Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[S:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[CH:32][C:27]=2[S:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[S:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)=[CH:32][C:27]=2[S:26][CH2:25][CH2:24]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(c1)SCCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)SCCS5)CC3)c2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.1 %

Procedure:
To 20 mL of a chloroform solution containing 205 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 120 mg of 2,3-dihydro-1,4-benzodithiin-6-carbaldehyde, 41 mg of acetic acid was added, and stirred at room temperature for 4.5 hours. To the reaction mixture, 216 mg of sodium triacetoxyborohydride was added, and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform: methanol=10:1] to give 195 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodithiin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[CH:3]=1.Cl.[N:13]([O-])=[O:14].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[C:3]=1[N:13]=[O:14]
Reactant: CCn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCn1c(N)c(N=O)c(=O)[nH]c1=O

Procedure:
To 100 g (0.65 mol) of 6-amino-1-ethyl-2,4-(1H,3H)-pyrimidinedione (II), dissolved in 1 liter hot water, was added 145 ml of 5 N HCl and 50 g of NaNO2 (0.72 mol) which was dissolved in water. After cooling the red crystals were filtered off and washed with water. Yield 97.7 g (83%) (III) NMR.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[CH2:46]([O:48][C:49](C1C=C(C=CC=1)N)=[O:50])[CH3:47]>>[CH2:46]([O:48][C:49]([C:22]1[CH:21]=[C:20]([NH:19][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:10][CH2:1][O:2][C:3]=4[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)[CH:25]=[CH:24][CH:23]=1)=[O:50])[CH3:47]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CCOC(=O)c1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-ethoxycarbonylaniline gave N2-(3-ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.04 (bs, 1H), 7.94 (bs, 1H), 7.90 (bd, 1H), 7.68 (bd, 1H, J=7.5 Hz), 7.35 (t, 1H, J=8.1 Hz), 7.28 (d, 1H, J=2.4 Hz), 7.07 (s, 1H), 6.93 (dd, 1H, J=3 and 8.7 Hz), 6.83 (d, 1H, J=9 Hz), 6.64 (bs, 1H), 4.36 (q, 2H, J=7.2 Hz), 4.26 9s, 4H), 1.35 (t, 3H, J=7.5 Hz); 19F NMR (CDCl3): −47247; LCMS: ret. time: 15.88; purity: 100%; MS (m/e): 411 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccccc1C(=C/C=C/C(=O)O)c1ccccc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccccc1C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1OC
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
As in Example 115. (E)-5.5-bis(2-methoxyphenyl)-2,4-pentadienoic acid (5 g) and 4-nitrophenol (2.7 g) in dichloromethane (35 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.34 g). The mixture was stirred at 0°-5° C. for 30 minutes and then at room temperature for 18 hours. After the usual work up. the crude Product was crystallized from 2-propanol to give 6.1 g of (E)-5,5-bis(2-methoxyphenyl)2,4-pentadienoic acid 4-nitrophenyl ester. mp 141.5°-143° C. A portion from the 2-propanol to yield the analytical sample, mp 142°-143° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCCC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)Nc1cccc(N)c1

Procedure:
A solution of N-(3-nitrophenyl)butyramide (8.60 g, 41.3 mmol) in MeOH (207 mL) was divided between two 500 mL flasks with stir bars. Each flask was flushed well with nitrogen, then 5% palladium on carbon (4.40 g, 2.065 mmol) was added, half to each flask. A 3-way adapter with a large hydrogen-filled balloon was attached to each flask, and the reactions were evacuated and back-filled with hydrogen five times, while stirring vigorously. The reactions were then stirred for 16 h, then filtered through a funnel packed with Celite. The filter cake was washed with MeOH, and the filtrate was concentrated, redissolved with DCM, then purified by column chromatography (EtOAc/hexanes gradient) to yield a white solid after precipitating from hexanes (5.87 g, 80%). LRMS (ESI+) (M+H): 179.18.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=O)[O:23]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-thiophen-3-yl-phenyl)-carbamic acid tert.-butyl ester (Example G6) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according the general procedure K. Obtained as a brown solid (104 mg) and used crude in the next step (Example 7).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:14]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:15])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: NCCCO
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCO)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 314.7 %

Procedure:
To a solution stirred under argon at room temperature of 3-amino-1-propanol (0.77 g, 1.1 mmol) and triethylamine (2.85 mL, 7 mmol) in THF (5 mL) was added a suspension of 4-nitrobenzyl chloroformate (2 g, 1 mmol) in THF (20 mL). The resulting mixture was allowed to stir at room temperature over the weekend, then was concentrated. The residue was purified by chromatography on silica gel (0%-2% MeOH/CH2Cl2) to give the title compound (0.80 g, 34%) as a pale yellow oil: MS (ES) m/e 254.3 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=[O:12])[NH:2]1.[OH-].[Na+].[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CCOCC>[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27]([N:2]1[CH:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(CSC(=O)c1ccccc1)C(=O)N1Cc2ccccc2CC1C(=O)O
Temperature: 5 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of (-)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (7.0 g., 0.04 M) and sodium hydroxide (1.6 g., 0.04 M) in water (160 ml.) at 10° C. was slowly added (-)-3-benzoylthio-2-methylpropionyl chloride (9.7 g., 0.04 M). At the same time, from a separate dropping funnel, was added a solution of sodium hydroxide (1.6 g., 0.04 M) in water (15 ml), at such a rate that the solution was maintained at a pH between 9.5 and 7.5 pH units (final pH 7.5). After stirring overnight at 5° C., the reaction mixture was filtered and the clear filtrate acidified with dilute hydrochloric acid. The product was extracted into methylene chichloride, washed and dried over sodium sulfate. After filtration the solvent was removed by evaporation at reduced pressure, leaving a residue (14 g.). This material was separated on an HPLC preparative column (Prep Pak C18 column, Waters) using a mobile phase of 50 parts methanol, 50 parts water and 0.5 parts acetic acid. Two main fractions were obtained, 15% and 84%. The residue from the major fraction was dissolved in ether, washed and dried over sodium sulfate. After filtration the solvent was removed by evaporation at reduced pressure, leaving a white solid, the title compound (10 g.), m.p. 61-63, [α]D25 =-76.39 (C=1.55% EtOH.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([CH2:21][CH3:22])[CH:3]=1.[CH3:23][O-:24].[Na+].O>CO>[CH2:21]([C:4]1[CH:3]=[C:2]([O:24][CH3:23])[N:7]=[N:6][C:5]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH3:22]
Reactant: CCc1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cc(OC)nnc1Cn1ccnc1-c1cccc(F)c1

Procedure:
A solution of 6-chloro-4-ethyl-3-[2-(3-fluoro-phenyl)-imidazol-1-ylmethyl]-pyridazine (73.3 mg, 0.23 mmol) and sodium methoxide (40 mg, 0.74 mmol) in methanol (5 mL) is heated under N2 for 5 hours. After cooling, water (10 mL) is added, followed by extraction with ethyl acetate (3×30 mL). The solvent is removed in vacuo and PTLC separation gives the title compound. LC-MS (M+1) 313.1 (retention time: 0.99 min).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH2:29][C:30]([NH2:32])=[O:31]>CN(C)C=O>[CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([O:5][CH2:28][CH2:29][C:30](=[O:31])[NH2:32])=[O:4]
Reactant: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)O)cc1C2
Reactant: NC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)OCCC(N)=O)cc1C2
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 70.3 %

Procedure:
To a solution of 2.7 g of α,2-dimethyl-5H-[1]benzopyrano [2,3-b]pyridine-7-acetic acid in 15 ml of dimethylformamide are added 0.8 g of potassium carbonate and 1.3 g of 3-chloropropionamide, and stirred at 70° C. for 7.5 hours under a nitrogen atmosphere. The reaction mixture is poured into ice water. The precipitate is extracted with ethyl acetate, washed with water and dried, and then concentrated. The residue is recrystallized from ethanol to obtain 2.4 g of 2-carbamoylethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine7-acetate as white crystals having a melting point of 143° to 145° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:42][C:43]([C@@H:45]([NH:50][C:51](=[O:54])[O:52][CH3:53])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:9]([OH:41])[CH2:10][C@@H:11]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:55][S:56]([CH3:58])=O.C(O)(=O)C.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C@H:8]([NH:42][C:43](=[O:44])[C@H:45]([C:46]([CH3:47])([CH3:48])[CH3:49])[NH:50][C:51]([O:52][CH3:53])=[O:54])[C@@H:9]([O:41][CH2:55][S:56][CH3:58])[CH2:10][C@@H:11]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)OCSC)C(C)(C)C
Yield: 59.6 %

Procedure:
A solution containing the product of Example 10E (1.71 g, 2.3 mmol) in DMSO (3.3 g, 42.3 mmol) was treated with acetic acid (4.1 g, 69 mmol) and acetic anhydride (2.35 g, 23 mmol) at 25° C. for 3 days. Excess ice was added to the mixture which was then made alkaline with 10% sodium carbonate. The mixture was extracted with ethyl acetate, the organic layer was separated, washed with 10% sodium carbonate, water (3×), brine, and dried over sodium sulfate. The solvents were evaporated, and the product was purified by chromatography on silica gel eluting with 30-100% ethyl acetate/dichloromethane to give the title compound (1.1 g, 60% yield).
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[CH3:11][C@H:12]([NH2:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:21][C@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Br)ccnc1Br
Reactant: C[C@H](N)CCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CCc1ccccc1)Nc1ccnc(Br)c1C#N
Yield: 60.2 %

Procedure:
Prepared according to the methods above using 2,4-dibromonicotinonitrile (100 mg, 0.382 mmol), (S)-1-Methyl-3-phenyl-propylamine (58.1 mg, 0.382 mmol) and Hunig's Base (0.080 mL, 0.458 mmol) in DMF (1.5 mL) at 120° C. for 30 min to give the desired product as a clear oil (76 mg). LC/MS (316/318, [M−H]/[M+H]+); 1H NMR (400 MHz, CHLOROFORM-d) δ 8.05 (d, J=5.5 Hz, 1H), 7.33-7.25 (m, 2H), 7.23-7.15 (m, 3H), 6.81 (d, J=5.3 Hz, 1H), 5.06 (br. s., 1H), 4.33 (dt, J=14.0, 6.9 Hz, 1H), 2.71 (t, J=8.0 Hz, 2H), 1.98-1.83 (m, 2H), 1.32-1.25 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]([CH:10]([CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12][C:13](O)=[O:14])[CH3:9])=[O:7].C(N(CC)CC)C.[NH2:45][C@H:46]([CH2:51][OH:52])[CH2:47][CH:48]([CH3:50])[CH3:49].C(P(=O)(OCC)OCC)#N>CN(C)C=O>[OH:52][CH2:51][C@@H:46]([NH:45][C:13](=[O:14])[CH2:12][CH2:11][CH:10]([N:8]([C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=1)[CH3:9])[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:47][CH:48]([CH3:50])[CH3:49]
Reactant: CC(C)C[C@H](N)CO
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)C(c1ccccc1)c1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO)NC(=O)CCC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 120 mg (0.23 mmol) of 4-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-5,5-diphenyl-pentanoic acid (example 32 h) and 45 μl (0.32 mmol) of triethylamine in 4 ml of N,N-dimethylformamide at 0° C. is treated with 36 μl (0.28 mmol) of (S)-leucinol, followed by 45 μl (0.28 mmol) of diethyl cyanophosphonate. After stirring for 4 h at room temperature, the reaction mixture is concentrated, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate solution. The aqueous layer is further extracted with ethyl acetate (3×). The organic layers are combined, dried with sodium sulfate and concentrated. The residue is then purified by flash chromatography (98:2 to 95:5 methylene chloride/methanol) to give the title compound as a white solid (mixture of diastereomers). TLC: methylene chloride/methanol (95:5) Rf =0.22, 0.19
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:25])[N:19]3[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18](=[O:25])[N:19]4[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]4)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[CH:30][C:29]=1[F:28])=[O:36]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n2ccccc12)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(=O)n4ccccc34)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 1-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-quinolizin-4-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a light yellow solid. MS (m/e)=534.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=1.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:33][CH2:32][CH2:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:8]
Reactant: Cc1cccc(CCN)c1
Reactant: COc1cccc(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)NCCc2cccc(C)c2)c1
Reaction time: 1 h

Procedure:
A solution of 3-methoxybenzoic acid (5.2 g, 0.034 mol) and carbonyldiimidazole (5.5 g, 0.034 mol) in THF (200 ml) was stirred in a flask protected from moisture. To this solution was added 4.6 g (0.034 mol) of 2-(3-methylphenyl)ethylamine in a small volume of THF. Stirring was continued for 1 h and then the reaction mixture was poured into 500 ml of water and extracted twice with 100 ml portions of methylene chloride. The methylene chloride solution was washed with 5% HCl, 10% Na2CO3, and water. Evaporation of this solution afforded the amide G1 (8.7 g, 94%) as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:4].C(Cl)(Cl)Cl.[Br:27]Br>N1C=CC=CC=1>[Br:27][C:8]1[S:7][C:6]([NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=1
Reactant: CCOC(=O)C(=CNc1sccc1C(=O)OC)C(=O)OCC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1sc(Br)cc1C(=O)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.3 parts of diethyl (3-methoxycarbonylthienyl)aminomethylenemalonate in a mixture of 20 parts by volume of chloroform and 4 parts by volume of pyridine, 0.6 part by volume of bromine is added dropwise. The solution is further stirred at room temperature for 15 minutes, after which the reaction mixture is washed with dilute hydrochloric acid, an aqueous sodium hydrogen carbonate solution and water, followed by drying over Na2SO4. The solvent is distilled off to give diethyl (5-bromo-3-methoxycarbonylthienyl)aminomethylenemalonate. Recrystallization from ethanol gives light-yellowish needles melting at 129°-130° C.
Reaction SMILES: [C:1](Cl)(=O)C.ClCC([NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)=O>CO>[CH3:1][O:21][C:19](=[O:20])[CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][C:10]([NH2:9])([CH3:23])[CH3:22])[CH:13]=1
Reactant: CC(C)(Cc1cccc(CC(=O)O)c1)NC(=O)CCl
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1cccc(CC(C)(C)N)c1
Yield: 87 %

Procedure:
Acetyl chloride (154.5 g, 1.97 mol) was added to a solution of {3-[2-(2-chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic acid (preparation 48), (20 g, 0.66 mol) in methanol (350 mL) and the mixture was heated under reflux for 18 hours. The reaction mixture was then concentrated in vacuo to afford the title compound as a brown oil in 87% yield, 154.5 g. 1H NMR (300 MHz, CDCl3) δ: 7.22 (1H, m), 7.18-7.05 (3H, m), 3.71 (3H, s), 3.58 (2H, s), 2.62 (2H, s), 1.12 (6H, s) ppm; GCMS m/z 206 [M−H]−.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.C(=O)([O-])O.[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:29])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccn2)c2cc(I)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: S=C1CN=C(c2ccccn2)c2cc(I)ccc2N1
Temperature: 105 °C
Reaction time: 3.5 h

Procedure:
A solution of 3.45 g of 7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2(1H)-one in 80 ml of hexamethylphosphoric acid triamide (HMPT) was treated with 4.24 g of Lawesson reagent and the mixture was stirred at 105° C. for 3.5 h. The reaction mixture was poured into 600 ml of saturated aqueous sodium hydrogen carbonate solution and 2 l of water. After stirring at room temperature for 30 min. the precipitate was filtered off. There were obtained 3.0 g of crude, yellow 7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione, m.p. 242° C., which was used in this form for the next step.