reactant: BrCCBr
Product: COC(=O)c1cc(C)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=514.9 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methyl-benzoic acid methyl ester (example 52, step 2) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.