Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[C:21]1([C:27]2[O:28][C:29]([CH3:34])=[C:30]([CH2:32]I)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:10]([CH2:9][O:8][CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([O:1][CH2:32][C:30]3[N:31]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:28][C:29]=3[CH3:34])[CH2:3]2)[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Cc1oc(-c2ccccc2)nc1CI
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4ccccc4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-phenyl-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 69 of molecular weight 435.52 (C26H29NO5), MS(ESI): 436.32 (M+H+).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][NH2:17])[CH:9]=[CH:8]1.C(N(CC)CC)C>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][NH:17][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[CH:9]=[CH:8]1
Reactant: CC(Br)C(=O)Cl
Reactant: NCc1cccc2cc[nH]c12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)NCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Add 2-bromopropionyl chloride to a solution of (indol-7-yl)methylamine and triethylamine (0.49 g, 47.6 mmol) in tetrahydrofuran (20 ml) at 0° C. Stir for 1 hour at room temperature and quench with saturated aqueous sodium bicarbonate. Extract with ethyl acetate, concentrate under reduced pressure and subject the residue to silica gel chromatography to provide the desired compound (0.62 g, 46%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH:20]([CH:22]1[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:25](=[O:36])[CH2:24][S:23]1)=O.Cl>COCCOC.O>[O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[CH:3]=[CH:20]/[CH:22]1[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:25](=[O:36])[CH2:24][S:23]1
Reactant: O=CC1SCC(=O)N1CCCCCCC(=O)O
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)CCCCCCN1C(=O)CSC1/C=C/C(=O)CCc1ccccc1
Temperature: 25 °C

Procedure:
Dimethyl 2-oxo-4-phenylbutylphosphonate (1 molar equivalent) is added dropwise over a 1/2 hour period to a stirred suspension of sodium hydride (2equivalents) in 1,2-dimethoxyethane maintained at or below 20° C. To the resulting reaction mixture is slowly added 7-(2-formyl-4-oxo-3-thiazolidinyl)heptanoic acid (1 molar equivalent) with good stirring and cooling (sufficient to maintain a reaction temperature at or below 20° C.). Upon completing this addition, the reaction is stirred at ambient temperature for 1 hour, then heated at reflux for 1/2 hour, cooled to room temperature, and diluted with water. The aqueous mixture is acidified with dilute hydrochloric acid and extracted with ether. The organic extract is dried over sodium sulfate, filtered, and evaporated in vacuo at 40° C. leaving the title compound as an oily residue which is purified chromatographically on silica gel.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[CH:24](=O)[CH2:25][CH3:26].[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH2:24][CH2:25][CH3:26])[C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C)CO3
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.6 %

Procedure:
This compound was prepared according General Method 6 (EXAMPLE 3) from (3R)-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (11 mg, 0.03 mmol), propionaldehyde (0.3 mmol, 10 eq) and NaCNBH3 (10 equiv) in 4 mL TFA (0.03 M) stirred at rt for 12 h to afford 12 mg (100%) of (R)-3,4-dihydro-8-isopropoxy-3-methyl-4-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (12 mg, 0.030 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 3 mL acetic acid and 3 mL concentrated HCl and heated at 90° C. for 4 h to afford 8 mg (75%) of Compound 105 after purification by silica gel chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ11.15 (bs, 1H), 7.10 (s, 1H), 6.99 (d, J=8.8, 1H), 6.88 (d, J=8.8, 1H), 4.11 (dd, J=10.7, 3.2, 1H), 4.03 (dd, J=10.7, 2.4, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 3.14 (m, 1H), 1.64 (m, 2H), 1.21 (d, J=6.4, 3H), 0.97 (t, J=7.3, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2([F:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([Cl:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>C(Cl)Cl>[ClH:45].[F:25][C:10]1([C:6]2[CH:5]=[C:4]([NH:3][S:42]([C:39]3[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=3)(=[O:44])=[O:43])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3(F)CCN(CCOc4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a suspension of 4-(3-aminophenyl)-1-(2-phenoxyethyl) 4-fluoropiperidine dihydrochloride (100 mg, 0.26 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (118 mg, 0.91 mmol) and the mixture stirred at room temperature until a clear solution resulted. This solution was then cooled to 0° C. and 4-methyl-benzenesulfonyl chloride (58 mg, 0.28 mmol) was then added and the reaction stirred at 0° C. for 1 hour then room temperature for 3 hours. After this time the mixture was quenched by the addition of 25% ammonium chloride solution (10 mL). The organic layer was separated and the aqueous extracted with ethyl acetate (2×10 mL). The combined extracts were dried over magnesium sulfate and filtered and concentrated. The residue was re-dissolved in ethyl acetate (20 mL), washed with water (2×10 mL) and brine (10 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated to a viscous yellow oil which was treated with 10% methanolic hydrogen chloride (10 mL) and re-concentrated. The residue was triturated with ethyl acetate (5 mL) and then dried under high vacuum to afford a 49% yield of the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38](=[O:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:38]([C:34]1[S:35][CH:36]=[CH:37][C:33]=1[NH:32][C:28]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]1)=[O:29])(=[O:40])[CH3:39]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)c1sccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1sccc1NC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 1-(3-aminothiophen-2-yl)ethanone (140 mg, 0.98 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.3 mL, 1.67 mmol) in CH2Cl2 (5 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetyl-thiophen-3-yl)-amide as a off white powder (40 mg, 15.8%). HRMS (ES+) m/z Calcd for C29H27Cl2F2N3O2S+H [(M+H)+]: 590.1242. found: 590.1244.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].[NH2:17][C:18]1[N:23]=[C:22](S(CC2C=CC=CC=2)=O)[N:21]=[C:20]([C:33]2[C:34]([Cl:44])=[CH:35][C:36]([Cl:43])=[C:37]([CH:42]=2)[O:38][CH2:39][C:40]#[N:41])[N:19]=1>CN(C)C=O>[NH2:17][C:18]1[N:23]=[C:22]([S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH3:8])[N:21]=[C:20]([C:33]2[C:34]([Cl:44])=[CH:35][C:36]([Cl:43])=[C:37]([CH:42]=2)[O:38][CH2:39][C:40]#[N:41])[N:19]=1
Reactant: COc1ccccc1S
Reactant: N#CCOc1cc(-c2nc(N)nc(S(=O)Cc3ccccc3)n2)c(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1Sc1nc(N)nc(-c2cc(OCC#N)c(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Triethylamine (12 μL) and 2-methoxybenzenethiol (12 mg) were added in succession to a solution of the above-described [5-(4-amino-6-phenylmethanesulfinyl-[1,3,5]triazin-2-yl)-2,4-dichlorophenoxy]-acetonitrile (12 mg) in dimethylformamide (0.5 mL). The mixture was stirred at room temperature for 8 hours. After dilution with ethyl acetate (7 mL), the mixture was washed twice with water and once with brine. The mixture was pre-dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=7:3) to give {5-[4-amino-6-(2-methoxy-phenylsulfanyl)-[1,3,5]triazin-2-yl]-2,4-dichlorophenoxy}-acetonitrile as white solid (10 mg).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)CCCCC.Cl>>[OH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:13](=[O:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC(=O)Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCC(=O)c1ccccc1O
Temperature: 120 °C

Procedure:
24 g (0.18 mole) of powdered aluminium trichloride were carefully added to 31 g (0.16 mole) of phenyl hexanoate and the mixture was slowly heated with occasional stirring to 120° C and was held there for 11/2 hours. The residue was ground into a powder and was poured into iced dilute hydrochloric acid with stirring. The mixture was extracted with ether and the ether extracts were washed with dilute sodium hydroxide solution, then with water, dried over magnesium sulfate and evaporated to dryness to obtain 14.2 of (1-(2'-hydroxyphenyl)-hexan-1one as a pale yellow oil. IR spectrum showed o-hydroxyphenylcarbonyl at 1650cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[O:20]=[C:18]([CH3:19])[CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: N#Cc1ccccc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(-c2ccccc2C#N)cc1
Temperature: 60 °C
Yield: 116.5 %

Procedure:
The title B compound of Example 1, 4'-hydroxy-[1,1'-biphenyl]-2-carbonitrile (3.00 g, 15.4 mmol) was dissolved in acetone (8 mL) and chloroacetone (1.59 mL, 20.0 mmol), freshly ground potassium carbonate (2.12 g, 15.4 mmol) and potassium iodide (128 mg, 0.77 mmol) were added. The mixture was heated to 60° C. for 15 hours then partitioned between hydrochloric acid (1.0 M) and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic extracts dried over magnesium sulfate, filtered and the solvent removed to yield a tan solid (4.51 g). This solid was recrystalized from a mixture of toluene and hexane to yield a tan solid (3.34 g, 87%); m.p. 102-105° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][S:24][C:25](=O)[CH3:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].Cl[C:33]1C=C[N:36]=[CH:35][N:34]=1>CO>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][S:24][C:25]3[CH:26]=[CH:33][N:34]=[CH:35][N:36]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)SCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Clc1ccncn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCCSc1ccncn1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
A solution of 1.00 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(acetylthio)butyramide [prepared as described in step (a) above] in 10 ml of methanol was added to a mixture of 0.48 g of 28% w/v methanolic sodium methoxide and 5 ml of methanol, whilst ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. At the end of this time, 0.28 g of 4-chloropyrimidine was added to the mixture and the mixture was heated under reflux for 2 hours. The solvent was then removed by evaporation under reduced pressure, and water was added to the resulting residue, which was then extracted with ethyl acetate. The solvent was removed from the extract by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.65 g (yield 60%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[NH:29])OCC)=[CH:20][CH:19]=1>C(O)C>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=N)Cc1ccc(F)cc1
Reactant: Nc1ncccc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccc(F)cc1)Nc1ncccc1OCc1ccccc1
Yield: 6 %

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (4.84 g, 24.2 mmol) and ethyl 4-fluorophenylacetimidate hydrochloride (5.8 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was converted to the free base and purified by flash chromatography (chloroform/methanol) to obtain the product (0.49 g), m.p. 86°-93° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:10]=[C:11]([C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[C:31]#[N:32])=[N:17]S(C(C)(C)C)=O)[CH:12]=[CH:13][C:14]=1[F:15]>>[Br:8][C:9]1[CH:10]=[C:11]([C:16]2([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:24]3[C:25](=[C:26]([F:30])[CH:27]=[CH:28][CH:29]=3)[C:31]([NH2:32])=[N:17]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1cccc(F)c1C#N
Reactant: Ic1ccncc1
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Yield: 37 %

Procedure:
The title compound was synthesized as described for example 11i in 37% yield, starting from 4-iodopyridine (0.530 g, 2.59 mmol) and N-((3-bromo-4-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.00 g, 2.35 mmol).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]([C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:17][CH:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[N:14]=[C:13]([C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:17][CH:16]=3)[S:1][C:2]=2[CH:10]=1
Reactant: COc1ccc(C(=O)O)c(S)c1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Solvent: c1ccncc1
Product: COc1ccc2c(=O)nc(-c3cccc(CCC(=O)OC(C)(C)C)n3)sc2c1
Yield: 46.3 %

Procedure:
2-Mercapto-4-methoxybenzoic acid (1.26 g, 6.8 mmol) and tert-butyl 3-(6-cyano-2-pyridyl)propanoate (1.21 g, 5.2 mmol) were dissolved in pyridine (10 ml), and the reaction mixture was refluxed for 24 hrs. The reaction mixture was concentrated under reduced pressure, subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (1:1, v/v) and recrystallized from ethyl acetate-hexane to give the titled compound (0.96 g, 46%)
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1>>[Cl:1][C:2]1[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:13]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][C:39]([OH:41])([CH3:40])[CH3:42])[N:34]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2ccc(OC(F)(F)F)cc2Cl)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCCC2)n2ncc(Oc3ccc(OC(F)(F)F)cc3Cl)cc2=O)n1
Yield: 52 %

Procedure:
Using the method described in Example 49, 2-[4-(2-chloro-4-trifluoromethoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-propionic acid (Intermediate 91) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-chloro-4-trifluoromethoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (130 mg, 52%); ES+-HRMS m/e calcd for C27H31N5O5F3Cl [M+H+] 598.2039 found 598.2038. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84-1.26 (m, 6H), 1.05 (br. s., 6H), 1.63 (br. s., 5H), 1.74-1.91 (m, 1H), 2.07-2.23 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.48-5.60 (m, 1H), 5.91 (d, J=2.7 Hz, 1H), 6.39 (s, 1H), 7.45-7.60 (m, 2H), 7.67 (dd, J=9.1, 2.1 Hz, 1H), 7.87 (br. s., 1H), 8.22 (d, J=2.7 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CNS(C)(=O)=O)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (17 mg, 0.039 mmol) in dichloromethane (DCM) (750 μl) was treated with Et3N (8.14 μl, 0.058 mmol) and MsCl (3.64 μl, 0.047 mmol), stirred for 1 hour, and then warmed to rt for 1 hour. Additional Et3N (8 uL) and MsCl (4 uL) were added at 00° C., the reaction was stirred at rt for 1 hour, and then concentrated. The residue was purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(methylsulfonamidomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (17 mg, 0.033 mmol, 85% yield) as yellow solid. The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(methylsulfonamidomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (14 mg, 0.027 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 (s, 1 H), 7.59-7.50 (m, 1 H), 7.40-7.29 (m, 1 H), 7.29-7.24 (m, 1 H), 7.17 (dd, J=8.4, 12.5 Hz, 1 H), 7.08-6.99 (m, 1 H), 5.35 (s, 1 H), 5.15-5.03 (m, 1 H), 4.44 (d, J=5.7 Hz, 2 H), 3.67 (s, 3 H), 2.97-2.89 (m, 3 H), 2.37 (s, 3 H), 2.32 (s, 3 H), 1.09-1.02 (m, 9 H); LCMS (m/z) ES+=501 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][OH:9])=[O:5])[CH3:3].FC1C([O:20][C:21](=O)[C@@H:22]2[CH2:26][C@@H:25]([OH:27])[CH2:24][N:23]2C(OC(C)(C)C)=O)=C(F)C(F)=C(F)C=1F.[ClH:40]>CN(C)C=O.C(O)(C)C>[ClH:40].[OH:27][C@H:25]1[CH2:24][NH:23][C@H:22]([C:21]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][OH:9])=[O:5])[CH3:3])=[O:20])[CH2:26]1
Reactant: C[C@H](N)C(=O)N[C@@H](CO)C(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: C[C@H](NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)N[C@@H](CO)C(=O)O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
N-alanylserine (1.5 kg, 8.515 M) and Boc-trans-4-hydroxy-L-proline (3.72 kg) (prepared as described in step 2) were heated at 50° C. in dimethylformamide (15 L) for 3 hours. The solution was cooled to 20° C., treated with concentrated hydrochloric acid (7.5 L) and stirred at room temperature for 24 hours. The resulting slurry was diluted with isopropanol (30 L), stirred at room temperature for 30 minutes and then cooled to 0° C. for 1 hour. The solid was collected by filtration and washed with isopropanol (20 L). The solid was dried in vacuo at 40° C. to afford the title compound as a white crystalline solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH:10]=C(C#N)[C:8]=2[CH:20]=1)([O-:3])=[O:2].[C:21]([OH:24])(=[O:23])[CH3:22].S(=O)(=O)(O)O>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH:10]=[C:22]([C:21]([OH:24])=[O:23])[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: N#CC1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
A mixture of 0.13 g of 6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carbonitrile, 10 ml of acetic acid, 5 ml of water and 5 ml of concentrated sulfuric acid was refluxed with heating for 2 hours. When the reaction mixture was poured into ice water, crystals were separated out. The crystals were dissolved into a sodium hydrogencarbonate solution and washed with methylene chloride. A water layer was acidified to be hydrochloric acid and extracted with methylene chloride. After an organic layer was washed with water and dried, the solvent was distilled. The resultant residue was crystallized by a mixed solvent of ethyl acetate and methanol to obtain 55 mg of 6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carboxylic acid with a melting point of 259°-261° C.