Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.[OH-].[Na+]>CO.[Pd]>[C:8]([C:5]1[N:4]=[C:3]([C:12]([OH:14])=[O:13])[CH:2]=[CH:7][N:6]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ncc(Br)c(C(=O)O)n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1nccc(C(=O)O)n1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A mixture of 5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid (1.65 g, 6.37 mmol) and aqueous sodium hydroxide (1.0 N, 19.1 mL, 19.1 mmol) in methanol (100 ml) was treated with a catalytic amount of 10% palladium on carbon. The mixture was degassed under vacuum/nitrogen, then hydrogenated at 50 psi for 2 hours. The catalyst was removed by filtration, the methanol was removed under vacuum, and the aqueous was acidified by the addition of 1.0 N aqueous hydrochloric acid (40 mL). The resulting suspension was extracted with ethyl acetate (4×50 mL), the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in-vacuo to yield 1.06 g of 2-tert-butylpyrimidine-4-carboxylic acid as a white powder. MS (ES+)=181 (M+H+).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:14])[CH:11]([C:29](=[O:30])[NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]#[N:13])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1cccc1C(=O)CC#N
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
The solution of 2.5 g of 1-isobutyl-β-oxo-2-pyrrolpropionitrile in 30 ml of toluene and 1.6 g of triethylamine is treated with 1.6 g of phenylisocyanate while stirring. After standing overnight the mixture is filtered and the residue dissolved in 5% aqueous sodium hydroxide. The solution is filtered, acidified with 5 N hydrochloric acid and extracted with diethyl ether-ethyl acetate. The organic solution is washed with water, dried, evaporated, the residue triturated with ethanol and recrystallized from methanol, to give the 1-isobutyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 134°-136°.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]([C:15]#[N:16])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:23]([C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[CH2:26]([C:25]([C:23]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:10][C:11]([C:15]#[N:16])=[N:12]3)=[CH:7][CH:6]=2)[CH:24]=1)([OH:30])[CH2:28][CH3:29])[CH3:27]
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CN=[N+]=[N-])cc2n1
Reactant: C#CC(O)(CC)CC
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cn(Cc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 7-(azidomethyl)-4-phenylquinoline-2-carbonitrile (100 mg, 0.35 mmol), 3-ethylpent-1-yn-3-ol (47 mg, 0.42 mmol), copper iodide (100 mg, 0.52 mmol) and diisopropylethylamine (305 μL, 1.75 mmol) in THF (4 mL) was stirred at rt for 6 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 398 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]2=[O:23].FOBOF.[CH2:29]([N:36]1[CH2:41][CH:40]2[CH2:42][CH:37]1[CH2:38][NH:39]2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>CS(C)=O.CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:39]1[CH2:38][CH:37]3[CH2:42][CH:40]1[CH2:41][N:36]3[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[N:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]2=[O:23]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Agent: FOBOF
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(N3CC4CC3CN4Cc3ccccc3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a solution of 1.5 g (4 m Mol) of the mixed anhydride of 6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with difluoroboronic acid in 10 ml of dimethylsulfoxide was added 0.9 g (4.78 m Mol) 2-benzyl-2.5-diazabicyclo(2.2.1)heptane and 0.4 g (4 m Mol) of triethylamine. After stirring for 4 hrs at room temperature, 150 ml of ether was added and the crystals that formed were collected by filtration. The residue was heated in a mixture of 60 ml dioxane and 90 ml 1.5N NaOH and heated at 100° C. for 1 hr. The hot solution was filtered to removed non-dissolved material. The solution was neutralized with conc HCl and the resultant crystals collected, washed with water and left to dry in the air. After recrystallization from DMF, 1.23 g (63%) of the product was obtained, mp 275° -280° dec.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 48.7 %

Procedure:
In a 500 mL round-bottomed flask, 5-bromo-2-nitropyridine (6.56 g, 32.3 mmol, Eq: 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g, 32.3 mmol, Eq: 1.00) were combined with dioxane (160 ml) to give a light yellow solution. Cs2 CO3 (21.1 g, 64.7 mmol, Eq: 2) and water (6 ml) were added. The reaction mixture was degassed with argon before bis(triphenylphosphine)palladium(II) dichloride (2.27 g, 3.23 mmol, Eq: 0.1) was added. The reaction mixture was heated to 80° C. and stirred for 15 h. The reaction mixture was poured into 500 mL H2O and extracted with EtOAc (3×200 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 10% to 40% EtOAc in hexanes) to afford a pink solid. The resulting solid was triturated with ether to afford the desired product as a solid (4.8 g). The filtrate from the trituration and mixed fractions from the first chromatography were combined and purified by flash chromatography (silica gel, 220 g, 20% to 40% EtOAc in hexanes) affording additional product (2.2 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9 H) 2.59 (d, J=1.52 Hz, 2 H) 3.72 (t, J=5.56 Hz, 2 H) 4.19 (d, J=3.03 Hz, 2 H) 6.35 (br. s., 1 H) 7.97 (dd, J=8.46, 2.40 Hz, 1 H) 8.27 (d, J=8.34 Hz, 1 H) 8.67 (d, J=2.27 Hz, 1 H).
Reaction SMILES: [CH3:1][CH:2]([NH:5][CH3:6])[CH2:3][CH3:4].[Cl:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[C:9](Cl)=[O:10].Cl>O1CCOCC1>[CH3:1][CH:2]([N:5]([CH3:6])[C:9](=[O:10])[CH:8]([Cl:7])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:3][CH3:4]
Reactant: CCC(C)NC
Reactant: O=C(Cl)C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CCC(C)N(C)C(=O)C(Cl)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Yield: 64.2 %

Procedure:
While stirring, 15.2 g of N-2-butyl-N-methylamine is dripped into a solution of 22.4 g of α-chloro-α-(2,4-dichlorophenyl)-acetyl chloride (see a)) in 100 ml of dioxane. After the exothermic reaction has subsided, the mixture is stirred overnight and then poured into 700 ml of ice water; the resultant mixture is acidified with dilute hydrochloric acid and the oil which has precipitated is extracted 8 times, each time with 100 ml of dichloromethane. The extracts are combined, dried over magnesium sulfate and concentrated; there is obtained 17.2 g of α-chloro-α-(2,4-dichlorophenyl)-acetic acid-N-2-butyl-N-methyl amide as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][C:12](=O)[NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1.B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C1SCC(=O)Nc2c1c(-c1ccccn1)nn2C
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 4-(4-bromo-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (2.92 g, 6.8 mmol) in anhydrous THF (50 mL) was added a solution of borane THF complex (27.2 mL, 1M in THF, 27.2 mmol, Acros) at about 0° C. Subsequently, the mixture was stirred at rt, overnight. After cooling to about 0° C., HCl (5 M aq, 20 mL) was added dropwise and the mixture was stirred for about 30 min at rt, then the solution was brought to about pH=7 with 2 M aq NaOH, at about 0° C. The resulting mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate) to give 4-(4-bromo-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e]-[1,4]thiazepine (2.1 g, 5.0 mmol, 74%) as an off white solid: LC-MS (Table 1, Method e) Rt=8.32 min, m/z 415 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.58 (3H, s) 2.69 (1H, ddd, J=15.0, 6.0, 2.0 Hz) 2.86 (1H, ddd, J=15.0, 9.0, 2.5 Hz) 3.21-3.31 (1H, m) 3.57-3.65 (1H, m) 3.79 (1H, br s) 3.83 (3H, s) 6.65 (1H, s) 7.04-7.09 (2H, m) 7.14 (1H, dd, J=8.5, 2.0 Hz) 7.31 (1H, d, J=2.0 Hz) 7.59 (1H, td, J=7.5, 2.0 Hz) 7.80 (1H, br.d, J=8.0 Hz) 8.45 (1H, br.d, J=5.0 Hz).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][Si:9]([CH3:12])([CH3:11])Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:8][Si:9]([CH3:12])([CH3:11])[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)Cl
Reactant: OC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C[Si](C)(C)OC1CCCCC1

Procedure:
1 mole of cyclohexanol, 1.5 moles of trimethylchorosilane and 0.0005 moles of tetra-n-butyl ammonium bromide were reacted at the reflux temperature (54°-97° C.) as in Example 1 and then worked up by distillation.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C:11]=1[CH:28]=O>CN(C)C=O>[C:16]1([C:13]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=[CH:15][C:10]3[C:11](=[CH:28][NH:2][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=CC1=C(Cl)C=CC(c2ccccc2)(c2ccccc2)C1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]cc2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 20 °C
Yield: 16 %

Procedure:
0.307 g of ethyl glycinate hydrochloride is added to a suspension of 0.589 g of 2-chloro-5,5-diphenylcyclohexa-1,3-dienecarbaldehyde in 20 cm3 of N,N-dimethylformamide. The reaction mixture is refluxed for about 20 hours. After cooling to a temperature in the region of 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 100 cm3 of ethyl acetate, washed with three times 50 cm3 of water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After purification by flash chromatography on a column of silica [eluent: dichloromethane], 0.11 g of ethyl 5,5-diphenyl-4,5-dihydro-2H-isoindole-1-carboxylate is obtained in the form of a brown solid, the characteristics of which are as follows:
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:23][C@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:31])[NH2:30].Cl.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl.C(OCC)(=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([NH:23][C@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:30])[NH2:31])=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a stirred solution of Boc-L-Trp-OH (761 mg, 2.5 mmoles), H-L-Arg-OMe dihydrochloride (718 mg, 2.75 mmoles), HOBt (1378 mg, 9 mmoles) and DIPEA (2.05 ml, 12 mmoles) in DMF (5 ml) and dichloromethane (2 ml) cooled on ice was added HBTU (1138 mg, 3 mmoles) in small portions over 10 minutes. The mixture was stirred on ice for 1 hour, 40 ml ethyl acetate was added and the organic phase washed successivly with 3×40 ml saturated NaHCO3, 2×30 ml 5% citric acid, 50 ml water and 2×30 ml brine. Evaporation afforded 1.1 g of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@@H](C(O)=O)CC(O)=O.[K+].[Br-]>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: N[C@H](CC(=O)O)C(=O)O
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)O1
Yield: 80 %

Procedure:
N-(Benzyloxycarbonyl)-D-aspartic anhydride (25) is prepared from N-(benzyloxycarbonyl)-D-aspartic acid (24) by the method of McGarvey et al. (G. J. McGarvey et al., J. Amer. Chem. Soc., 1986, 108, 4943) with an overall yield of 80% with respect to D-aspartic acid (D-23). The melting point is 126-127° C. [α]D+26° (c 1.22, MeOH). Infrared (KBr): 1529, 1697 (O—CO—N), 1781 and 1866 (anhydride).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[CH2:43][NH:42][CH2:41][CH2:40][N:39]2[CH2:44][CH2:45][CH2:46][C@@H:38]12.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:43][CH2:37][C@@H:38]4[CH2:46][CH2:45][CH2:44][N:39]4[CH2:40][CH2:41]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1C[C@H]2CCNCCN2C1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@@H]3CCCN3CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 44.9 %

Procedure:
A 8 ml sealed vial was charged with 60 mg (0.112 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl) -3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 47 mg (0.335 mmol) of (9aS) -octahydro-1H -pyrrolo[1,2-d][1,4]diazepine (D6), 31 mg of potassium carbonate (0.224 mmol); the reagents were dissolved in 0.5 ml of DMSO. The reaction mixture was heated at 150° C. overnight and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 1:1, to ethyl acetate 100% and affording 32 mg of the title compound as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[OH-].[Na+].O>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:25])[F:26]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(Cc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
To a mixed solution of the compound (270 mg, 0.66 mmol) obtained in Example 40a in ethanol/tetrahydrofuran (v/v=1/1, 8 ml) was added 2N aqueous sodium hydroxide solution (2.0 mL, 4.0 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethanol-hexane) to give the title compound (67 mg, 18%) as pale-yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.Br[C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][N:29]=1.OC(C1C=CN=C(C2C=NC(N3C4C(=CC=C(C(N5CCOCC5)=O)C=4)C(SC)=C3)=NC=2)C=1)(C)C>>[Cl:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]5[CH2:20][CH2:21][O:22][CH2:23][CH2:24]5)=[O:18])[CH:15]=4)[C:10]([S:25][CH3:26])=[CH:9]3)=[N:6][CH:7]=2)[CH:33]=1
Reactant: Clc1ccnc(Br)c1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: CSc1cn(-c2ncc(-c3cc(C(C)(C)O)ccn3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CSc1cn(-c2ncc(-c3cc(Cl)ccn3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Coupling of (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino) methanone and 2-bromo-4-chloropyridine analogously in an analogous manner as described for 289a). White solid. Yield: 1.7 g (79% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:27][C:28]3[CH:35]=[CH:34][C:31]([CH3:32])=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(C)cc2)CC1
Yield: 98.3 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 4-methylbenzaldehyde (0.69 g) were reacted and treated in the same manner as in Example 121 to give 2.5 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-methylbenzylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:28]([S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O)([CH3:31])([CH3:30])[CH3:29].C(=O)(O)[O-].[Na+]>CCOCC>[C:28]([S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=[CH2:2])([CH3:31])([CH3:30])[CH3:29]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)Sc1ccccc1C=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Product: C=Cc1ccccc1SC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl triphenylphosphonium iodide (1.57 g, 3.88 mmol) was dissolved in 25 ml ether in a 50 mL round-bottomed flask under dry nitrogen. To the mixture was added in one portion at 0° C. potassium tert-butoxide (0.47 g, 4.19 mmol) and it was stirred for 10 min at room temperature. 2-(tert-butylsulfanyl)benzenecarbaldehyde (2.77 mmol) was added in one portion at 0° C. and the reaction mixture was stirred until complete disappearance of the reactants (24 hr) at room temperature (followed by TLC). The mixture was added to 50 mL of saturated sodium bicarbonate solution, followed by extraction with 3×50 ml portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using petroleum ether 60-80 as eluent. 0.37 g, 70%, colorless oil. 1H NMR (200 MHz, CDCl3): δ 1.26 (s, 9H), 5.28 (dd, J1=11.0, J2=1.2, 1H), 5.68 (dd, J1=17.8, J2=1.2, 1H), 7.17-7.67 (m, 5H) ppm.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[NH:66][C:67](=[O:69])[CH3:68])[CH:57]=[CH:58][CH:59]=1>CN(C=O)C>[C:67]([NH:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([NH:53][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:55]=1)(=[O:69])[CH3:68]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: CC(=O)Nc1ccccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1-c1cccc(NC(=O)c2cc3cccc(OC(F)(F)F)c3oc2=O)c1
Temperature: 25 °C
Yield: 25.1 %

Procedure:
DIEA (0.013 mL, 0.073 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, N-(3′-Amino-biphenyl-2-yl)-acetamide (0.015 g, 0.066 mmol) was added and allowed to react overnight and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.008 g of product in 26% yield: LCMS (ESI) m/z 483 (MH+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Cl:16][C:17]1[C:18]([O:35][CH2:36][CH3:37])=[C:19]([C:32](=O)[CH3:33])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:31])[CH3:30]>>[Cl:16][C:17]1[C:18]([O:35][CH2:36][CH3:37])=[C:19](/[C:32](/[CH3:33])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:30])[CH3:31]
Reactant: CCOc1c(C(C)=O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Cl)c1OCC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (1.8 mL, 8.64 nmol) and 1-(8-chloro-4-isopropyl-7-ethoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 145, 930 mg, 2.88 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).