Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To 6-formyl-indole-1-carboxylic acid tert-butyl ester (1.2 g) in methanol (5 mL) in an ice bath was added sodium borohydride (0.27 mg) portion wise. The reaction was allowed to warm to room temperature over 1.5 hr. The reaction diluted with ethyl acetate (200 mL) washed with water (200 mL), brine (100 mL), dried over sodium sulfate, concentrated, adsorbed onto silica gel and purified by flash chromatography with a gradient from 5-40% ethyl acetate in hexanes to yield 6-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester as a clear viscous oil (0.91 g, 78%) LC-MS (ES) calculated for C14H17NO3, 247.1; found m/z 246 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-pyridyl)piperazine (9.78 g), ethyl 4-fluorobenzoate (9.7 ml) and powdered potassium carbonate (9.9 g) in dried dimethylsulphoxide (60 ml) was heated at 95° C. for 18 hours. The mixture was poured into water (1200 ml) and stirred for 30 minutes. The precipitate was filtered off, washed with water and dried. The solid was purified by flash column chromatography on alumina (ICN alumina N32-63) using 1% methanol/dichloromethane as eluent, to give ethyl 4-[4-(4-pyridyl)-1-piperazinyl]benzoate (4.85 g) as a cream solid, mp 162-164° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:31])[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]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([C:4]2[CH:5]=[CH:6][C:7]([C:18]([N:26]3[CH2:27][C:23]([F:31])([F:22])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5 g)) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=404.5 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]([CH2:18][CH3:19])[C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]([CH2:18][CH3:19])[C@H:8]([O:17][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC[C@H](Oc1ccc(Br)cc1)[C@H](O)CCc1cccnc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Yield: 40 %

Procedure:
To a solution of (3R,4S)-4-(4-bromophenoxy)-1-pyridin-3-yl-hexan-3-ol (1.34 g, Example 87d)) in dry N,N-dimethylformamide (30 ml) was added tertbutyldimethylsilyl chloride (0.80 g) and imidazole (0.77 g) and the resulting solution heated at 50° C. for 20 hours. The solution was concentrated in vacuo. The residue was made basic by addition of saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate:isohexane (1:1) to give the sub-title compound as an oil (0.71 g).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: COc1cc(CCc2cnc3[nH]c(-c4cnc(N)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (from Boron Molecular). LCMS calculated for C20H11N6O2 (M+H)+: m/z=377.2. Found 377.1.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[F:4].[N-:12]=[N+:13]=[N-:14].[Na+]>CS(C)=O>[N:12]([CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[F:4])=[N+:13]=[N-:14]
Reactant: Fc1cccc(C(F)CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(F)c1cccc(F)c1
Temperature: 65 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
To a solution of 11 (2.3 g, 10.5 mmol) in dry DMSO (15 mL) was added NaN3 (1.0 g, 15.7 mmol). The reaction solution was allowed to stir at 65° C. for 4 h then cooled to room temperature. The reaction mixture was partitioned between EtOAc (300 mL) and H2O (200 mL). The organic layer was washed with H2O (200 mL), brine (200 mL), and dried over Na2SO4. The solvents were removed by rotary evaporation and the crude product was purified by flash column chromatography (EtOAc/hexanes, 1:18-1:9) to yield 12 (1.6 g, 85%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 3.40-3.50 (dd, J=3.0, 13.5, 0.5H), 3.50-3.60 (dd, J=3.0, 13.5 Hz, 0.5H), 3.60-3.75 (m, 1H), 5.50-5.60 (dd, J=3.0, 8.0 Hz, 0.5H), 5.65-5.80 (dd, J=3.0, 8.0 Hz, 0.5H), 7.00-7.20 (m, 3H), 7.30-7.50 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 55.9, 56.1, 91.82, 91.84, 93.2, 93.3, 112.78, 112.84, 112.96, 113.03, 116.19, 116.20, 116.36, 116.38, 121.24, 121.27, 121.30, 121.33, 130.7, 130.8, 139.09, 139.15, 139.25, 139.31, 162.1, 164.1; GC-MS calcd for C8H7F2N3 183. found 183.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[Cl:24][C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(Cl)c2)c2ccccc21
Product: NC1=NC(c2cccc(-c3cncnc3)c2)(c2ccnc(Cl)c2)c2ccccc21
Yield: 51 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-chloropyridin-4-yl)-1H-isoindol-3-amine (Example 120) as described in Example 67 Scheme #10, D in 51% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.18 (s, 1 H), 9.04 (s, 2 H), 8.31 (d, J=5.30 Hz, 1 H), 8.06-7.94 (m, 1 H), 7.89-7.81 (m, 1 H), 7.72-7.65 (m, 2 H), 7.57-7.45 (m, 4 H), 7.38 (dd, J=5.31, 1.52 Hz, 1 H), 7.36-7.33 (m, 1 H), 7.01 (br s, 2 H); MS (ESI) m/z 398 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[N:10][C:11]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=1)([OH:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[Cl:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:18]([NH:17][C:11]1[N:10]=[CH:9][C:8]([C:5]([OH:7])([CH3:6])[C:4]([OH:30])=[O:3])=[CH:13][C:12]=1[O:14][CH2:15][CH3:16])=[O:19])=[CH:28]2
Reactant: CCOC(=O)C(C)(O)c1cnc(NC(=O)c2cc3cc(Cl)ccc3[nH]2)c(OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(C(C)(O)C(=O)O)cnc1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To an ethanol (24 mL) slurry of 2-{6-[(5-chloro-1H-indole-2-carbonyl)-amino]-5-ethoxy-pyridin-3-yl}-2-hydroxy-propionic acid ethyl ester (1.2 g) was added 1N NaOH, and the reaction mixture was shaken for 1 hr. The reaction mixture was filtered, the filtrate was acidified with 1N HCl, and then evaporated to yield 190 mg of the title compound. LC/MS+=404.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:14](O)=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=CC2N(O)N=NC=2C=1.[NH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40]>CN(C=O)C>[C:5]([O:9][C:10](=[O:11])[NH:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=1)[C:14]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[O:15])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(N)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(CO)NC(=O)C(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
360 mg (1.88 mmol) of EDC were added to a mixture of 400 mg (1.25 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 254 mg (1.88 mmol) of HOBt in 10 ml of DMF, and the mixture was stirred at RT for 20 min. The resulting solution was added dropwise to a solution of 168 mg (1.88 mmol) of 2-amino-2-methyl-1-propanol in 2 ml of DMF. The reaction mixture was stirred at RT for 20 min. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 364 mg (74% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].[CH3:32]I.O>O1CCCC1>[CH3:32][N:3]1[CH:4]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[C:5]2[C:20](=[O:21])[CH2:19][CH2:18][C:6]=2[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:2]1=[O:1]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Reaction time: 0.33 h

Procedure:
Under an atmosphere of argon, 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 200 mg, 0.50 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 24 mg, 0.60 mmol) in dry tetrahydrofuran. After 20 min, methyl iodide (41 μL, 0.66 mmol) is added. After 20 min water is added and the mixture is concentrated. The residue is purified by flash a) chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate). Yield: 49 mg; ESI mass spectrum [M+H]+=412; Retention time HPLC: 0.59 min (X012_S01).
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[NH3:31]>C(O)CCC.CO>[NH2:31][C:7]1[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[CH:24]=[CH:23][N:22]=[CH:21][C:20]=4[N:19]=[C:18]3[CH3:26])=[CH:13][CH:12]=2)=[N:10][C:4]2[CH:3]=[C:2]([CH3:1])[C:29]([CH3:30])=[CH:28][C:5]=2[N:6]=1
Reactant: N
Reactant: Cc1cc2c(cc1C)NC(=S)CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Solvent: CCCCO
Solvent: CO
Product: Cc1cc2c(cc1C)N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(N)=N2
Temperature: 120 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A mixture of the thioamide (from Example 19) (2.98 g, 7.24 mmol) and red mercuric oxide (1.57 g, 7.24 mmol) in n-butanol (40 ml) was saturated with ammonia gas at room temperature, and then stirred at 120° C. for 3 hours. After being cooled, the mixture was diluted with methanol (150 ml) and filtered through Arbocel filter aid. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting with ethyl acetate:methanol:diethylamine=100:10:5). Fractions containing the product were evaporated to give the title compound as a bright yellow solid (1.085 g, 38%), m.p. 299°-302° C.
Reaction SMILES: Cl.O.[NH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[NH2:4].[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH:24][C:25](=[O:37])[C:26](=[CH:33]N(C)C)[C:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21]2>CO>[CH:16]12[CH2:22][CH:20]3[CH2:19][CH:18]([CH2:23][CH:14]([CH2:21]3)[CH:15]1[NH:24][C:25]([C:26]1[CH:33]=[N:4][N:3]([C:5]3[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=3)[C:27]=1[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:17]2
Reactant: CN(C)C=C(C(=O)NC1C2CC3CC(C2)CC1C3)C(=O)C(C)(C)C
Reactant: NNc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
Hydrochloric acid (34.5% w/w, 15.88 g, 5.48 g @100.0%, 0.1504 mole, 1.0 mol. eq) and water (70 ml, 1.4 rel. vol) were added to a suspension of 4-hydrazinobenzoic acid (23.35 g, 22.88 g @100.0%, 0.1504 mole, 1.0 mol. eq) in methanol (1250 ml, 12.5 rel. vol). The resulting suspension was stirred for 30 min at 20 to 25° C. and a solution of N-(2-adamantyl)-2-(dimethylaminomethylidene)-4,4-dimethyl-3-oxo-pentanamide (intermediate #4) (53.47 g, 50.0 g @100.0%, 0.150 in 4 mole, 1.0 mol. eq) at 20-25° C. in methanol (250 ml, 5.0 rel. vol)] added over a period of 20 minutes followed by hydrochloric acid (34.5% w/w, 2.38 g, 0.82 g @100.0%, 0.02264 mole, 0.15 mol. eq) and water (70.0 ml, 1.4 rel. vol). The reaction mass temperature was increased to 62-65° C. and maintained for 90.0 min. For work up methanol solution was concentrated atmospherically until the residual volume 6.0 rel. vol (300.0 ml) remained. The resulting suspension was cooled to 20-25° C. and stirred for 1.0 hr. The product was filtered and washed with ethyl acetate (200.0 ml, 4.0 rel. vol) and sucked dry for 30 min. The product was dried under vacuum (100 mbar) at 50° C. for 8 hrs to give crude 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (47.0 g, 73.0%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N+:22]([O-])=O>C1COCC1>[N:3]1([CH2:8][CH2:9][O:10][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[NH2:22])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1OCCN1CCCC1

Procedure:
To a suspension of NaH (60%, 248 mg, 6.21 mmol) in dry THF was added 2-Pyrrolidin-1-yl-ethanol (0.68 mL, 5.74 mmol). Bubbling was observed. The reaction was stirred for 5 minutes, at which time 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (0.67 mL, 4.79 mmol) was added. The solution turned red, and LCMS indicated completion of the reaction. The reaction was quenched by addition of H2O, and the mixture was extracted with EtOAc, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange oil.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][O:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:14][NH2:15]>CO>[CH3:14][NH:15][CH2:13][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[OH:12]
Reactant: CC(C)Sc1ccc(C2CO2)cc1
Reactant: CN
Solvent: CO
Product: CNCC(O)c1ccc(SC(C)C)cc1

Procedure:
A solution of 842 mg of 4-isopropylthiophenyloxirane in 30 ml of methanol which contained 20% of methylamine was reacted at 70° C. in a sealed tube for 41 hours. After allowing the reaction mixture to cool down, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: a 10:1 mixture of chloroform and methanol) to give 428 mg of an oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]1[CH:24]=[C:25](Br)[CH:26]=[CH:27][C:10]2=1)=[O:5])[CH3:2].[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(#N)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]1[CH:24]=[C:25]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:26]=[CH:27][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(Br)ccc1-2
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 138 (69.3 mg, 0.16 mmol) and bis(triphenylphosphine)palladium (II) acetate (11.68 mg, 0.015 mmol) was dissolved in a mixed solvent system of acetonitrile (120 mL) and TEA (80 mL). The mixture was degassed under vacuum and argon gas was added, after which trimethylsilylacetylene (0.044 mL, 0.31 mmol) was added into the mixture. The mixture was degassed again under vacuum (argon) and heated to reflux. The mixture was heated at reflux until analysis by TLC (EtOAc) indicated that all of the starting material 138 had been consumed. The mixture was cooled to rt and the precipitate which formed was removed by filtration through celite. The filtrate was concentrated under reduced pressure and partitioned between H2O and EtOAc. The combined layers of EtOAc were washed with brine and dried (Na2SO4), after which the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, EtOAc:hexane 1:1). The conditions for TLC were EtOAc on silica gel. A white solid 139 (58.8 mg, 80%) was obtained. mp 186-187° C.; IR (KBr, cm−1) 2410, 2358, 1716, 1497, 1253; 1H NMR (CDCl3) δ 7.92 (s, 1 H), 7.72 (dd, J=8.5, 1.5 Hz, 1 H), 7.6 (t, J=6.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1 H), 7.42-7.49 (m, 2H), 7.23-7.29 (m, 1 H), 7.05 (t, J=9.3 Hz, 1H), 6.71 (q, J=7.3 Hz, 1 H), 4.41 (m, 2 H), 1.42 (t, J=7.1 Hz, 3 H), 1.29 (d, J=7.2, 3 H), 0.24 (s, 9 H). MS (EI) m/e (relative intensity) 459 (M+, 28), 445 (32), 399 (51), 371 (100), 235 (71), 178 (75); [α]26D=28.2 (c 0.48, EtOAc).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[NH2:13][NH2:14].O>CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:13][NH2:14])=[O:2])=[CH:5][CH:6]=1)#[N:11]
Reactant: NN
Reactant: COC(=O)c1ccc(C#N)cc1
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-cyano-benzoic acid methyl ester (1.0 g, 13 mmol) in 30 mL of MeOH was added 3 mL of H2NNH2.H2O. The mixture was stirred at ambient temperature for 16 h. The solid was collected and washed with CH3OH to give 4-cyano-benzoic acid hydrazide 9 as a solid. Yield: 0.8 g, 80%.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]1([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CCCCC>[C:27]1([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][I:25])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCC1CCC(c2ccccc2)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: ICC1CCC(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
Imidazole (4.4 g, 0.065 mol) is added in one portion to a solution of triphenylphosphine (17.0 g, 0.065 mol) in dichloromethane (300 mL) at 25° C. After all of the solids dissolved, iodine (16.5 g, 0.065 mol) is added in four portions. The mixture is stirred for 10 min. then a solution of 4-phenylcyclohexylmethanol (10.5 g, 0.055 mol) is added dropwise and the mixture is stirred at 25° C. for 18 h. The reaction mixture is poured into pentane and the resulting solids filtered. The filtrate is concentrated in vacuo and the residue is dissolved in dichloromethane. This solution is poured into hexanes, the solids were filtered, and the filtrate is concentrated in vacuo. The residue is passed through a pad of silica gel using hexanes as eluent to afford 14.6 g (89%) of 4-phenylcyclohexylmethyl iodide as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.CC(OC([N:15]([C:23]1[NH:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][C:41]3[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[C:43]([Cl:49])[CH:42]=3)[C:34]=2[F:50])=[O:30])=[C:26]([Br:28])[N:27]=1)C(OC(C)(C)C)=O)=O)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:15][C:23]1[NH:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][C:41]3[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[C:43]([Cl:49])[CH:42]=3)[C:34]=2[F:50])=[O:30])=[C:26]([Br:28])[N:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
TFA (2 ml, 26.0 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-bromo-5-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (1.130 g, 1.616 mmol) in dichloromethane (10 mL). The mixture was stirred at RT overnight. The reaction mixture was stirred with saturated aqueous sodium bicarbonate for 1 hr and the resulting solid was isolated by filtration. A portion (0.100 g) was recrystallized from ethanol to give the title compound (0.071 g, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (br. s., 1H), 7.79-7.85 (m, 1H), 7.72-7.79 (m, 1H), 7.44-7.55 (m, 2H), 7.29-7.39 (m, 1H), 5.53 (br. s., 2H), 4.24-4.68 (m, 2H). ES MS: m/z 498, 500.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]1([N:31]=[C:32]=[O:33])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:32]([NH:31][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:33])[C:3]1=[O:20]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2cccc3ccccc23)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 1-naphthylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 234°-235° C.