Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH3:15])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[C:18]1([C:24]2[C:25]3[C:30]([C:31]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[C:32]4[C:37]=2[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33]4)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=[CH:22][CH:21]=[CH: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.COCCOC>[C:18]1([C:24]2[C:37]3[C:32]([C:31]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[C:30]4[C:25]=2[CH:26]=[C:27]([C:2]2[CH:17]=[CH:16][C:5]5[N:6]([CH3:15])[C:7]([C:9]6[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=6)=[N:8][C:4]=5[CH:3]=2)[CH:28]=[CH:29]4)=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: Cn1c(-c2ccccc2)nc2cc(Br)ccc21
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: COCCOC
Product: Cn1c(-c2ccccc2)nc2cc(-c3ccc4c(-c5ccccc5)c5ccccc5c(-c5ccccc5)c4c3)ccc21
Yield: 76.1 %

Procedure:
1.4 g (4.9 mmol) of 5-bromo-1-methyl-2-phenyl-1H-benzimidazole, 2.0 g (5.3 mmol) of 9,10-diphenylanthracene-2-boronic acid, and 0.11 g (0.097 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 20 mL of 1,2-dimethoxyethane. Then, 10 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 2.0 g of a greenish white solid (76% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 536 with respect to a molecular weight of 536.23.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[N+]=[N-]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: Cc1ccc(Cl)cc1[C@H](OCCN=[N+]=[N-])[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
(R)-tert-butyl 3-((R)-(2-azidoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (7 g, 17.1 mmol.) was dissolved in EtOAc (300 mL), 0.8 g of Pd(OH)2 was added and the air in bottle was replaced 3 times with H2, the reaction was stirred at rt for 3 hr. The solution was filtered and concentrated to give (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (6.2 g), which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:20]#[N:21])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>>[C:20]([C:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][CH2:2][N:23]([CH3:22])[CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)#[N:21]
Reactant: COC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Reactant: CNCCc1ccc(C(=O)OC)cc1
Product: COC(=O)c1ccc(CCN(C)CCCC(C#N)(C(=O)OC)c2ccc(OC)c(OC)c2)cc1

Procedure:
Reaction of 1b with 2b produced 3i. MS found M+H=469. The oxalate salt of 3i was recrystallized from ethyl acetate; mp 80-83° C.
Reaction SMILES: [O:1]1[C:6]2[CH2:5][O:4][CH2:3][C:2]1=2.[C:7]1([C@H:13]([NH2:15])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Al](C)C>>[C:7]1([CH:13]([NH:15][CH:3]2[CH:2]([OH:1])[CH2:6][CH2:5][O:4]2)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: C1OCC2=C1O2
Agent: C[Al](C)C
Product: CC(NC1OCCC1O)c1ccccc1

Procedure:
According to the procedure of Overman, et al. (J. Org. Chem. 1985, 50, 4154), 3,4-epoxy-2,5-dihydrofuran was treated with (R)-1-phenylethylamine and trimethylaluminum to give a 1:1 mixture of diastereomers. The mixture was purified by silica gel chromatography to provide the desired compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:12][O:13][CH2:14][CH2:15]Br>CN(C=O)C>[CH3:7][O:6][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][O:1][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COC(=O)C(C)(C)CO
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCC(C)(C)C(=O)OC
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of methyl 3-hydroxy-2,2-dimethyl-propionate (2.72 mL, 21.28 mmol) in 3 mL of DMF is added 60% sodium hydride in mineral oil (1.70 g, 42.56 mmol) in one portion, followed by the addition of 2-bromoethyl methyl ether (4.0 mL, 42.56 mmol). The reaction mixture is stirred at room temperature for 3 hs. After this time, the reaction mixture is quenched with saturated aqueous NH4Cl solution and the product is extracted with DCM twice. The organics are combined and washed with water 4 times then brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound. Yield: 76%; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (6H, s), 3.36 (3H, s), 3.48 (2H, s), 3.48-3.52 (2H, m), 3.54-3.60 (2H, m), 3.67 (3H, s).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3[C:12]([C:20]([OH:22])=[O:21])=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17]2)=[CH:9][CH:8]=1)([OH:3])=[O:2].[CH:23](OCC)=[O:24].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH:23]([CH:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11]=2[C:10]2[C:18]1=[CH:19][C:7]([CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:8][CH:9]=2)=[O:24]
Reactant: O=C(O)CCCc1ccc2c(c1)Cc1cccc(C(=O)O)c1-2
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=CC1c2cc(CCCC(=O)O)ccc2-c2c(C(=O)O)cccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In a dry argon-purged flask with a reflux condenser, 7-(3-carboxy-propyl)-4-fluorenecarboxylic acid (4.0 g, 0.0135 mol) was dissolved in anh. DMF (120 mL) at 40° C. Ethyl formate (40 mL, stored over K2CO3 anh.) was added followed by addition of potassium tert-butoxide 95% (12.8 g, 0.108 mol, added in 2 portions). The reaction was stirred at about 40° C.-50° C. for four hours with the addition of anh. DMF (80 mL), anhydrous THF (5 mL) and ethyl formate (25 mL) at various intervals to aid solubility. The reaction was then stirred another 17 hours at room temperature. The ethyl formate was evaporated at reduced pressure. The reaction was quenched with water (150 mL) and acidified to pH 2 with concentrated HCl. The product was twice extracted with ethyl acetate (600 mL then 200 mL). The combined organic layers were washed 3 times with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product (4.7 g, ˜100%, purity 80%) contained some unreacted starting material. 1H-NMR (d6-DMSO): δ (ppm) 11.4 (s, 1H, formyl); 8.3-7.0 (m, 7H, Ar); 2.7 (m, 2H, CH2); 2.3 (m, 2H, CH2); 1.9 (m, 2H, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Br[CH2:26][C:27]#[N:28].O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:26][C:27]#[N:28])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.50 g, 1.84 mmol) in dimethyl formamide (50 ml) under nitrogen at room temperature, was added sodium hydrogen carbonate (1.50 g) followed by bromoacetonitrile (1.9 ml). The reaction mixture was stirred at room temperature for 16 h, then poured into water and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (MgSO4), filtered and the solvent was removed in vacuo to leave an oily residue. Trituration with diethyl ether, followed by recrystallisation from an ethyl acetate, petrol (60-80) mixture, gave the title compound as a white solid (0.15 g). Mp 209°-211° C. Found: C, 65.60; H, 3.74; N, 8.75; C17H11N2O2Cl requires C, 65.71; H, 3.57; N, 9.02%. δ (360 MHz, DMSO-d6) 4.59 (2H, s, OCH2CN), 7.31 (1H, dd, J=8.63 Hz, J=2.10 Hz, 6-H), 7.40-7.49 (6H, m, Ph+8-H), 7.83 (1H, d, J=88.63 Hz, 5-H), 12.10 (1H, bs, NH). m/z (CI+), 311, (M+1).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)c1c[nH]c2ccc(N)cc12
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1c[nH]c2ccc(NS(=O)(=O)c3ccccc3)cc12
Reaction time: 16 h
Yield: 99 %

Procedure:
A solution of 3-acetyl-5-aminoindole (1.57 g, 9 mmol) in pyridine is treated dropwise at 0° C. with benzenesulfonyl chloride (1.25 g, 9.9 mmol), stirred for 16 h at ambient temperatures, poured into dilute aqueous HCl and extracted with ethyl acetate. The combined extracts are washed sequentially with water and brine, dried over Na2SO4 and concentrated in vacuo to afford the title product as a white solid, 2.8 g (99% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([I:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:14]1([CH3:27])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][C:22](OCC)=[O:23].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Cl:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4]([OH:6])=[C:21]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:27])[C:22](=[O:23])[NH:1]2)=[CH:8][C:9]=1[I:13]
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Reactant: CCOC(=O)COc1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1c(O)c2cc(I)c(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (1 g, 3.21 mmol) and ethyl 2-(o-tolyloxy)acetate (Aldrich, 0.655 g, 3.37 mmol) were dissolved in THF (10 mL) and KHMDS 1M/THF (9.63 mL, 9.63 mmol) was added in one portion at room temperature under N2. The reaction mixture was stirred at room temperature for 1 h before quenched with MeOH and concentrated under reduced pressure. The residue was dissolved in 1N NaOH then extracted with Et2O. The aqueous extracts were acidified with 1N HCl and the resulting precipitate was collected by filtration then washed successively with water and diethyl ether to give 7-chloro-4-hydroxy-6-iodo-3-(o-tolyloxy)quinolin-2(1H)-one (1.03 g, 2.409 mmol, 75% yield) as white solid. LCMS: (M+H)+=428; Rt=2.46 min.
Reaction SMILES: [CH3:1][C:2]1([OH:15])[C:7]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:6][CH2:5][CH:4]=[C:3]1[CH3:14].[Li][CH2:17]CCC.CI>C1COCC1>[CH3:17][O:15][C:2]1([CH3:1])[C:3]([CH3:14])=[CH:4][CH2:5][CH2:6][C:7]1([CH3:13])[CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]
Reactant: CC(C)=CCC1(C)CCC=C(C)C1(C)O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC1(C)C(C)=CCCC1(C)CC=C(C)C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 1,2,6-trimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enol (5.00 g, 24.0 mmol) in THF (80 ml) was added n-BuLi (1.6M in hexane, 16.5 ml, 26.4 mmol) at 0° C. After the mixture was stirred for 30 min, methyl iodide (5.18 g, 36.5 mmol) was added. The mixture was stirred at room temperature over night and then poured on ice and extracted with MTBE. The organic phase was washed with H2O and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled (bp. 75° C./0.2 Torr) to yield 5.0 g (93%) of an colorless oil containing 2 isomers: 1H-NMR (400 MHz, CDCl3): 5.64 (bs, 1H, 2-H), 5.23-5.15 (m, 1H, CH2CH═C(CH3)2), 3.30, 3.28 (2s, 3H, O—CH3), 2.22-2.12 (m, 1H), 1.99-1.88 (m, 3H), 1.75-1.58 (m, 10H), 1.20,1.18 (2s, 3H), 0.93, 0.79 (2s, 3H) ppm. MS (EI): 222 (M+, 1), 190 (11), 175 (10), 147 (60), 121 (100), 112 (30), 105 (57), 91 (40), 79 (25), 69 (14), 41 (45). IR (ATR): 2966s, 2926s, 1449s, 1377s, 1083vs, 858m cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([C:28](O)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:28]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:29])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step A except using 1-tert-butoxycarbonyl-2(S)-n-butylpiperazine (0.325 g, 1.34 mmol), 1-naphthalene carboxylic acid (0.230 g, 1.34 mmol), HOBT (0.203 g, 1.34 mmol), EDC.HCl (0.254 g, 1.34 mmol) and triethylamine to adjust the pH to 7. The title compound was obtained as a thick oil (0.490 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])[C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@H:20]3[C:26]([CH3:28])([CH3:27])[C@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
Trifluoroacetic acid (80 mL) was added to a solution of crude N′-(2,4-difluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜100 mmol) in dichloromethane (80 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, and then at room temperature for 4 h. The solvent was evaporated. The residue was taken up in dichloromethane (500 mL) and washed with water (4×600 mL) adding brine to help separate the layers when necessary. The solution was further washed with brine (250 mL), dried (magnesium sulfate), filtered, and evaporated. The solids were triturated with 10% dichlormethane/hexanes, filtered, washed with 5% dichloromethane/hexanes and then hexanes, stored over a weekend in the freezer, and then dried under high vacuum to give (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (25.71 g, 84%) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:27][CH2:26]1.Cl.O1CCOCC1>CS(C)=O>[NH2:32][CH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(COc2cccc(-c3cc(F)ncc3Cl)n2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(OCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 102.5 °C
Reaction time: 40 h

Procedure:
To 5′-chloro-2′-fluoro-6-(3-fluorobenzyloxy)-2,4′-bipyridine (30 mg, 0.090 mmol) was added DMSO (0.8 ml), TEA (0.025 ml, 0.180 mmol), and tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (41.2 mg, 0.180 mmol). The reaction mixture was flushed with argon and stirred at 100-105° C. for 40 hr. Formation of the intermediate product tert-butyl(trans-4-(5′-chloro-6-(3-fluorobenzyloxy)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methylcarbamate was indicated by LCMS. (LCMS (m/z): 541.4 (MH+), retention time=1.05 min.). The solvent DMSO was removed under reduce pressure. The Boc group was removed from the intermediate by adding 4M HCl in Dioxane (1.5 ml, 6.00 mmol), followed with stirring at ambient temperature for 90 minutes. The solvent was removed under reduced pressure. The crude product was dissolved in 1.0 ml of DMSO with 0.075 ml of water, filtered and purified by prep LC. After lyophilization, 28.3 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 441.3 (MH+), retention time=0.76 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.12-1.29 (m, 2 H) 1.29-1.47 (m, 2 H) 1.60-1.76 (m, J=14.76, 7.51, 3.66, 3.66 Hz, 1 H) 1.92 (d, J=12.60 Hz, 2 H) 2.16 (d, J=10.55 Hz, 2 H) 2.84 (d, J=6.74 Hz, 2 H) 3.58-3.71 (m, 1 H) 5.43 (s, 2 H) 6.92-6.99 (m, 2 H) 6.99-7.08 (m, 1 H) 7.18 (d, J=9.67 Hz, 1 H) 7.25 (d, J=7.62 Hz, 1 H) 7.30-7.42 (m, 2 H) 7.83 (t, J=7.77 Hz, 1 H) 8.01 (s, 1 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[N:23]([CH3:22])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CNc1ccccc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: CN(C(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)c1ccccc1
Yield: 70 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using N-methylaniline (23 μL, 0.21 mmol) as the coupling partner. Concentration (no chromatography) yielded 45 mg (70%) of the titled compound. ESI-MS m/z 381 (MH+), 379 (M−H−).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9](CC2C=CC(OC)=CC=2)[NH:8][C:7](=[O:21])[CH:6]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:10](=[O:11])[NH:9][NH:8][C:7](=[O:21])[CH:6]=1
Reactant: COc1ccc(Cn2[nH]c(=O)cc(CCCO)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=c1cc(CCCO)c(=O)[nH][nH]1
Temperature: 40 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
5-(3-Hydroxypropyl)-1-{[4-(methyloxy)phenyl]methyl}-1,2-dihydro-3,6-pyridazinedione (2.734 g) was treated with anisole (10 ml) and TFA (100 ml) and stirred at 40° C. overnight. The solution was cooled, evaporated to dryness and kept under high vacuum for 30 minutes. The residue was taken up in MeOH (150 ml), refluxed for 12 hours, cooled and evaporated. The residue was kept for 1 hour under high vacuum, triturated under ether and the solid was filtered off. Drying under vacuum gave the product as a solid (1.48 g, 92%).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH3:20])=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:17][C:16]=2[C:27](N(OC)C)=[O:28])=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[CH2:33]1COC[CH2:34]1>>[CH3:20][C:19]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=2)=[C:16]([C:27](=[O:28])[CH2:33][CH3:34])[S:17][C:18]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CON(C)C(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reactant: C1CCOC1
Product: CCC(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 72.5 °C

Procedure:
To a stirred solution of 3-(4-(N-((dimethylamino)methylene) sulfamoyl)phenyl)-N-methoxy-N,4-dimethyl-5-morpholinothiophene-2-carboxamide (compound 24f, 0.120 g, 0.25 mmol) in anhydrous THF (10 ml) at 25° C., Grignard reagent (ethyl magnesium bromide, 0.17 g, 1.25 ml, 1.25 mmol) was added dropwise and the reaction mixture was heated to 70-75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., reaction mixture was quenched by adding a saturated ammonium chloride solution (10 ml) and the resulting mixture was extracted with ethyl acetate (2×20 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent in the dried organic layer was evaporated under a reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 40-45% ethyl acetate in hexane as an eluent to obtain the title compound which was further purified by precipitation by dissolving 0.056 g of this compound in ethyl acetate (1.0 ml) and precipitating it by the slow addition of diisopropyl ether. The precipitate was filtered to obtain the title compound. (0.047 g, 48%).
Reaction SMILES: C[O-].[Na+].[C:4]([OH:8])(=[O:7])[CH2:5][SH:6].Cl[CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CO>[C:4]([OH:8])(=[O:7])[CH2:5][S:6][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)CS
Reactant: CCCCCCCCC#CCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCC#CCC#CCSCC(=O)O
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
2.02 ml of a 30% solution of sodium methoxide in methanol were added dropwise to a solution of 372 μl of thioglycolic acid in 5 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then a solution of 1.2 g of 1-chloro-2,5-tetradecadiyne in 6 ml of methanol was added under an inert atmosphere. The mixture was maintained under stirring for 20 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4) filtered and concentrated under vacuum in a rotary evaporator. The oily residue obtained crystallized on cooling. 3-Thia-5,8-heptadecadiynoic acid was recrystallized from heptane and then from hexane and finally from diisopropyl ether. The acid was thus isolated in the form of beige crystals with a yield of 49.4%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18](O)=[O:19])(=O)[CH3:10].P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:10][C:9]1[N:4]([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Br:1])[C:18](=[O:19])[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[N:12]=1
Reactant: CC(=O)Nc1ccsc1C(=O)O
Reactant: Nc1ccccc1Br
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: Cc1nc2ccsc2c(=O)n1-c1ccccc1Br
Temperature: 105 °C
Yield: 42.7 %

Procedure:
To a mixture of pyridine (6 mL), 2-bromoaniline (1.03 g, 6 mmol), and 3-acetamidothiophene-2-carboxylic acid (0.555 g, 3 mmol) was added phosphorus trichloride (0.03 mL, 3.45 mmol). The reaction was heated to 105° C. for 4 hours, cooled to ambient temperature and partitioned between chloroform and water (an insoluble precipitate was removed by filtration). Phases were separated and the aqueous layer was extracted with chloroform. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to a dull yellow film. This residue was flash chromatographed on silica gel (30×125 mm) eluting with 15-25% ethyl acetate/hexane to afford 0.411 g (47%) of 2-methyl-3-(2-bromophenyl)-3H-thieno[3,2-d]pyrimidin-4-one as a yellow foam.