Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[C:22](=[O:27])[C:21]=4[C:28]=3[CH3:29])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.CO>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[CH:22]([OH:27])[C:21]=4[C:28]=3[CH3:29])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Yield: 89.9 %

Procedure:
Sodium borohydride (300 mg, 7.93 mmol) was added to a solution of 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine (740 mg, 1.88 mmol) obtained in Reference Example 13 in THF (7 ml) and methanol (7 ml) at room temperature and stirred for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted 1 N potassium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual crystals were washed with hexane to obtain 670 mg (yield 90%) of the title compound. mp. 159–161° C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].C(O)(C(F)(F)F)=O.[CH2:16]([O:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH3:17]>>[N+:5]([CH:4]=[CH:3][C:25]1[C:24]2[C:28](=[CH:29][C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:22][CH:23]=2)[NH:27][CH:26]=1)([O-:7])=[O:6]
Reactant: CN(C)C=C[N+](=O)[O-]
Reactant: CCOC(=O)c1ccc2cc[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(C=C[N+](=O)[O-])c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-dimethylamino-2-nitroethylene (1.93 g, 16.58 mmol) and TFA (110.0 ml) and stir until dissolved. Add 6-ethoxycarbonyl-1H-indole (3.14 g, 16.58 mmol) and stir at ambient temperature. After 1 hour, pour the reaction mixture into ice/water, extract with ethyl acetate, then evaporate to residue. Stir the residue in warm ethanol, cool to ambient temperature, then filter and dry to give the title compound as a dark yellow powder: mp 241° C. MS (ACPI): m/e 261.1 (M+1). Analysis for C13H12N2O4: Calcd: C, 60.00; H, 4.65; N, 10.76. found: C, 59.99; H, 4.63; N, 10.59.
Reaction SMILES: [NH:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:2]([C:15](OC)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C1COCC1.O>[NH:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:2]([CH:15]=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccc(OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
All four stereoisomers of 3 were synthesized according to the following procedure: To a stirred solution of Boc-D-Tyr(tBu)-OMe (2.2 g, 6.3 mmole) in toluene/THF (1:1, 20 mL) at −78° C. under N2 was added DIBAL-H (1.5 M in toluene, 10.4 mL, 15.7 mmole) dropwise over 30 minutes. The reaction was stirred for 30 minutes, then quenched by the slow addition of MeOH (1.3 mL, 31.5 mmole) and warmed to room temperature. Rochelle's salt (9 g, 31.5 mmole) in water (50 mL) was added, and the mixture was stirred for 1 hour, then filtered and extracted with ether (50 mL). The ether extract was dried over MgSO4, filtered, and concentrated under vacuum to give Boc-D-Tyr(tBu)-H.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][C:8]2([CH2:13][CH:12]([CH2:14][CH2:15][CH2:16][CH3:17])C(=O)[C:10]2=[O:19])[C:7](=[O:20])C1=O)[CH2:2][CH2:3][CH3:4].Cl.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>NC1C=CC=CC=1>[CH2:14]([CH:12]1[CH2:13][C:8]2([CH2:9][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:7]2=[O:20])[C:10](=[O:19])[N:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Nc1ccccc1
Reactant: CCCCC1CC2(CC(CCCC)C(=O)C2=O)C(=O)C1=O
Agent: Cl
Product: CCCCC1CC2(CC(CCCC)N(c3ccccc3)C2=O)C(=O)N1c1ccccc1
Yield: 86 %

Procedure:
A mixture of 53.6 g (0.02 mole) of 3,8-dibutyl-2,7-dioxospiro-[4.4]nonane-1,6-dione, 10.32 g (0.08 mole) of aniline hydrochloride and 40 ml of aniline was placed in a 500 ml round bottom flask and heated to reflux. After refluxing for 6 hours, the aniline was removed by distillation at reduced pressure. The resulting mixture was subjected to column chromatography employing a 2:1 mixture of diethyl ether and petroleum ether as eluent. The product, 3,8-dibutyl-2,7-diphenyl-2,7-diazaspiro[4.4]nonane-1,6-dione, was isolated as a viscous oil in a yield of about 86%. The infrared, 13C-NMR and mass spectra of the product were consistent with this structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH3:13].[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24](Cl)[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:14][C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[CH:11][N:10]=[C:9]3[CH3:13])=[C:2]([F:1])[CH:3]=2)[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nccn1-c1ccc(N)cc1F
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-n3ccnc3C)c(F)c2)n1

Procedure:
The title compound was prepared from 3-fluoro-4-(2-methyl-imidazol-1-yl)-phenylamine (87 mg, 0.46 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (100 mg, 0.46 mmol) in analogous manner to the procedure described in example 1e). Obtained as a light yellow oil (140 mg, 82%).
Reaction SMILES: CS([Cl:5])(=O)=O.C(N1CCNCC1)=O.C([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)=O.Cl>C(N(CC)CC)C.C(Cl)Cl>[CH3:25][S:22]([N:19]1[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]1)(=[O:24])=[O:23].[ClH:5]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CCN(C=O)CC1
Agent: Cl
Agent: O=CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (3.65 ml) was added to a methylene chloride (50 ml) solution containing N-formylpiperazine (5.08 g) and triethylamine (6.85 ml) under ice-cooling, and the mixture was stirred at room temperature for 18 hours to undergo reaction, thereby obtaining 1-formyl-4-methanesulfonylpiperazine. This compound was acid-treated with hydrochloric acid to obtain 1-methanesulfonylpiperazine•hydrochloride. Also, 1-(phenylsulfonyl)piperazine•hydrochloride was obtained in the same manner as mentioned above by using the corresponding starting material.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2C#N)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:14][C:15]([C:10]([CH3:17])([CH3:11])[CH3:9])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1COc1cc(Br)cnc1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(COc2cc(-c3ccc(C(=O)O)cc3)cnc2N)cc1
Temperature: 88.5 °C
Yield: 160.6 %

Procedure:
2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 26.8 mmol), 4-carboxybenzeneboronic acid (4.9 g, 30.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13.1 g, 95 mmol), dimethylformamide (72 mL), and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 96° C. over a period of 2 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.8, product at Rf 0.5 and an impurity at Rf 0.4. The mixture was cooled to 45° C. and filtered to remove the solids. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and 4 g of Celite and 2 g of Norit were added. The solids were collected by vacuum filtration through 4 g of Celite, washed with 30 mL of ethanol:water 1:1 and discarded The filtrate was cooled in an ice bath and acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL water and dried under vacuum to give 8.1 g (80% yield) 4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoic acid as a dark solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([O:6][C:7]1[N:8]=[C:9]([CH3:24])[C:10]2[C:15]([C:16]=1[N+:17]([O-])=O)=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[O:5])[CH3:2]>CO.[Pd]>[NH2:17][C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[C:13]([O:20][CH3:21])[CH:14]=2)[C:9]([CH3:24])=[N:8][C:7]=1[O:6][C:4](=[O:5])[N:3]([CH2:25][CH3:26])[CH2:1][CH3:2]
Reactant: CCN(CC)C(=O)Oc1nc(C)c2cc(OC)c(OC)cc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C(=O)Oc1nc(C)c2cc(OC)c(OC)cc2c1N

Procedure:
A slurry of 3-(diethylcarbamyloxy)-6,7-dimethoxy-1-methyl-4-nitroisoquinoline (500 mg, 1.38 mmol) in methanol (50 mL) was hydrogenated in a Parr hydrogenator over 10% Pd/C (100 mg) for 4 hours. The reaction mixture was filtered through a celite pad, the solids were washed with methanol and the combined filtrate and washings were evaporated to dryness in vacuo to yield a yellow solid residue. One recrystallization from methylene chloride/ether afforded pure title compound (437 mg, 95.3%), mp 206°-207° C. IR (KBr) 3455, 3340, 3220, 1720, 1655, 1495, 1440, 1265, 1160 cm-1 ; NMR (CDCl3): δ 1.25 and 1.30 (two partly superimposed br t, 6H, N(CH2CH3)2 ], 2.67 (s, 3H, 1-CH3), 3.20-3.70 [br m, 4H, N(CH2CH3)2 ], 3.93 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.82 (s, 1H, 5- or 8-H), 6.93 (s, 1H, 5- or 8-H); MS (DCI): 334 (MH)+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:8].[Na+].[I-:24]>CC#N>[I:24][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:8]
Reactant: C[C@H](CSC(=O)OCCCCCl)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](CSC(=O)OCCCCI)C(=O)N1CCC[C@H]1C(=O)O
Yield: 102 %

Procedure:
1-[(2S)-3-(4-chlorobutoxycarbonyl)mercapto-2-methyl-1-oxopropyl]-L-proline (5.80 g, 0.0157 Mol) was dissolved in CH3CN (100 ml) and NaI (23.9 g, 0.160 Mol) was added to the solution. The mixture was refluxed for 7 h, then concentrated and diluted with CH2Cl2. The solid formed was filtered off and the organic phase was washed with H2O (3×50 ml), dried over sodium sulphate and evaporated under reduced pressure affording 1-[(2S)-3-(4-iodobutoxycarbonyl) mercapto-2-methyl-1-oxopropyl]-L-proline (7.10 g) as an oil that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:41]([O:43][C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45])[CH3:42].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:41]([O:43][C:44]([N:46]1[CH2:47][CH2:48][N:49]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:50][CH2:51]1)=[O:45])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a solution of 2 g of (S)-2-tert-Butoxycarbonylamino-4-methanesulfonyl-butyric acid, 3.2 g of NEM and 2.3 g of TOTU in 10 ml of DMF, 1.2 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 2 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution and extracted with 400 ml of ethyl acetate. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.9 g.
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([P:1]([Cl:4])[Cl:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccccc1
Reactant: ClP(Cl)Cl
Product: ClP(Cl)c1ccccc1

Procedure:
8800 g (64 mols) phosphorus(III)chloride, 780 g (10 mols) benzene and 1361 g (10 mols) anhydrous aluminum chloride of 98% strength were boiled for 5 hours under reflux in a reactor provided with a stirrer and reflux condenser. Next, 1535 g (10 mols) phosphorus oxychloride was added dropwise within 30 minutes. After a post-reaction period of 30 minutes, the whole was cooled to 25° C., the formed aluminum chloride/phosphorus oxychloride-complex was filtered off and washed with phosphorus(III)chloride. 3128 g crystalline matter moist with PCl3 was obtained (theoretically: 1535 g POCl3 +1361 g AlCl3 =2896 g). Phosphorus(III)chloride in excess and unreacted benzene were expelled from the filtrate under atmospheric pressure and the residue was distilled under vacuum. 1561 g phenyldichlorophosphane (bp: 95° C. at 25 millibars) was obtained. Yield: 0.87 mol C6H5PCl2 per mol AlCl3.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH3:18][C:19]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Si:7]([O:6][CH2:5][C:4]1[C:3]([F:17])=[C:2]([N:28]2[CH2:29][CH2:30][N:25]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[CH:24]=3)[CH2:26][CH2:27]2)[CH:16]=[CH:15][CH:14]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1F
Reactant: Cc1cc(N2CCNCC2)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)CC2)ccn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
[(3-Bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (300 mg) was mixed with toluene (6 ml), and 1-(2-methylpyridin-4-yl)piperazine (200 mg), Pd2(dba)3 (43 mg), BINAP (88 mg), and sodium tert-butoxide (135 mg) were added thereto, followed by stirring at 80° C. for 5 hours. After cooling to room temperature, filtration was carried out by the addition of CHCl3 and Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/28% aqueous ammonia/MeOH/) to obtain 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4-(2-methylpyridin-4-yl)piperazine (259 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[O:20][CH:19]=[N:18][CH:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.II.[Br-].[CH2:30]([Zn+])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[O:20][C:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:18][CH:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Cc1nc(-c2cnco2)sc1C(=O)NCc1ccccc1
Agent: II
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nc(-c2cnc(Cc3ccccc3)o2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To a solution of N-benzyl-4-methyl-2-(oxazol-5-yl)thiazole-5-carboxamide (0.20 g, 0.67 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium (0.88 mL of 1.6 M solution in hexanes, 1.40 mmol) at −78° C. The reaction mixture was stirred for 30 minutes, and iodine (0.17 g, 0.67 mmol) was added. The reaction was slowly warmed to ambient temperature over 4 hours and stirred for another 18 hours. Tetrakis-(triphenylphosphine)palladium (0.04 g, 0.03 mmol) and benzylzinc bromide (2.5 mL of 0.5 M solution in tetrahydrofuran, 1.25 mmol) were added. The reaction mixture was heated to 50° C. for 17 hours, cooled to ambient temperature, added saturated ammonium chloride solution (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in 5% yield (0.02 g): mp 141-142° C.; 1H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 7.44-7.15 (m, 10H), 6.07 (t, J=5.6 Hz, 1H), 4.61 (d, J=5.6 Hz, 2H), 4.34 (s, 2H), 2.74 (s, 3H); MS (ES+) m/z 390.2 (M+1).
Reaction SMILES: Cl[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:3][CH:4]=O.[NH2:12][C:13]1[C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][NH:15][N:14]=1>C(O)(=O)C>[C:20]1([C:18]([C:17]2[CH:16]=[N:15][N:14]3[C:2]([C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:3][CH:4]=[N:12][C:13]=23)=[O:19])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=CC=C(Cl)c1ccccc1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-chloro-3-phenyl-2-propenal and 0.01 mole of (3-amino-1H-pyrazol-4-yl)phenyl-methanone in 25 ml of acetic acid was refluxed for 6 hours. The solvent was removed in vacuo and the product isolated as described in Example 1, giving the desired product as crystals, mp 163°-165° C.
Reaction SMILES: [CH2:1]([NH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)[CH3:2].Cl[C:21]1[C:22]2[CH:29]=[CH:28][N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:23]=2[N:24]=[CH:25][N:26]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH2:1]([N:3]([C:21]1[C:22]2[CH:29]=[CH:28][N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:23]=2[N:24]=[CH:25][N:26]=1)[C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:5]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CCN[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of (S)-benzyl 3-(ethylamino)piperidine-1-carboxylate (200 mg, 0.76 mmol), 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (234 mg, 0.76 mmol) and DIEA (0.27 mL, 1.52 mmol) in DMF (3 mL) was heated to 100° C. for 4 h. The reaction was cooled to rt, diluted with ice cooled water (10 mL) and extracted with EtOAc (3×25 mL). The combined EtOAc layer was dried over Na2SO4 and concentrated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient 0-10% EtOAc hexane) to afford the titled intermediate (300 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J=5.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.95 (s, 1H), 7.58-7.57 (m, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.39-7.29 (m, 5H), 5.12 and 5.09 (2s, 2H), 4.69-4.63 (m, 1H), 4.05-3.98 (m, 3H), 3.65-3.63 (m, 2H), 3.01-2.77 (m, 1H), 2.36 (s, 3H), 1.89-1.75 (m, 3H), 1.51-1.39 (m, 1H), 1.17 (t, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=534.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=1)[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7].[CH:25]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][CH:38]([CH3:40])[CH3:39])[CH:36]=1)[CH:32]=O)([CH3:27])[CH3:26].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH:38]([O:37][C:35]1[CH:34]=[C:31]([CH:30]=[C:29]([O:28][CH:25]([CH3:27])[CH3:26])[CH:36]=1)[CH2:32][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:15]=[C:16]([O:18][CH2:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13]1)([CH3:39])[CH3:40]
Reactant: COc1cc(OCc2nnn[nH]2)cc(C(=O)NC2CCNCC2)c1
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCc2nnn[nH]2)cc(C(=O)NC2CCN(Cc3cc(OC(C)C)cc(OC(C)C)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 3-methoxy-N-piperidin-4-yl-5-(1H-tetrazol-5-ylmethoxy)-benzamide (example 170c) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 539.4 (MH+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][P:5]([O-:12])[O:6][CH2:7][C:8]([F:11])([F:10])[F:9].[H-].[Na+].CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>C1COCC1>[CH3:33][N:32]([CH3:34])[C:30](=[O:31])[CH2:29][P:5](=[O:12])([O:6][CH2:7][C:8]([F:11])([F:9])[F:10])[O:4][CH2:3][C:2]([F:1])([F:13])[F:14]
Reactant: CN(C)C(=O)CBr
Reactant: [O-]P(OCC(F)(F)F)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Temperature: 10 °C
Yield: 34 %

Procedure:
Bis(2,2,2 trifluoroethyl)phosphite (5.0 mmol, 0.79 mL) was added to a solution of sodium hydride (0.420 g, 0.018 mol) and HMPA (8.6 mmol, 1.5 mL) at 10° C. in THF (20 mL). Immediately after addition, 2-bromo-N,N-dimethylacetamide (3.9 mmol) was added dropwise. The reaction temperature was maintained at 10° C. for 4.5 hours. The reaction was then quenched with saturated aqueous ammonium chloride (2 mL) and standard aqueous work-up was performed. Final purification by flash column chromatography (silica gel, 80% hexane, 20% ethyl acetate) yielded the desired compound (34%) as a colorless oil. c). To a solution of potassium tert-butoxide (705 mg, 6.33 mmol) in anhydrous THF (25 mL) at 0° C., bis(2,2,2-trifluoroethyl)phosphite (1.00 mL, 6.33 mmol) was added. 2-bromo-N,N-dimethylacetamide (12.66 mmol) was then added by syringe. Upon completion of the addition step, the reaction was allowed to proceed for one hour with monitoring by TLC. The reaction was then quenched with a saturated solution of aqueous ammonium chloride (20 mL). The aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic extracts were washed with water (3×20 mL) and with a saturated sodium chloride solution (1×20 mL). The solvent was removed by rotary evaporation and the crude material was further concentrated under oil pump vacuum. The final product was purified by column chromatography (silica gel, 2:1 hexanes/ethyl acetate) yielding the desired compound (41%). (ii) From bis-(2,2,2-trifluoroethyl)phosphonoacetic acid.