Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[CH:28][CH:27]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([C:36]2[S:37][C:38]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:39][CH:40]=2)(=[O:34])=[O:35])=[CH:28][CH:27]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(Nc1ccncc1)c1ccc(Br)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncc1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid pyridin-4-ylamide (example B.57) (160 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (160 mg, 54%). MS (ISN) 592.1 [(M−H)−]; mp 209° C.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:21][S:22]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[O:23])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][C:12]1(CCC)OC[CH2:15][CH2:14][O:13]1.OCC1O[C:39]2[CH:41]=[CH:42]C=C[C:38]=2[O:37]C1>>[Na:1].[O:37]1[C:38]2[CH:39]=[CH:41][CH:42]=[CH:15][C:14]=2[O:13][CH2:12][CH:11]1[CH2:10][O:9][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:21][S:22]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[O:23])[C:3]=1[CH3:2]
Reactant: OCC1COc2ccccc2O1
Reactant: CCCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCCO1
Agent: [Na]
Product: Cc1c(OCC2COc3ccccc3O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 3 %

Procedure:
The same procedure as in the steps (8c) to (8g) of Example 8 was repeated using 2-hydroxymethyl-1,4-benzodioxane to obtain the title compound (141 mg, total yield: 3%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]([CH3:29])([CH3:28])[C:10]([NH:12][C:13]2[S:14][C:15]([C:25]([OH:27])=O)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:17]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[CH:32]1([C:35]([NH:37][NH2:38])=O)[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH:32]1([C:35]2[O:27][C:25]([C:15]3[S:14][C:13]([NH:12][C:10]([C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=4)([CH3:29])[CH3:28])=[O:11])=[N:17][C:16]=3[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:38][N:37]=2)[CH2:34][CH2:33]1
Reactant: NNC(=O)C1CC1
Reactant: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccc(F)cc2)c(C(=O)O)s1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccc(F)cc2)c(-c2nnc(C3CC3)o2)s1
Temperature: 150 °C

Procedure:
To a stirred solution of 2-(2-(4-Fluorobenzamido)-2-methylpropanamido)-4-(4-fluorophenyl)thiazole-5-carboxylic acid (100 mg, 0.224 mmol) and cyclopropanecarbohydrazide (27 mg, 0.27 mmol) were added HATU (128 mg, 0.34 mmol) and TEA (78 uL, 0.56 mmol). Volatiles were removed in vacuo. The residue was taken up in EtOAc and washed with 1N HCl (2×10 mL) followed by sat. NaHCO3 (2×10 mL). Organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated to dryness to afford a solid. The solid was dissolved in THF (5 mL) and treated with Burgess reagent (68 mg, 0.28 mmol) and heated in microwave at 150° C. for 30 minutes. Purification by silica gel chromatography (30-45% EtOAc/Heptanes) gave the title compound. 1H NMR (400 MHz, DMSO-d6) 0.82 (dd, J=4.74, 2.59 Hz, 3H) 1.08 (dd, J=8.34, 2.78 Hz, 3H) 2.19 (s, 1H) 7.33 (t, J=8.91 Hz, 3H) 7.25 (t, J=8.91 Hz, 3H) 7.71 (dd, J=8.84, 5.56 Hz, 3H) 8.03 (dd, J=8.78, 5.62 Hz, 3H) 8.65 (s, 1H) 12.61 (s, 1H). MS m/z 510.4 (M+H), 508.4 (M−1). HRMS cald for C25H18N2O4S=509.1333, found=509.1334. (M+H)+ 510.4, Rt=1.37 min, method A.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2csc(C(=O)O)n2)cc1
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2csc(C(=O)Nc3nnn[nH]3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A mixture of 4-(4-methylphenyl)-2-thiazolecarboxylic acid (300 mg, 1.37 mmol) and N,N -carbonyl diimidazole (CDI) (444.3 mg, 2.74 mmol) dissolved in dry DMF (5 ml) was stirred at room temperature for 1 hour. Under the same conditions, a solution of 5-aminotetrazole (139.5 mg, 1.64 mmol) in dry DMF was added thereto, and the resulting mixture was allowed to react at 85° C. for 2 hours. After removing of the solvent from the reaction mixture by distillation, the residue was treated with water and acidified with 1N-HCl to pH 2. The deposited solids were filtered with suction, washed with water and recrystallized from methanol-THF-water to give 258 mg (yield 66%) of 4-(4-methylphenyl)-N-(1H-tetrazole-5-yl)-2-thiazolecarboxamide as pale yellow crystals, m.p. 276°-278° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.Br.[Br:17][C:18]1[CH:19]=[C:20]([CH2:25]Br)[C:21]([NH2:24])=[N:22][CH:23]=1>CN(C)C=O>[NH2:24][C:21]1[C:20]([CH2:25][NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[CH:19][C:18]([Br:17])=[CH:23][N:22]=1
Reactant: CCOC(=O)CN
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNCc1cc(Br)cnc1N
Reaction time: 8 h

Procedure:
Glycine ethyl ester hydrochloride (805 mg, 5.7 mmol) and triethylamine (2.6 mL, 18.46 mmol) were successively added to a solution of 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (2, 5.7 mmol) in dimethylformamide (65 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (70 ml) and water (100 mL). The aqueous phase was separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (10:0 to 95:5) as eluent. The title product was obtained as a yellow solid (1.1 g, 68%).
Reaction SMILES: [NH:1](/C(=C\C([O-])=O)/C([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18](Cl)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[NH:1](/[C:18](=[CH:17]\[C:25]([O:27][CH2:28][CH3:29])=[O:26])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])/C=C(\Nc1ccccc1)C(=O)[O-]
Reactant: CCOC(=O)C(Cl)C(Cl)C(=O)OCC
Product: CCOC(=O)/C=C(\Nc1ccccc1)C(=O)OCC

Procedure:
The crude yield (14.7 g) assays as 63.1% anilinofumarate. This is a 73% yield based on aniline as the limiting reagent or 66.5% yield based on the real diethyl dichlorosuccinate charged.
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH3:17]COCC.C([O-])(O)=O.[Na+]>CO>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=C(Cc1ccccc1)C(=O)OC
Yield: 95 %

Procedure:
α-Benzylacrylic acid (1.00 g, 6.17 mmol) in methanol (20 ml) was treated with BF3.Et2O (2 ml). The mixture was heated to reflux for 14 h, cooled, and poured into saturated NaHCO3 solution. Extraction with ether followed by drying over Na2SO4 and evaporation afforded 1.03 g (95%) of a mobile oil. 1H NMR (CDCl3) δ7.17-7.35 (m,5H), 6.23 (m,1H), 5.47 (m,1H), 3.74 (s,3H), 3.63 (s,2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[CH:18]=1)([O-])=O.C(O)C.Cl>[Pd].O>[N:11]1[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:18][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=12
Reactant: O=[N+]([O-])c1ccccc1-c1cn2ccccc2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1-c1cn2c(n1)CCCC2
Reaction time: 120 h

Procedure:
In a dry flask was charged 2-(2-Nitro-phenyl)-imidazo[1,2-a]pyridine (239 mg, 1 mmol), 10% Pd/C (15 mg), Ethanol (25 ml), water (1.5 ml) and 4M HCl (0.5 ml). The atmosphere was flushed with nitrogen and stirred over 1 atm. hydrogen over 5 days with an additional charge of Pd/C catalyst (15 mg) and 4 N HCl (4.5 ml) until reaction completion was obtained. The reaction mixture was filtered through Celite, and neutralized to pH=6 with a saturated NaHCO3 solution. The solution was roto-evaporated to remove the ethanol, the aqueous layer was extracted with CH2Cl2 (2×5 ml), and the combined organic layer dried over Na2SO4 and concentrated to obtain the product as an oil in quantitative yield (205 mg). (MS, M++H=214.1)
Reaction SMILES: [H][H].C([N:10]1[C:14]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][N:12]=[N:11]1)C1C=CC=CC=1>C(O)(C)C.O.[Pd](Cl)Cl>[NH:10]1[C:14]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][N:12]=[N:11]1
Reactant: [H][H]
Reactant: O=C(O)COCCc1cnnn1Cc1ccccc1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CC(C)O
Product: O=C(O)COCCc1cnn[nH]1
Yield: 120.3 %

Procedure:
Pressurize 1 atmosphere of hydrogen (g) to a flask containing [2-(1-benzyl-1H-1,2,3-triazol-5-yl)ethoxy]acetic acid (10.1 g; 1.00 equiv; 38.66 mmoles) and palladium (II) chloride (3 g; 16.92 mmoles; 3.00 g) in isopropyl alcohol (300 mL) and water (60 mL). Maintain the flask under a hydrogen atmosphere for 3 h, then filter through Celite™ and concentrate. Add toluene (2×50 mL) and concentrate to afford the title compound (7.96 g, 100%). 1H NMR (d6-DMSO): 2.86 (t, J=7 Hz, 2H), 3.65 (t, J=7 Hz, 2H), 3.98 (s, 2H), 7.77 (s, 1H), 13.4-13.6 (br s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][C@H:32]([CH3:40])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=2)=[CH:21][CH:22]=1)[C:13]([NH:31][C@@H:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH3:40])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccc(-c2ncc(Br)cn2)cc1)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 89.3 %

Procedure:
Prepared using General Procedure 7: To a stirred solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoic acid (962 mg, 2.11 mmol) and (R)-tert-butyl 2-aminopropanoate hydrochloride (383 mg, 2.11 mmol) in DMF (20 mL) was added DIEA (1.2 mL, 6.32 mmol). The mixture was cooled to 0° C. and HATU (802 mg, 2.11 mmol) was added portionwise. The cooling bath was removed and the mixture was allowed to warm to room temperature. After 1 h the mixture was poured onto citric acid (100 mL of a 0.1 M aqueous solution) and iso-hexanes (20 mL) and the resulting precipitate collected by filtration, washing successively with water (2×10 mL), ACN (3 mL) and iso-hexanes (2×5 mL) to afford 1.1 g (89%) of tert-butyl ((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-42 as a white solid. LCMS-ESI (m/z) calculated for C28H31BrN4O5: 582.2. found 605.2 [M+Na]+, tR=7.94 min (Method 10).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1.CCN=C=NCCCN(C)C.Cl.[NH2:44][CH2:45][C@H:46]([OH:49])[CH2:47][OH:48]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[OH:49][C@H:46]([CH2:47][OH:48])[CH2:45][NH:44][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][N:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: NC[C@H](O)CO
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Reaction time: 25 h
Yield: 53.5 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.07 g, 2.39 mmol) synthesized in Example (97e) was dissolved in methylene chloride (20 mL), and WSCI.HCl (732 mg, 3.82 mmol), (S)-(−)-3-amino-1,2-propanediol (500 mg, 5.49 mmol) and 4-dimethylaminopyridine (146 mg, 1.19 mmol) were added at room temperature, followed by stirring for 25 hours under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate (50 mL), washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired product (666 mg, 54%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].[NH2:12][C:13]1[C:18]([C:19]#[N:20])=[C:17](F)[CH:16]=[CH:15][CH:14]=1.O>CN1C(=O)CCC1>[NH2:12][C:13]1[C:18]([C:19]#[N:20])=[C:17]([O:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: OCCN1CCOCC1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1c(N)cccc1OCCN1CCOCC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
4-(Hydroxyethyl)morpholine (1.02 equivalents) was added to NaH (1.2 equivalents) in NMP. After 10 minutes, 6-amino-2-fluorobenzenecarbonitrile (1.0 equivalent) was added in NMP. The resulting mixture was heated at 100° C. for 1 hour. The mixture was then cooled and poured into H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yield a brown gum. The crude material was purified by silica gel chromatography (5:1:95 MeOH:Et3N:EtOAc) to give the desired product. LC/MS m/z 248.3 (MH+), Rt 1.26 minutes.
Reaction SMILES: [ClH:1].[NH:2]1[C:10]23[CH2:11][CH2:12][CH2:13][CH2:14][C:5]2([CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=23)[CH2:4][CH2:3]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:1].[C:20]1([CH2:19][N:2]2[C:10]34[CH2:11][CH2:12][CH2:13][CH2:14][C:5]3([CH2:6][CH2:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=34)[CH2:4][CH2:3]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccc2c(c1)CCC13CCCCC21NCC3
Agent: Cl
Product: c1ccc(CN2CCC34CCCCC23c2ccccc2CC4)cc1
Yield: 42 %

Procedure:
In a manner similar to that described in Example 32, the product from Example 23 (0.34 g, 1.50 mmol) and benzaldehyde are reacted. Workup, followed crystallization from ether and HCl gave the title compound (0.22 g, 42%) as a white solid mp 235°-237° C.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:48]=[CH:49][CH:50]=1)[CH2:43][NH:44][C:45](=[O:47])[CH3:46]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:49]2[CH:50]=[CH:40][CH:41]=[C:42]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[CH:48]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)NCc1cccc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)NCc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 44.5 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.30 g), N-(3-bromobenzyl)acetamide (1.05 g) and tetrakis(triphenylphosphine)palladium(0) (0.18 g), the title compound (1.24 g) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(-c2cccc(F)c2)nc2ncccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,8-naphthyridine (200 mg, 0.939 mmol), 3-fluorophenylboronic acid (131 mg, 0.939 mmol), sodium carbonate (199 mg, 1.877 mmol) and Pd(PPh3)4. Product used without further purification in the next step. Mass Spectrum (ESI) m/e=273.0 (M+1)
Reaction SMILES: I[C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:28][C:29]1(C)[C:33](C)(C)OB(C(C)=C)O1>CN(C=O)C.O>[CH3:33][C:29]([C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[CH2:28]
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1I
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1C#N
Temperature: 110 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
To a solution of 2-iodo-4-[(5-nitro-2-pyridinyl)oxy]benzonitrile (Intermediate 129, 5.0 g) in DMF (50 mL) were added K3PO4 (5.77 g, 27.24 mmol), Pd(tBu3)2 (696 mg, 1.36 mmol) and 4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (3.84 mL, 20.43 mmol) and the reaction mixture was stirred for 4 hours at 110° C. After cooling the reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with ice cold brine (3×50 mL), dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 100 g) eluting from 100:0 to 80:20 cyclohexane/ethyl acetate to afford the title compound (1.8 g) as white solid.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]2[CH:3]=[CH:2]1.B.O1CCCC1>O1CCCC1.O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(c2ccc(C(=O)N3C=C4CC=CN4Cc4ccccc43)cc2C)CCCC1=O
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCC[C@H]1O
Yield: 92.2 %

Procedure:
(S)-(−)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaboro-borane [(S)-2-methyl-CBS-oxazaborolidine] (1.0 M in tetrahydrofuran, 1.06 mL, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (53.1 mL, distilled from sodium/benzophenone ketyl). To this solution was simultaneously added a solution of 3-[4-(5H,1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methyl-phenyl]-2-methyl-cyclohex-2-enone of Example 4 (2.18 g, 5.31 mmol) in anhydrous tetrahydrofuran (20 mL) via syringe pump (1.6 mL/min) and borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 3.19 mL, 3.19 mmol) at a rate such that enone addition was complete upon addition of approximately ⅔ of the borane-tetrahydrofuran complex. Upon completion of the borane-tetrahydrofuran complex addition, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide, 1 N hydrochloric acid and brine and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexane followed by reprecipitation from diethyl ether upon addition of petroleum ether, to afford 2.02 g of the title compound as a white solid, [α]589=+34.30 (c=1, chloroform). Analytical HPLC (Chiralpak AD, 4.6×250 mm, 50% ethanol/hexane, 0.5 mL/min.) indicated an enantiomeric excess of 96.4%.