Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][CH2:6]N=C=NCC.[CH3:13][N:14]([CH3:42])[CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:18]1[C:39](O)=[O:40].C(N)CC.O>C(Cl)Cl>[CH2:4]([NH:3][C:39]([C:18]1[N:17]([CH2:16][CH2:15][N:14]([CH3:13])[CH3:42])[C:25]2[C:20]([C:19]=1[CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:40])[CH2:5][CH3:6]
Reactant: CN(C)CCn1c(C(=O)O)c(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCCN
Solvent: ClCCl
Product: CCCNC(=O)c1c(C(c2ccccc2)c2ccccc2)c2ccccc2n1CCN(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 59.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.45 g, 7.53 mmol) was added to a solution of Compound 93 (1.5 g, 3.76 mmol) obtained in Example 93 and propylamine (0.47 ml, 5.65 mmol) in 50 ml of methylene chloride, followed by stirring at room temperature for 4.5 hours. Water was added to the reaction solution followed by extraction with chloroform. The resulting organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. The obtained crude product was purified with silica gel column chromatography (chloroform/methanol=40/1) followed by recrystallization from diisopropyl ether to give 0.98 g (yield: 59%) of the title compound.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[CH2:8][CH:9]([CH:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[OH:16])[C:10]([O:12]CC)=[O:11])([F:4])[CH3:3].[OH-].[Na+]>O1CCCC1CCO>[F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[CH2:8][CH:9]([CH:15]([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[OH:16])[C:10]([OH:12])=[O:11])([F:4])[CH3:3]
Reactant: CCOC(=O)C(Cc1cccc(C(C)(F)F)c1)C(O)c1ccc(F)cc1
Agent: OCCC1CCCO1
Agent: [Na+]
Agent: [OH-]
Product: CC(F)(F)c1cccc(CC(C(=O)O)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of ethyl (2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate (5.97 g, 17.6 mmol) in tetrahydrofuran-ethanol (30 ml)-(20 ml) was added 2N sodium hydroxide (18 ml, 36 mmol) at room temperature, and the mixture was stirred overnight at room temperature. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the aqueous layer was acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was recrystallized from hexane-ethyl acetate to give (2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionic acid(4.48 g, 82%) as colorless crystals.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:14]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=2)=[N:15][CH:16]=1>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:22]=2)=[N:15][CH:16]=1
Reactant: ClCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cnc(Nc2nc(COc3ccccc3)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
Phenol (0.0356 g, 0.378 mmol) was dissolved in 3 mL THF at ambient temperature. NaH (0.00907 g, 0.378 mmol) was added and the mixture stirred for 30 minutes at ambient temperature. Solid N-(5-Bromo-3-phenoxypyridin-2-yl)-4-(chloromethyl)thiazol-2-amine (0.030 g, 0.0756 mmol) (Example 322) was then added to the reaction and the mixture was stirred at ambient temperature overnight. The reaction was concentrated to dryness, dissolved in CH2Cl2, washed with water, dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (0.007 g, 20.4% yield) as the least polar of the two major products. 1H NMR (CDCl3) δ 5.07 (s, 2H), 6.88 (s, 1H), 6.96 (t, J=7.3 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.14 (d, J=2.0 Hz, 1H), 7.23-7.31 (m, 3H), 7.43 (t, J=8.0 Hz, 2H), 8.14 (d, J=2.0 Hz, 1H), 8.76 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[F:35][C:36]1([C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:39]1[CH2:40][CH2:41][C:36]([C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)([F:35])[CH2:37][CH2:38]1)=[O:12]
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]ncc1Cl
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CCC(F)(c3ccc(C#N)cc3)CC2)cc1-c1[nH]ncc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 5, except 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 51.3) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 13.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 423 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[C:10]([C:12]1([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:14][CH2:13]1)#[N:11].C(Cl)(=O)C(Cl)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1.CN(C)C=O>[C:10]([C:12]1([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=2)=[O:19])[CH2:13][CH2:14]1)#[N:11]
Reactant: Cc1ccc(N)cc1O
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1O
Yield: 87.5 %

Procedure:
Using 5-amino-2-methylphenol (6.00 g, 48.5 mmol), 3-(1-cyanocyclopropyl)benzoic acid (6.00 g, 48.5 mmol) produced in Example A1(iii), oxalyl chloride (6.40 mL, 73.0 mmol), N,N-dimethylformamide (40 μL), tetrahydrofuran (250 mL), sodium hydrogencarbonate (6.20 g, 73.0 mmol) and water (60 mL) as starting materials, and in the same manner as in Example A32(i), the title compound (12.4 g, 87%) was obtained as a white powder. The title compound was washed with a mixed solvent of ethyl acetate and hexane.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][OH:27])[CH2:23][O:22]1.[N+]([O-])([O-])=O>ClCCl>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([O:27][CH2:26][CH:24]2[CH2:23][O:22][C:21]([CH3:28])([CH3:20])[O:25]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CC1(C)OCC(CO)O1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OCC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Pyridine (29.96 g, 0.37 mol) was added to a solution of 4-nitrobenzenesulfonyl chloride (58.7 g, 0.26 mol) in dichloromethane (300 mL) at 0° C. followed by the dropwise addition of 2,2-dimethyl-1,3-dioxolane-4-methanol (50 g, 0.37 mol). After stirring the mixture at temperature for 1 h, the reaction mixture was allowed to warm to room temperature and stirring continued for 4 h. The reaction nitrate was washed with 1N HCl (2×200 mL), dried (MgSO4), and evaporated to a solid which was recrystallized (ethyl acetate/hexane) to give 60 g (50%) of the desired product: mp 92°-94° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([Cu])#[N:16]>CN(C=O)C.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>[C:15]([C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])#[N:16]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C#N
Yield: 46.9 %

Procedure:
A mixture of methyl 2-chloro-4-nitrobenzoate (2 g, 9.3 mmol), CuCN (3.3 g, 37.2 mmol), and Pd(PPh3)4 (1.075 g, 0.93 mmol) was suspended in DMF (15 mL) and then subjected to microwave irradiation at 150° C. for 4 hours. After the mixture was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude material was purified by column chromatography (20% EA/PE) to afford 0.9 g of title compound. LC-MS: m/z 207.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]#[C:24][CH2:25]Cl)[C@H:17]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CS(C)=O>[N:36]([CH2:25][C:24]#[C:23][CH2:22][N:18]1[CH2:19][CH2:20][O:21][C@H:16]([O:15][C@@H:13]([C:5]2[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH3:14])[C@@H:17]1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[N+:37]=[N-:38]
Reactant: C[C@@H](O[C@H]1OCCN(CC#CCCl)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](O[C@H]1OCCN(CC#CCN=[N+]=[N-])[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 20 h

Procedure:
To a solution of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-chlorobut -2-ynyl)morpholine (4 g) in dimethyl sulphoxide (17 ml) was added sodium azide (0.562 g). The solution was stirred for 20 h and aqueous ammonium chloride and ethyl acetate were added. The organic phase was washed with water (2 times), saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue chromatographed on silica gel (eluting with 20% ethyl acetate in petroleum ether bp 60°-80° C.) to give the title compound. 1H NMR (360 MHz, CDCl3) δ 1.48 (3H, s, J=6.6 Hz), 2.87 (1H, app t, J=10.2 Hz), 2.98 (1H, td, J=3.6, 11.7 Hz), 3.35 (2H, t, J=1.9 Hz), 3.61 (1H, d, J=2.8 Hz), 3.72 (1H, dq, J=1.4 Hz, 10.0 Hz), 3.92 (2H, t, J=1.9 Hz), 4.30-4.40 (2H, m), 4.89(1H, q, J=6.6 Hz), 7.03 (2H, t, J=8.7 Hz), 7.17 (2H, s), 7.27 (2H, br s), 7.63 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccccc1F
Product: N#Cc1cccnc1-c1ccccc1F
Yield: 74 %

Procedure:
Prepared in 74% yield from 2-chloro-3-cyanopyridine and 2-fluorophenylboronic acid according to the procedure described for Example 153A. MS (ESI+) m/z 199.0 (M+H)+; 1H NMR (CDCl3) δ 7.22-7.34 (m, 2H), 7.42-7.55 (m, 2H), 7.57-7.63 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.91 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br>CN(C)C=O.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[C:5]([N:12]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[Cl:27])[C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CCOC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N(Cc1ccccc1Cl)c1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 4-bromo-2-nitro-6-(trifluoromethyl)phenylcarbamate (475.5 mg) was dissolved in N,N-dimethylformamide (10 ml), and to the solution were added potassium carbonate (220.9 mg) and 2-chlorobenzyl bromide (0.207 ml). Then the mixture was heated at 50° C. and stirred for 1 hour. After allowing to cool, to the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (757.2 mg, quantitative yield).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=2)[C:7]=1[CH2:8][CH3:9])[CH3:2].O.[NH2:24][NH2:25]>>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=3)=[CH:12][CH:11]=2)[C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCc1ncn(-c2ccc(C(=O)CCC(=O)O)cc2)c1CC
Reactant: NN
Solvent: O
Product: CCc1ncn(-c2ccc(C3=NNC(=O)CC3)cc2)c1CC

Procedure:
Similarly, the reaction of 4-(4,5-diethyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(4,5-diethyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone (3h).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].CC(N=NC(C#N)(C)C)(C#N)C.Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.Cl>C1COCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[CH2:1][C:2]([CH3:4])=[O:3]
Reactant: Clc1ncccn1
Reactant: CC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)Cc1ncccn1
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
In a 100 mL flask, acetone (1.44 mL, 19.6 mmol) was added to KH (30% in oil, 2.89 g, 21.6 mmol) in THF (15 mL) at 0° C. under nitrogen. The reaction mixture was stirred for 0.25 h then additional THF (15 mL) was added. AIBN (74 mg, 0.45 mmol) followed by 2-chloropyrimidine (500 mg, 4.36 mmol) were added cautiously and the reaction mixture kept at 0° C. for 1 h. HCl 3N was added until the pH=6. The two layers were separated and the aqueous phase extracted with dichloromethane. The combined extracts were dried over Na2SO4 then concentrated. The residue was purified on column chromatography (eluent: EtOAc/pentane 20/80 to 80/20) to give the title compound (247 mg, 42%) as a yellow oil (keto/enol form 2:1).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1cncnc1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
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+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2cncnc2)CC1
Yield: 93 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), pyrimidin-5-yl boronic acid (12 mg, 0.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and a 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (26 mg, 95%), LC-MS (ESI, 3.5 min) Rt 1.19 min, m/z 318 (100%, [M+H]+); m/z (ESI) C15H17ClN5O requires 318.1116 found [M+H]+ 318.1114.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=O)[CH:2]=[CH2:3].[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:6](=[O:8])[CH:5]([CH3:10])[N:4]([CH2:1][CH:2]=[CH2:3])[C:20]2=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: C=CCNC(C)C(=O)OC
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: C=CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C1C
Yield: 114.5 %

Procedure:
To a solution of 10.5 g (0.073 mole) of methyl 2-allylaminopropionate in 50 ml of toluene is added 15 g (0.08 mole) of 3,5-dichlorophenylisocyanate in small portions. The resulting mixture is heated to reflux for 2 hours. The reaction mixture is cooled and filtered. The filtrate is concentrated under vacuum to give 25 g of a yellow oil. This material is further purified by passing it through a silica gel column using 40/60 ethyl acetate/hexane as the solvent followed by trituration with hexane/ether to give 18 g of a light yellow solid., m.p. 78°-80°.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][OH:27])[CH:21]=[N:20][CH:19]=1>>[N:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][O:27][C:2]2[C:11]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:21]=[N:20][CH:19]=1
Reactant: Clc1nc2ccccc2nc1N1CCNCC1
Reactant: OCCOc1cncnc1
Product: c1ccc2nc(N3CCNCC3)c(OCCOc3cncnc3)nc2c1

Procedure:
The title compound was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)quinoxaline (0.66 g, 2.65 mmol; from Example 162, Step 1) and 2-(5-pyrimidinyloxy)ethanol (0.45 g, 3.20 mmol). Yield 0.55 g (59%); mp 115-117° C.; HRMS m/z calcd for C18H20N6O2 (M)+ 352.1648, found 352.1654. Anal. (C18H20N6O2) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([OH:11])=[O:10])=[C:4]([F:27])[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:45]=[C:44]6[C:39]([CH:40]=[CH:41][CH:42]=[N:43]6)=[CH:38][CH:37]=5)=[CH:3][C:4]=4[F:27])[C:9]([OH:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: O=C(O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 67.1 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid (0.408 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.449 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.020 mmol) and 2M aq potassium carbonate (1.224 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The reaction mixture was diluted with methanol (10 mL), treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-40% acetonitrile/water with 0.1% NH4OH) followed by lyophilization from water afforded the title compound as a white solid (134 mg, 63%). MS(ES)+ m/e 490.3 [M+H]+.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1F.[CH2:15]([NH2:18])[CH2:16][NH2:17].C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>O1CCOCC1>[N+:10]([C:9]1[C:4]2[C:3](=[O:14])[NH:18][CH2:15][CH2:16][NH:17][C:5]=2[CH:6]=[CH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: NCCN
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCNc2cccc([N+](=O)[O-])c21
Yield: 25.9 %

Procedure:
2-fluoro-6-nitrobenzoic acid methyl ester (4.54 g, 22.8 mmol), ethylenediamine (1.50 mL, 22.4 mmol) and diisopropylethylamine (8.71 mL, 50 mmol) were dissolved in 1,4-dioxane (40 mL). The reaction mixture was then irradiated at 140° C. for 40 minutes. After cooling, the reaction mixture was poured over saturated ammonium chloride (50 mL), and organics were extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered and reduced. The residue was then purified by flash column chromatography (0% MeOH/DCM-20% MeOH/DCM over 35 minutes) to afford 1.2 grams of 6-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a yellow oil. LC/MS (ESI)=208.24 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(F)cc1Cl
Yield: 62 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2-chloro-4-fluorobenzenesulfonyl chloride (12.6 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 62% yield (10.9 mg). MS (ESI+) calcd mass for C13H9ClFN5O2S 353.014951, found 353.015041.
Reaction SMILES: C([Mg][Cl:5])(C)C.[Br:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=1Br.C(C(Cl)C)CCCCC>O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=1[Cl:5]
Reactant: COC(=O)c1cc(Br)c(Br)o1
Reactant: CC(C)[Mg]Cl
Agent: CCCCCCC(C)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(Cl)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Isopropylmagnesium chloride (1.20 ml, 2.40 mmol) was added dropwise to a solution of methyl 4,5-dibromo-2-furancarboxylate (568 mg, 2.0 mmol) in Tetrahydrofuran (THF) (16 ml) at 0° C. The resulting mixture was stirred at this temperature for 30 min and then cooled to −78° C. A solution of hexylchloroethane (568 mg, 2.401 mmol) in THF (1 mL) was added dropwise, and the resulting mixture was stirred at this temperature for 1 hr. The reaction was quenched with addition of NH4Cl (sat. aq) and the resulting mixture was stirred at rt overnight. Ether and water were added and the aqueous layer was discarded. The organic layer was washed with brine, dried (Na2SO4) and concentrated to give 0.34 g of the product containing its isopropyl ester.