Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32]C)[CH2:30]C.Cl.ClCl>ClCCl.CO>[ClH:1].[Cl:19][C:20]1[CH:21]=[C:22]([NH:34][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:32]
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: Cl
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccc(Cl)cc3)cc2)cc1Cl

Procedure:
Prepared analogously to Example 3.7.c. from (4′-chlorobiphenyl-4-yl)propynoic acid and 3-chloro-4-(2-diethylaminoethoxy)phenylamine. Yield: 0.28 g (58% of theory); melting point: 226° C.-233° C.; C27H26Cl2N2O2 (M=481.41)*HCl; calc.: molecular ion peak (M+H)+: 481/3/5 (Cl2); found: molecular ion peak (M+H)+: 481/3/5 (Cl2); Rf value: 0.45 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15])=[S:4].[IH:16].[CH3:17]I>CO>[IH:16].[IH:16].[CH3:1][NH:2][C:3](=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15])[S:4][CH3:17]
Reactant: CI
Reactant: CNC(=S)NCCSCc1nc[nH]c1C
Agent: I
Solvent: CO
Product: CNC(=NCCSCc1nc[nH]c1C)SC

Procedure:
N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea (10.0 g) was dissolved in methanol (400 ml) and 55% aqueous hydriodic acid (12.2 ml) was added, followed by methyl iodide (5.3 ml). The solution was heated under reflux for 4 hours and concentrated. The residue was dissolved in methanol (100 ml) and ether was added to afford the title product as the dihydriodide (5.48 g) m.p. 185°-186° (from isopropyl alcohol). (Found: C, 23.4; H, 3.9; N, 10.9; I, 49.6; S, 12.6; C10H18N4S2.2HI requires: C, 23.4; H, 3.9; N, 10.9; I, 49.4; S, 12.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:7][C@@H:6]([O:8][C:9]2[CH:32]=[CH:31][C:12]3[C:13]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:17])[O:16][C:11]=3[C:10]=2[CH3:33])[C@H:5]([OH:34])[C@H:4]([OH:35])[C@H:3]1[O:36][CH3:37].C(N(C(C)C)CC)(C)C.N1C=CN=C1.[CH2:53]([Si:55]([CH2:59][CH3:60])([CH2:57][CH3:58])Cl)[CH3:54].P([O-])(O)(O)=O.[Na+]>C(Cl)Cl>[CH3:38][C:2]1([CH3:1])[O:7][C@@H:6]([O:8][C:9]2[CH:32]=[CH:31][C:12]3[C:13]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:17])[O:16][C:11]=3[C:10]=2[CH3:33])[C@H:5]([OH:34])[C@H:4]([O:35][Si:55]([CH2:59][CH3:60])([CH2:57][CH3:58])[CH2:53][CH3:54])[C@H:3]1[O:36][CH3:37]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2ccc(O[C@@H]3OC(C)(C)[C@H](OC)[C@@H](O)[C@H]3O)c(C)c2oc1=O
Reactant: CC[Si](Cl)(CC)CC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1c(OCc2ccccc2)c2ccc(O[C@@H]3OC(C)(C)[C@H](OC)[C@@H](O[Si](CC)(CC)CC)[C@H]3O)c(C)c2oc1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 g of a solution from stage A in 500 ml of methylene chloride is agitated under arcon at ambient temperature. 42 ml of diisopropylethylamine and 9.66 g of imidazole are added. The solution is agitated for 15 minutes or cooled down to 0° C., 20.64 ml of triethylchlorosilane is added dropwise over 30 minutes, and agitation is carried out for 2 hours at 0° C. The reaction medium is poured into a molar solution of sodium dihydrogen phosphate. Extraction is carried out with methylene chloride followed by drying and evaporating to dryness. 66.27 g of product is recovered that is purified on silica eluting with a methylene chloride mixture at 0.75% of acetone. When the product is nearly isolated,, eluting is carried out with a methylene chloride solution at 1% of acetone. 41.04 g of sought product is obtained after saponification in a hexane/ethyl acetate mixture (9-1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9](=O)[CH2:10][CH:11](O)[C:12](OCC)=[O:13])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9]2[CH:10]=[CH:11][C:12](=[O:13])[NH:27][N:28]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(O)CC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: O
Solvent: CCCCO
Product: O=c1ccc(C(c2ccc(F)cc2)c2ccc(F)cc2)n[nH]1
Temperature: 130 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
To a solution of ethyl 5,5-bis(4-fluorophenyl)-2-hydroxy-4-oxopentanoate (796 mg) in 1-butanol (4 mL) was added hydrazine hydrate (137 mg) at ambient temperature. The reaction mixture was stirred at 130° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was evaporated in vacuo. The resulting residue was stirred at 160° C. for 3 hours. After cooling, the reaction mixture was purified by silica gel column chromatography (EtOAc:n-hexane=2:1) and crystallized from solvent (EtOAc:n-hexane=1:2) to give 6-[bis(4-fluorophenyl)methyl]pyridazin-3(2H)-one (344 mg) as a pale brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35](CO)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35]([CH2:20][Cl:24])[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2cc(CCl)cc(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To a solution of triphenylphosphine (2.8 g, 10.6 mmol) in anhydrous tetrahydrofuran (16 mL) was added carbon tetrachloride (5 mL). After the mixture was stirred at room temperature for 10 minutes, (4-benzyloxy-6-fluoro-naphthalen-2-yl)-methanol (1.5 g, 5.3 mmol) was added as a solid under a nitrogen atmosphere. After being stirred at reflux for 2 hours, the resulting mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL×2). The combined aqueous layers were extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (elution with 5% ethyl acetate in petroleum ether) to afford 1-benzyloxy-3-chloromethyl-7-fluoro-naphthalene (1.4 g, 87.5%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([C:8]([N:24]([O:25][CH3:26])[CH3:23])=[O:9])=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ncc(Br)cc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.7 %

Procedure:
In N,N-dimethylformamide (24 mL) was dissolved 5-bromo-3-chloropyridine-2-carboxylic acid (2.36 g), 1-hydroxybenzotriazole (2.2 g) and 3-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.87 g), N,O-dimethylhydroxylamine hydrochloride (1.27 g) and triethylamine (1.95 mL) was added to the solution, and the resulting mixture was stirred at room temperature for 20 hours. Water was added to the obtained residue, extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated brine. After drying the mixture over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 5-bromo-3-chloro-N-methoxy-N-methylpyridine-2-carboxamide (2.67 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:11]2[CH:12]=[N:13][C:14]3[NH:15][CH2:16][CH2:17][CH2:18][C:19]=3[CH:20]=2)[C:7]=1[CH:8]([OH:10])[CH3:9].[NH2:21][C:22](N)=[O:23].CO.C(=O)=O>CC(O)C.CCO>[Cl:1][C:2]1[C:7]([CH:8]([OH:10])[CH3:9])=[C:6]([C:11]2[CH:20]=[C:19]3[C:14](=[N:13][CH:12]=2)[N:15]([C:22]([NH2:21])=[O:23])[CH2:16][CH2:17][CH2:18]3)[CH:5]=[N:4][CH:3]=1
Reactant: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2
Reactant: NC(N)=O
Agent: O=C=O
Solvent: CC(C)O
Solvent: CO
Solvent: CCO
Product: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2C(N)=O

Procedure:
Two enantiomers of 1-[3-chloro-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-ethanol are each converted to Compounds 175 and 176 in Table 1 according to the procedure of Urea Formation Method II (Analytical conditions: LUX 5μ Cellulose 4 Analytical column; 30% 1:1:1 MeOH:EtOH:IPA (1% DEA):CO2 @ 3 mL/min; 40° C.; 200 bars; Retention time, Compound 176: 5.2 min, Compound 175: 6.0 min).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.C[CH:24]1[NH:28][CH2:27][CH:26]2[CH2:29][NH:30][CH2:31][CH:25]12.[CH2:32]1N2CCN(CC2)C1>C(#N)C.CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([N:28]4[CH2:27][CH:26]5[CH:25]([CH2:31][N:30]([CH3:32])[CH2:29]5)[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CN2CCN1CC2
Reactant: CC1NCC2CNCC21
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=Cc1c(F)c(N2CC3CN(C)CC3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 80.9 %

Procedure:
0.46 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.29 g of 4-methyl-octahydropyrrolo[3,4-c]pyrrole and 0.18 g of DABCO are refluxed for 2 hours in a mixture of 3 ml of acetonitrile and 1.5 ml of dimethylformamide. The reaction mixture is subsequently concentrated, and the residue is treated with 10 ml of water. The solid is filtered off with suction, washed with water and dried. 0.5 g of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: [C:1]1(/[CH:19]=[CH:20]\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][C:13]3[O:16][CH:17]=[CH:18][C:12]=3[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:17]1[O:16][C:13]2[CH2:14][CH2:15][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1](/[CH:19]=[CH:20]\[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:11][C:12]=2[CH:18]=1)[CH3:29]
Reactant: CNC
Reactant: O=S(=O)(c1ccc(/C=C\c2ccccc2)cc1)N1CCc2occc2C1
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(S(=O)(=O)c1ccc(/C=C\c3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.153 g (0.419 mmol) of (Z)-5-(4-stilbenesulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 10 ml of acetic acid, 57 mg (0.63 mmol) of 50% aqueous dimethylamine and 51 mg (0.63 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:3]1.[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26])[CH3:24]>>[CH3:8][CH:6]1[NH:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2/[CH:21]=[C:31]2\[C:32](=[O:37])[NH:33][C:34]3[C:30]\2=[CH:29][C:28]([S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])=[CH:36][CH:35]=3)[CH2:5]1
Reactant: CC1CN(CCCc2c(C=O)[nH]c3c2CCCC3)CC(C)N1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CC(C)NC(C)C1)CCCC3)C(=O)N2
Yield: 53.4 %

Procedure:
3-[3-(3,5-Dimethyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (62 mg, 0.22 mmol), prepared as described in Example 24, was condensed with 50 mg (0.22 mmol) of 5-ethylsulfonyloxindole to provide (60 mg, 53% yield) of the desired compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:21])[C:18]([OH:20])=O)[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[Cl:32].NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:21])[C:18]([NH:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=3[Cl:32])=[O:20])[C:12]2=[O:22])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)O)C2=O)cc1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Product: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3Cl)C2=O)cc1

Procedure:
According to the Step 1-3 in synthetic method for EXAMPLE 1, a cyclic carbonate analogue (0.2 g) derived from compound 52-4 and 4-amino-3-chlorobenzonitrile (91.6 mg) were used instead of 1-2 and 6-amino-1-bis(tert-butoxy carbonyl)aminoisoquinoline, under high concentration condition (1M), to obtain compound 66-1 (93.1 mg) as a colorless amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(O)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a round-bottomed flask was added 5-bromopyridin-3-amine (0.80 g, 4.6 mmol, Matrix Scientific, Columbia, S.C.), ethanol (15 mL) and 4-fluorobenzenesulfonyl chloride (2.2 g, 12 mmol, Fluka (Sigma-Aldrich) Buchs, Switzerland). The mixture was allowed to stir at ambient temperature overnight. The mixture was diluted with CH2Cl2 and sat. NaHCO3 and then the solution was extracted with CH2Cl2 (3×25 mL). The combined extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10-30% EtOAc/CH2Cl2) afforded N-(5-bromopyridin-3-yl)-4-fluorobenzenesulfonamide as an off-white crystalline solid (0.35 g, 23% yield). MS (ESI pos. ion) m/z: 333 (M+1). 1H NMR (400 MHz, MeOH-d4) δ ppm 8.35 (s, 1H), 8.22 (s, 1H), 7.83-7.89 (m, 2H), 7.76-7.81 (m, 1H), 7.25-7.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[C:12]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: NNC(=O)c1ccc(Cl)nc1
Product: CC(=O)NNC(=O)c1ccc(Cl)nc1
Yield: 64 %

Procedure:
The title compound was prepared from 6-chloronicotinic acid hydrazide and acetyl chloride, using the method of preparation 33, as a white solid in 64% yield.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl-:1].[Cl-:1].[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([N+:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][C:2]=1[N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccncc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: [Cl-]
Product: c1cc[n+](-c2nc(-[n+]3ccccc3)c3ccccc3n2)cc1
Reaction time: 2 h

Procedure:
A 20-g portion of 2,4-dichloroquinazoline was added to 200 ml of pyridine. The reaction mixture was stirred 11/2 hours, refluxed 11/2 hours, and then allowed to stir under a calcium sulfate drying tube for 3 days. The reaction mixture was filtered. The resulting solid rinsed well with pyridine, then ether, and was dried in vacuo giving 35.9 g of 1,1'-(2,4-quinazolinediyl)bis[pyridinium] dichloride (m.p. 150°-164° ).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.75 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.CN([C:17]([O:21][N:22]1N=NC2C=CC=N[C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CONC>CN(C=O)C>[CH3:17][O:21][N:22]([CH3:23])[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)=[O:13]
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of quinoxaline-6-carboxylic acid (5.1 g, 29.3 mmol, 1.0 eq) in DMF (100 mL) were added HATU (13.3 g, 35 mmol 1.2 eq), DIEA (20 mL, 117.2 mmol, 4.0 eq) and O,N-dimethyl-hydroxylamine hydrochloride salt (3.38 g, 35 mmol, 1.2 eq). The mixture was stirred at rt overnight, then the solvent was evaporated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-methoxy-N-methylquinoxaline-6-carboxamide as yellow solid (5.1 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:8]1[C:13](Cl)=[N:12][CH:11]=[CH:10][N:9]=1)([CH3:7])[CH3:6])[CH3:2].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1C(F)(F)F)#[CH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:7])([C:8]1[C:13]([C:17]#[C:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:12][CH:11]=[CH:10][N:9]=1)[CH3:6])[CH3:2]
Reactant: C#Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)c1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)c1nccnc1C#Cc1ccccc1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a solution of 2-(3-Chloro-pyrazin-2-yl)-2-methyl-propionic acid ethyl ester (0.70 g) in acetonitrile (7.0 ml) was added 1-ethynyl-2-trifluoromethylbenzene (0.781 g) and caesium carbonate (“Cs2CO3”) (2.99 g) and nitrogen bubbled through the solution for 20 min. To this solution was added as 4,5-(bisdiphenylphosphino)-9,9-dimethylxanthene (“Xantphos”) (0.133 g) and (1,1′-bis(diphenylphosphino)-ferrocene)dichloro palladium(2) (0.125 g) and the reaction mixture heated to reflux for 30 min. The reaction mixture was cooled to ambient temperature then filtered and concentrated. The residue was purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give 2-methyl-2-(3-phenylethynyl-pyrazin-2-yl)-propionic acid ethyl ester (compound B1 of Table B) (0.52 g).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O:29]C)=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[C:31]#[N:32])=[CH:14][CH:13]=2)=[O:11])=[N:7][CH:8]=1.[OH-].[Na+].CO>C1COCC1.C(OCC)(=O)C.Cl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[C:31]#[N:32])=[CH:14][CH:13]=2)=[O:11])=[N:7][CH:8]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(C(F)(F)F)cn4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3ccc(C(F)(F)F)cn3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 23 %

Procedure:
Methyl 7-(4-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (9 mg, 0.018 mmol) was diluted with THF (500 μL) followed by the addition of sodium hydroxide (0.11 mL, 0.11 mmol) and methanol (100 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 1N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a reverse phase biotage 12iC18 column eluting with 0.1% TFA/5% ACN/95% water to 0.1% TFA/95% ACN/5% water to yield 7-(4-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid (2.0 mg, 23% yield). MS (ESI)=484.0 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([C:19]2[CH:18]=[CH:17][C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:21][CH:20]=2)=[CH:34][CH:33]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)cc1
Temperature: 95 °C
Yield: 60.1 %

Procedure:
A mixture of compound 3 (4.01 g, 10.1 mmol), 1-bromo-4-iodobenzene (5.73 g, 20.2 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and potassium carbonate (4.2 g, 30 mmol) in dioxane/water (60 ml/10 ml) was degassed and heated at 95° C. overnight. After being cooled to RT, the mixture was filtered to collect the precipitate, which was redissolved in hot dichloromethane. The dichloromethane solution was filtered and concentrated with presence of methanol till large amount white precipitate forms. Filtration and drying in air gave a white solid 12 (2.58 g, in 60% yield).