Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]1[N:6]=[N:7][S:8][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:11].Cl[S:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>O>[CH3:4][C:5]1[N:6]=[N:7][S:8][C:9]=1[C:10]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[S:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:11]
Reactant: Cc1ccc(NC(=O)c2snnc2C)cc1
Reactant: ClSN1CCOCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(SN2CCOCC2)C(=O)c2snnc2C)cc1
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To 10 ml of methylene chloride were added 0.50 g (2.1 mmol) of 4-methyl-N-(4-methylphenyl)-1,2,3-thiadiazole-5-carboxamide and 0.50 g (3.3 mmol) of N-(chlorosulfenyl)morpholine. Then, 0.33 g (3.3 mmol) of triethylamine was slowly added thereto, and the resulting mixture was reacted with stirring for 5 hours. After the reaction was completed, the reaction mixture containing the objective product was poured into water, the objective product was extracted with ethyl acetate, the organic layer was washed with water and dried on anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude crystal thus obtained was washed with ether. As a result, 0.38 g of the objective compound was obtained (Property: m.p. 60° C. (decomposed); Yield: 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][C:7](=[O:15])[NH:8]2.[CH3:16][Mg]Br>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:16])[NH:6][C:7](=[O:15])[NH:8]2
Reactant: COc1ccc2[nH]c(=O)ncc2c1OC
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1OC)C(C)NC(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a partial solution of 5,6-dimethoxy-2(1H)quinazolinone (10.0 g, 48.5 mM) in dry tetrahydrofuran (1100 ml) under nitrogen, is added at 0° C. over 20 minutes, an excess of methyl magnesium bromide in ether (62.60 ml of a 3.1M solution in ether, 194.06 mM). The reaction mixture is then removed from the cooling bath, allowed to reach room temperature and is stirred at room temperature for 16 hours. Additional methyl magnesium bromide is added (15.65 ml of a 3.1M solution in ether; 48.52 mM) and the reaction mixture is heated at reflux for 2 hours, cooled in an ice-water bath and an aqueous solution of NH4Cl (100 ml of saturated NH4Cl and 100 ml H2O) is added with stirring. After the addition is complete, 10% aqueous HCl is added until a pH of ~6.0 is reached. The layers are separated and the aqueous layer is extracted with CHCl3 (3× 250 ml). The CHCl3 extract is combined with the previously separated tetrahydrofuran layer, and the combined organic layers are washed with a saturated aqueous solution of NaCl (200 ml) and dried (Na2SO4). Filtration followed by concentration to ~250 ml affords an off-white precipitate which is filtered and recrystallized from isopropanol (200 ml) to give the product as a colorless solid; yield 9.7 g (87.8%), m.p. 210°-212° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Using General Procedure 1; a solution of ethyl 4-[4-(1-benzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 111, 75.0 mg, 0.19 mmol) in ethanol (4 mL) and tetrahydrofiran (4 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (50%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][C:26]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:26]=2[CH3:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(C=O)c1C
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Cc1cccc(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1C

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2,3-dimethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 450.2.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][N:6]2[N:5]=1.[CH3:33][N:34]1[CH:38]=[C:37]([C:39](O)=[O:40])[N:36]=[CH:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CCOC(C)=O.O.CN(C=O)C>[CH3:33][N:34]1[CH:38]=[C:37]([C:39]([NH:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][N:6]3[N:5]=[C:4]([CH3:3])[C:16]([C:17]4[S:18][C:19]([C:28]5[N:32]=[CH:31][NH:30][N:29]=5)=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)=[C:7]3[CH:8]=2)=[O:40])[N:36]=[CH:35]1
Reactant: Cc1nn2ccc(OCCN)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn2ccc(OCCNC(=O)c3cn(C)cn3)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 29.5 %

Procedure:
A mixture of 2-({2-methyl-3-[4-phenyl-5-(1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridin-5-yl}oxy)ethanamine di-hydrochloride (100 mg, 0.20 mmol) obtained in Example 73-B(i), TEA (1.5 mL), 1-methyl-1H-imidazole-4-carboxylic acid (120 mg, 0.95 mmol), HOBT (220 mg, 1.6 mmol), EDCI (350 mg, 1.8 mmol) and DMF (10 mL) was stirred at rt for 14 h. To the reaction mixture were added water (200 mL) and EtOAc (200 mL) and the mixture was stirred for 30 min. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc and diisopropyl ether, and dried to give the title compound (31 mg, 29%) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[C:18]=3[F:28])[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:26](=[CH:25][C:20]5[O:21][CH2:22][CH2:23][O:24][C:19]=5[C:18]=4[F:28])[O:27][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1C(c2c(O)cc3c(c2F)OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(c(F)c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one was obtained (95%) as an off-white solid: MS (ES+) m/z 479.8 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[Si](C=[N+]=[N-])(C)(C)[CH3:14]>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([O:8][CH3:14])=[O:7])#[N:2]
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(F)cc(C#N)c1
Reaction time: 1 h

Procedure:
(Step 1) To a solution of 3-cyano-5-fluorobenzoic acid (1.0 g) in methanol (20 ml) was added TMS diazomethane (2M diethyl ether solution, 5 ml) at 0° C., and the mixture was stirred for 1 hr. The reaction solution was quenched with water and diluted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give methyl 3-cyano-5-fluorobenzoate (0.58 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:31])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[CH:32]([Mg]Br)=[CH2:33]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([OH:31])([CH:32]=[CH2:33])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=1
Reactant: C=C[Mg]Br
Reactant: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C1OCCCO1
Solvent: C1CCOC1
Product: C=CC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C1OCCCO1
Temperature: -60 °C

Procedure:
To a solution of 1-(2-(1,3-dioxan-2-yl)phenyl)-2-(3,5-bis(trifluoromethyl)benzyloxy)ethanone (1.06 g, 2.36 mmol) in tetrahydrofuran (15 mL) at −78° C. was added vinylmagnesium bromide (1 M in tetrahydrofuran, 4.73 mL, 4.73 mmol). The reaction was allowed to warm to −60° C. in the Dewar flask before quenching with saturated ammonium chloride. The reaction was poured into diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%-->25% EtOAc/Hex) gave 810 mg (72%) as a colorless oil. Mass spec.: 499.30 (MNa)+.
Reaction SMILES: FC1C=C(C2C(C)=C(O)C(=O)N(CC(C)C)N=2)C=CC=1C.[C:22]([C:25]1[C:26](=[O:41])[N:27]([CH2:37][CH:38]([CH3:40])[CH3:39])[N:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=1)(O)=[O:23]>>[OH:23][CH2:22][C:25]1[C:26](=[O:41])[N:27]([CH2:37][CH:38]([CH3:39])[CH3:40])[N:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=1
Reactant: CC(C)Cn1nc(-c2ccccc2)cc(C(=O)O)c1=O
Agent: Cc1ccc(-c2nn(CC(C)C)c(=O)c(O)c2C)cc1F
Product: CC(C)Cn1nc(-c2ccccc2)cc(CO)c1=O
Yield: 22.3 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-isobutyl-6-phenyl-2H-pyridazin-3-one was reacted to yield the title compound as colorless fine-needles (yield: 22.3%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40]>C1COCC1.CCOC(C)=O>[OH:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][NH:34][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: NCCOCCO
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCCOCCO)c3)n2)n1
Yield: 61.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with commercially available 2-(2-aminoethoxy)ethanol (0.194 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.210 g, 61%) as a white solid. MS (ISP) 558.2 [(M+H)+]; mp 123° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: C#CCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#CCON=C(C(=O)O)c1csc(N)n1
Yield: 77.3 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 2.8 g.), methanol (23 ml.), tetrahydrofuran (20 ml.) and 1N aqueous solution of sodium hydroxide (22.17 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.924 g.).
Reaction SMILES: O.[C:2]([C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[OH:22])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23](O)[CH3:24]>>[C:2]([C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:13]([C:14]([O:16][CH2:23][CH3:24])=[O:15])=[CH:12][C:11]=1[OH:22])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: O=C(O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Solvent: O
Product: CCOC(=O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1

Procedure:
A solution of 4-benzoyl-3-hydroxy-5-nitrobenzoic acid, monohydrate prepared as described in Example 1, step A, (100 g) in dry ethanol (2 liter) is evaporated in vacuo in order to remove the water of crystallization. The residue is redissolved in dry ethanol (2 liter), conc. sulfuric acid (45 ml) is added and the solution is refluxed for 20 hours. The excess of ethanol is removed in vacuo, and the residue is triturated with a saturated sodium hyrogen carbonate solution (about 900 ml). The resulting material is collected by filtration and washed with water. After drying and recrystallization from aqueous ethanol, ethyl 4-benzoyl-3-hydroxy-5-nitrobenzoate is obtained with a melting point of 167°-168° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=CCCCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCCCc2ccccc2)CC1

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(4-phenylbutylidene)piperidine (216 mg, 0.69 mmol) in MeOH (10 mL) was added 20% Pd(OH)2/C (50 mg). The mixture was warmed to reflux under a H2 atmosphere for 6 h. After filtration and concentration, 1-(tert-butoxycarbonyl)-4-(4-phenylbutyl)piperidine was obtained (202 mg, 92%) as a pale yellow oil, which was used in the following step without purification. 1H NMR (CDCl3, 400 MHz) δ 7.27 (m, 2H), 7.19 (m, 3H), 4.07 (d, 2H, J=12.0 Hz), 2.63 (m, 4H), 1.57 (m, 3H), 1.46 (s, 9H), 1.34 (m, 3H), 1.24 (m, 3H), 1.06 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:23][CH2:22][C:6]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:4]1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:26].Cl>C(N(CC)CC)C>[O:20]=[C:19]1[C:9]2[S:8][CH2:7][C:6]3([CH2:22][CH2:23][CH:3]([NH:2][C:25](=[O:26])[O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=4)[CH2:4][CH2:5]3)[O:11][C:10]=2[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]1=[O:21]
Reactant: NC1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O
Reactant: O=C(Cl)Oc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NC1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O)Oc1cccc(C(F)(F)F)c1

Procedure:
Compound 108 was synthesized using 4-aminospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione hydrochloride, 3-(trifluoromethyl)phenyl chloroformate, triethyl amine to neutralize the hydrochloride and conditions outlined in procedure S. M.p.=198-199° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.08 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.4 Hz, 1H), 7.83 (t, J=7.1 Hz, 1H), 7.78 (t, J=7.1 Hz, 1H), 7.66-7.43 (m, 4H), 3.56-3.47 (m, 1H), 3.04 (s, 2H), 2.16-2.05 (m, 2H), 1.94-1.80 (m, 2H), 1.78-1.66 (m, 7H), LCMS: 504 [M+H].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24]>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C#N)cc4)c3)cnc2c1F
Yield: 10 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-cyanobenzeneboronic acid were coupled in the same way as in Example 30 to give 2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)-imidazo[1,2-α]pyridin-3-yl]biphenyl-4-carbonitrile as an off-white solid (12 mg, 10%): m/z (ES+) 390 [MH+].
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][N:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: C[C@H]1CCCCN1c1nnc2ccc(F)cn12
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58.4 %

Procedure:
To a solution of Intermediate A (374 mg, 2.29 mmol) in dry DMF (3 mL) under N2 was added NaH (60% dispersion in oil, 183 mg, 4.58 mmol) and the resulting opaque brown solution was stirred at RT for 45 min (CARE: gas evolution). A solution of Intermediate 81c (537 mg, 2.29 mmol) in dry DMF (7 mL) was added and the dark brown solution stirred at 60° C. under N2 for 90 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (3 mL) and AcOH (0.10 mL) and then applied to an SCX-2 cartridge (20 g), washing with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave a dark brown solid. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave the title compound as a pale brown foam (505 mg, 58%). LCMS (Method 3): Rt 2.29 min, m/z 378 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16](=[O:30])[C@@H:17]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]([C:31]([NH:33][C@:34]1([C:39](O)=[O:40])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:32])[CH2:9]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:57]1([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:59][CH2:58]1.N12CCCN=C1CCCCC2>ClCCCl.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16](=[O:30])[C@@H:17]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[C:18]([CH3:19])([CH3:21])[CH3:20])[CH:10]([C:31]([NH:33][C@:34]1([C:39](=[O:40])[NH:63][S:60]([CH:57]3[CH2:59][CH2:58]3)(=[O:62])=[O:61])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:32])[CH2:9]2
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1Cc2cc(Oc3cccc(Cl)c3)ccc2CN1C(=O)[C@@H](Nc1ccc(F)cc1)C(C)(C)C)C(=O)O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=C[C@@H]1C[C@]1(NC(=O)C1Cc2cc(Oc3cccc(Cl)c3)ccc2CN1C(=O)[C@@H](Nc1ccc(F)cc1)C(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The crude (1R,2S)-1-(6-(3-chlorophenoxy)-2-((S)-2-(4-fluorophenylamino)-3,3-dimethylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-2-vinylcyclopropanecarboxylic acid (112 mg, 0.180 mmol) was dissolved in 1.0 mL of 1,2-dichloroethane (DCE) and 1,1′-carbonyldiimidazole (CDI, 88 mg, 0.54 mmol) was added. The reaction was heated to 40° C. for 4 h. TLC run in 10% MeOH/CHCl3 showed conversion to a higher Rf spot. Cyclopropyl sulfonamide (65 mg, 0.54 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 81 μL, 0.54 mmol) were added and the reaction heated to 50° C. and stirred overnight. The reaction was concentrated to 400 μL volume and loaded on a Biotage size 12, C-18 samplet for purification using the Horizon LC (12 m, C-18 column) eluting with a gradient from 0% acetonitrile/water to 100% acetonitrile/water over 40-6 mL fractions. Upon concentration product is a white solid. Compound 10 (26 mg, 20%) 1H NMR (CDCl3, 500 MHz): δ 9.72 (br s, 1H), 7.32-7.22 (m, 1H), 7.20-7.07 (m, 2H), 7.02-6.68 (m, 7H), 6.58 (br s, 1H), 5.85-5.49 (m, 2H), 5.31-5.03 (m, 2H), 4.83-4.67 (m, 2H), 4.54-4.42 (m, 1H), 4.32 (br s, 1H), 4.18 (br s, 1H), 3.24-2.76 (m, 3H), 1.94 (br s, 1H), 1.86-1.18 (m, 5H), 1.17-0.95 (m, 10H); MS m/e 722 (M−−H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:42](I)[CH3:43]>CC(C)=O>[CH2:42]([C:25]1([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])[CH3:43]
Reactant: O=C1c2ccccc2C(=O)C1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(=O)c2ccccc2C1=O
Temperature: 20 °C

Procedure:
The intermediate 2-(1-Trityl-1H-imidazole-4-yl)indan-1,3-dione (79.4 g, 0.175 mol), potassium carbonate (72.5 g, 0.875 mol) and ethyl iodide (71 mL, 0.522 mol) were added to stirred acetone (1300 mL) in a 4-liter glass reactor, fitted with a mechanical stirrer, a thermometer and a reflux condenser. The reaction mixture was heated to reflux for 7 hours, then cooled to 20° C. and filtered. The inorganic residue on the filter was washed with acetone. The filtrate was concentrated in vacuo and poured into water.