Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:39]([OH:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])[C:3]([NH:5][C@:6]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH:36]([CH3:38])[CH3:37])[CH:29]=1)([C:14]1[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.B.[H][H]>C1COCC1>[NH2:1][CH:2]([CH2:3][NH:5][C@:6]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH:36]([CH3:38])[CH3:37])[CH:29]=1)([C:14]1[CH:19]=[C:18]([O:20][C:21]([F:25])([F:26])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:39]([C:44]([F:45])([F:46])[F:47])([OH:48])[C:40]([F:43])([F:42])[F:41]
Reactant: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C(N)C(O)(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: [H][H]
Agent: B
Solvent: C1CCOC1
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NCC(N)C(O)(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 100 °C
Yield: 20 %

Procedure:
To a solution of 2-amino-4,4,4-trifluoro-N—((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamide, prepared as described in Example 293, (20 mg, 0.028 mmol) in THF (0.5 mL) was added borane (0.2 mL, 1.0 M solution in THF). After hydrogen evolution ceased, the solution was heated in a sealed microwave vial under microwave irradiation at 100° C. for 5 min. The solvents were removed under a stream of nitrogen then THF (0.5 mL) was added to the residue followed by BF3Et2O (30 mg, 0.21 mmol) and LAH (0.2 mL, 1.0 M solution in THF). After evolution of hydrogen gas had ceased, the sealed microwave vial was heated at 100° C. for 10 min. The solvents were removed under a stream of nitrogen and the residue dissolved in NH4OH (ca. 10 mL). LiCl (10%, ca. 10 mL) was added and the aqueous extracted with DCM (3×10 mL). The combined organic portions were concentrated under reduced pressure and purified by preparative TLC (25×25 mm, silica gel 1 mm elution with hexane:EtOAc 4:1). 3-Amino-1,1,1-trifluoro-4-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylamino)-2-(trifluoromethyl)butan-2-ol (Example 327, 5 mg, 20% yield) was isolated as a colorless oil at Rf of 0.5. LCMS: RT=3.88 min [M+H] 693.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.88 min, Purity 91% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) 7.15 ppm, 3H, m; 7.05 ppm, 1H, m; 6.86 ppm, 2H, d, J=8.0 Hz; 6.83 ppm, 3H, m; 6.61 ppm, 2H, d, J=8.0 Hz; 5.87 ppm, 1H, t, t, J=52.0 Hz and J=4.0 Hz; 4.41 ppm, 1H, sept, J=8.0 Hz; 3.57 ppm, 1H, d, J=12.0 Hz; 3.48 ppm, 1H, d, J=12.0 Hz; 2.99 ppm, 2H, m; 2.53 ppm, 1H, brt; 1.27 ppm, 3H, d, J=8.0 Hz; 1.25 ppm, 3H, d, J=8.0 Hz.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:31])[C:8]([CH2:29][CH3:30])=[C:9]([C:27]#[N:28])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:31])[C:8]([CH2:29][CH3:30])=[C:9]([C:27]#[N:28])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Oc3ccccc3[N+](=O)[O-])cc2)c(C#N)c(CC)n1C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Oc3ccccc3N)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 4-cyano-5-ethyl-3-[4-(2-nitro-phenoxy)-phenyl]-1-methyl-1H-pyrole-2-carboxylic acid ethyl ester (prepared in example E-230) and tin(II) chloride dihydrate (5 Eq.) in absolute ethanol (20 mL), and heat at reflux with stirring under a nitrogen atmosphere for 3 hours. Cool the reaction mixture to room temperature and dilute with ethyl acetate. Wash the organic layer with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum. Purify the material by silica gel chromatography eluting with methylene chloride to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[Cl:12][C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C=C(F)C=CC=1C=O.CNC>>[Cl:12][C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: C[N+](C)=Cc1ccc(F)cc1Cl
Agent: CNC
Agent: O=Cc1ccc(F)cc1Cl
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1ccc(F)cc1Cl)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (2-chloro-4-fluoro-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-chloro-4-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]1[OH:54].CCN(C(C)C)C(C)C>CN(C=O)C.C(O)(=O)C>[CH2:1]([NH:8][C:9]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:12]([C:13]([NH:47][C@@H:48]2[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]2[OH:54])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(NCc2ccccc2)c(-c2ccc(Cl)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(NCc2ccccc2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A mixture of 16.2 mg (0.047 mmol) 6-benzylamino-5-(4-chloro-phenyl)-nicotinic acid, 19.6 mg (0.06 mmol) TBTU, 6.9 mg (0.06 mmol) (1R,2R)-2-amino-cyclohexanol and 23 mg (0.18 mmol) DIPEA in DMF was shaken at room temperature over night. Acetic acid was added and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 14.1 mg (55%) of the title compound. MS (m/e): 436.4 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(O[C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.Cl.Cl.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH:44]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:39][CH2:38]1>O1CCCC1.O>[CH:44]1([CH2:43][N:40]2[CH2:41][CH2:42][CH:37]([NH:36][C:26]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[NH:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6]4)=[O:32])[CH2:38][CH2:39]2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCN(CC2CCCCCCC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCN(CC2CCCCCCC2)CC1)c1cccc2c1Nc1ccccc1O2
Yield: 88.2 %

Procedure:
50.3 mg of phenoxazine was dissolved in 3 ml of tetrahydrofuran at room temperature, and 0.15 ml of triethylamine and 86 mg of triphosgene were successively added thereto. After refluxed under heating for 30 minutes, 110 mg of 4-amino-1-cyclooctylmethylpiperidine dihydrochloride and 0.15 ml of triethylamine were added thereto, followed by reflux under heating for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by preparative thin layer chromatography (Kieselgel™60F254, Art5744 produced by Merck Co.: chloroform/methanol=30/1), and 105 mg of the title compound as a yellow solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1.CCO.O>[Cl-].[Cl-].[Zn+2].O>[Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of N-[4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (1.0 g, 1.89 mmol), ZnCl2 (1.29 g, 9.47 mol, 5.0 eq.), and EtOH/H2O solution (25 mL, volumetric ratio 100:5) was stirred at 80° C. overnight. The reaction mixture poured into water, and the solid was collected by filtration, washed with water (10 mL×3), and recrystallized from MeOH to give the title product (0.67 g, 85% yield; HPLC purity 98%). tR: 5.39 min. 1H-NMR (DMSO-d6) δ 8.07 (s, 1H), 7.28 (s, 1H), 6.75 (br. s, 2H), 5.29 (s, 2H), 3.73 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH2:54])[S:52][CH:53]=1)[CH3:45].Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH:54][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])[S:52][CH:53]=1)[CH3:45]
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)c2cn(C(C)C)c3cc(Cl)ccc23)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
A solution of triphenylphosphine (182 mg, 0.69 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (124 mg, 0.69 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150 mg, 0.63 mmol). This solution was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with (2-amino-thiazol-4-yl)-acetic acid ethyl ester (294 mg, 1.58 mmol) and was stirred at 25° C. for 16 h. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (10 mL). The organic layer was separated and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded {2-[(6-chloro-1-isopropyl-1H-indole-3-carbonyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester (62 mg, 24%) as an orange foam: mp 65-75° C.; (ES)+-HRMS m/e calcd for C19H20ClN3O3S (M+H)+ 406.0987, found 406.0986.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.C(O)(=O)C(O)=O.[NH:27]1[C:30]2([CH2:33][O:32][CH2:31]2)[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:27]3[C:30]4([CH2:33][O:32][CH2:31]4)[CH2:29][CH2:28]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1CC2(COC2)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC12COC2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 6-oxa-1-azaspiro[3.3]heptane oxalate (CAN 1359655-43-8) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=366.4 [MH+].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[N:12][C:11]([O:15][CH3:16])=[CH:10]2)=[O:4].[OH-].[K+]>C(O)C.O>[CH3:16][O:15][C:11]1[N:12]=[CH:13][C:14]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cccc2cc(OC)ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2cccc(C(=O)O)c2cn1
Yield: 115.7 %

Procedure:
To a solution of methyl-3-methoxyisoquinoline-8-carboxylate (Description 55; 280 mg, 1 mmol) in ethanol (10 ml) was added potassium hydroxide (145 mg, 3 mmol) in water (6 ml). This mixture was heated at reflux for 30 minutes, cooled and the ethanol removed by evaporation. The remaining aqueous mixture was acidified with 1M HCl (3 ml) to pH 5. The solid was collected by filtration and dried in a vacuum oven to give the title compound (235 mg, 90%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccs1
Reaction time: 0.33 h

Procedure:
2-(Thiophen-2-yl)ethanol (1.05 g) was dissolved in tetrahydrofuran (25 ml), triethylamine (1.63 ml) and methanesulfonyl chloride (725 μl) were added and the mixture was stirred for 20 min. Saturated aqueous sodium hydrogen carbonate (50 ml) was added to the reaction mixture, and the mixture was extracted with diisopropyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object product (1.62 g).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([Sn:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:25])=[O:5].[CH2:17]([Sn+2:16][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Product: CCCCCCCC[Sn+2]CCCCCCCC
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
Maleic anhydride and dioctyltin oxide are mixed with one another, and the mixture is reacted in a twin-screw laboratory extruder in accordance with Example 1. Dioctyltin maleate (compound 4) is obtained as the end product in the form of a white free-flowing powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cccc(CC(=O)O)c1
Product: COC(=O)Cc1cccc(N)c1
Yield: 77 %

Procedure:
3-Aminophenylacetic acid (5 g, 33.1 mmol) was esterified with MeOH using Method B to give the title compound Yield: 4.22 g, 77%; LC/MS tr 0.70 min; MS(ES+) m/z 166 (M+H)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])=[O:3].[CH3:19][C:20]([CH3:22])=O.N1CCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:18][C:20]([CH3:22])([CH3:19])[CH2:1][C:2]2=[O:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.8 %

Procedure:
A mixture of 25.0 g (0.103 mole) 2-hydroxy-5-benzyloxyacetophenone, 8 mL (6.0 g, 0.130 mole) acetone and 4 mL (3.7 g, 0.052 mole) pyrrolidine in 100 mL toluene was stirred at room temperature for 4 hours, then refluxed over a Dean-Stark trap for 3 hours. An additional 8 mL (6.0 g, 0.130 mole) acetone and 4 mL (3.7 g, 0.052 mole) pyrrolidine was added and the mixture refluxed for 18 hours. The mixture was concentrated, poured into water, basified to pH 8 with ammonium hydroxide, then extracted with ether. The ether extract was washed successively with 1N KOH, 1N HCl, water and brine, then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes afforded a solid. Recrystallization from ethyl acetate in hexanes afforded a solid. Recrystallization from ethyl acetate in hexanes yielded the title product as a solid 13.6 g (47%), mp 105°-107° C. NMR (CDCl3): δ1.4 (s, 6H); 2.7 (s, 2H); 5.1 (s, 2H).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:19]([CH3:22])([O-:21])=[O:20].Cl.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@H:10]([OH:11])[CH2:22][N+:19]([O-:21])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@H](O)C[N+](=O)[O-]
Yield: 60.6 %

Procedure:
To a stirred solution of 62.3 mg (0.25 mmol) of (R)-2-t-butoxycarbonylamino-3-phenylpropanal [synthesized by the method described in Journal of Medicinal Chemistry, 130, 1162 (1987)] in 1.0 ml of THF was added at 0° C., 0.27 ml (5 mmol) of nitromethane, followed by dropwise addition of 0.5 ml (0.025 mmol) of the lanthanum/(R)-1,1'-bi-2-naphthol complex solution (Reference Example 1, 0.05 mol/l). The resultant mixture was stirred at 0° C. for 2 hours. To this solution were added 0.5 ml of 1N hydrochloric acid and 3 ml of water. The mixture was extracted with diethylether, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent; n-hexane-ethyl acetate 8:2) to give 47 mg of ⟦(2S,3R)⟧ (2R,3R)-3-t-butoxycarbonylamino-1-nitro-4-phenyl-2-butanol. Yield 60%. ⟦(2S,3R)⟧ (2R,3R)-3-t-Butoxycarbonylamino-1-nitro-4-phenyl-2-butanol:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([NH2:21])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:7]=1.C(N(CC)CC)C.C([O:32][C:33](=O)[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:43]Br)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20]2)[CH:7]=1)[N:21]1[CH2:43][C:35]2[C:34](=[C:39]([N+:40]([O-:42])=[O:41])[CH:38]=[CH:37][CH:36]=2)[C:33]1=[O:32]
Reactant: COC(=O)CC(N)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CCOC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Temperature: 90 °C
Yield: 77 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid methyl ester (490 mg, 1.5 mmol) and triethyl amine (0.43 ml, 3.1 mmol) in DMF (10 ml) was added 2-bromomethyl-6-nitro-benzoic acid ethyl ester (460 mg, 1.6 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester as a yellowish solid (550 mg, 75%). 1HNMR (CDCl3): δ 0.31-0.37 (m, 2H), 0.59-0.67 (m, 2H), 1.22-1.28 (m, 1H), 3.09 (dd, J=7, 15 Hz, 1H), 3.28 (dd, J=9, 15 Hz, 1H), 3.65 (s, 3H), 3.79-3.91 (m, 2H), 4.18 (d, J=17 Hz, 1H), 4.46 (d, J=17 Hz, 1H), 5.83 (dd, J=7, 9 Hz, 1H), 6.61 (t, JH-F=75 Hz, 1H), 7.04-7.05 (m, 3H), 7.58-7.76 (m, 3H).
Reaction SMILES: C(O)(=O)CC(O)=O.[CH:8]1[C:13](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[C:10]([OH:19])[CH:9]=1.[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:31]([O:19][C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: O=C(O)CC(=O)O
Product: CCCCCCCCCCCCOc1ccc(C=CC(=O)O)cc1

Procedure:
4-Dodecyloxycinnamic acid is prepared by generally known processes by condensation of a 4-alkoxybenzaldehyde with malonic acid or by reaction of coumaric acid with dodecyl bromide. The colourless crystals have a melting point of 158-159° C. The corresponding acid chloride is obtained therefrom virtually quantitatively by reaction with oxalyl chloride in benzene (18 hours, room temperature).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].CCN(CC)CC.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[C:21]([Cl:38])[CH:20]=1>C(Cl)Cl>[Cl:38][C:21]1[CH:20]=[C:19]([NH:18][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:24]=[CH:23][C:22]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2Cl)CC1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccccn3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
According to Scheme 5 Step 3: Picolinoyl chloride hydrochloride (3.68 mmol, 656 mg) and Et3N (7.37 mmol, 1.03 mL) were added to a solution of tert-butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate (2.46 mmol, 766 mg) in DCM (40 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure to afford tert-butyl 4-(2-chloro-4-(picolinamido)phenyl)piperazine-1-carboxylate (2.46 mmol, 1.02 g, 100%).