Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.[N:22]1([S:27](N2C=C[N+](C)=C2)(=[O:29])=[O:28])[CH:26]=[CH:25][N:24]=[CH:23]1>CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[S:27]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)(=[O:29])=[O:28])=[CH:12][CH:13]=1
Reactant: CC(C)CNCc1ccc(F)cc1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)n1ccnc1
Yield: 32 %

Procedure:
A solution of (4-fluoro-benzyl)-isobutyl-amine (500 mg, 2.76 mmol) in MeCN (20 mL) was treated with 3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (1.49 g, 4.14 mmol) and heated at reflux for 18 hours. The cooled reaction mixture was concentrated under vacuum and purified by silica gel chromatography (0-50% EtOAc in DCM) to afford the title compound (275 mg, 32%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.17 (m, 4H), 7.02 (m, 2H), 4.40 (s, 2H), 3.01 (d, J=7.6 Hz, 2H), 1.77 (m, 1H), 0.80 (d, J=6.6 Hz, 6 H). LCMS (m/z, Method A) ES+ 312.0 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-fluoro-4-(trifluoromethyl)benzoic acid (CAS RN 115754-21-7) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (20%). MS (ESI): m/z=389.13 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:26]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccccc1
Reactant: Nc1cnccn1
Reactant: Clc1ncnc2ccc(I)cc12
Product: c1ccc(Oc2ccc3ncnc(Nc4cnccn4)c3c2)cc1

Procedure:
The compound of Example 4 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, 2-amino-pyrazine and phenol.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:21](=[O:32])[CH2:20]3)(=[O:18])=[O:17])=[CH:13][C:12]=2[CH:33]=1.Cl.Cl[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:40]5[CH:39]=[CH:38][N:37]=[CH:36][CH:41]=5)[CH2:30][CH2:31]4)[C:21](=[O:32])[CH2:20]3)(=[O:18])=[O:17])=[CH:13][C:12]=2[CH:33]=1
Reactant: Clc1ccccn1
Reactant: O=C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CCN1CC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 37.1 %

Procedure:
To sodium bicarbonate solution were added 4-(5-chlorobenzofuran-2-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (215 mg) and chloropyridine hydrochloride (144 mg), and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (15 ml), and the mixture was allowed to react at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=15:1) to give colorless solid of 4-(5-chlorobenzofuran-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone (87 mg), which was treated with hydrochloric acid to give colorless solid of the title compound (80 mg) as hydrochloride salt.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[NH2:15][CH2:16][CH:17]1[CH2:19][CH2:18]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Reactant: NCC1CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with aminomethyl-cyclopropane in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-chloro-6-(cyclo-propylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=268.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1cc(C#N)ccc1C(=O)OCc1ccc(OC)cc1
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOP(=O)(OCC=C)OCc1cc(C#N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-cyanobenzoate (949.1 mg, 2.07 mmol) obtained from Example 4-(5) and anisole (1.0 g, 9.2 mmol) was cooled to 0° C., and trifluoroacetic acid (5 ml) was added thereto. The resulting mixture was warmed to room temperature and allowed to stand for 15 minutes, diluted with toluene, and concentrated under reduced pressure to eliminate the volatile components (repeated three times). Hexane was added to the residue, and then the supernatant solution was removed to give crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-cyanobenzoic acid. This crude product was dissolved in dichloromethane (20 ml), and oxalyl chloride (1.27 g, 10 mmol) and N,N-dimethylformamide (15 μl) were added thereto at 0° C. The mixture was warmed to room temperature and stirred for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was diluted with toluene, and the solution was concentrated under reduced pressure to eliminate the volatile components (repeated three times), and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-cyanobenzoyl chloride was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:12](=[O:13])[NH:11][C:10]([C:14]([OH:16])=O)=[CH:9][CH:8]=2)[CH:6]=1.[F:17][C:18]1[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27]O)=[C:20]([C:31]([F:34])([F:33])[F:32])[CH:19]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.ClCCl>[F:17][C:18]1[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:11]3[C:12](=[O:13])[C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[CH:8][CH:9]=[C:10]3[C:14]2=[O:16])=[C:20]([C:31]([F:32])([F:33])[F:34])[CH:19]=1
Reactant: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Reactant: OCCNCCOc1ccc(F)cc1C(F)(F)F
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
Solvent: O
Product: Cc1cn(-c2ccc3n(c2=O)CCN(CCOc2ccc(F)cc2C(F)(F)F)C3=O)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-(4-Methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid, 0.7 hydrobromide salt (P1) (201 mg, 0.729 mmol) and 2-({2-[4-fluoro-2-(trifluoromethyl)phenoxy]ethyl}amino)ethanol (C36) (214 mg, 0.801 mmol) were combined with dichloromethane (15 mL) and N,N-diisopropylethylamine (0.508 mL, 2.92 mmol), and the mixture was stirred for 5 minutes at room temperature. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 97%, 857 mg, 2.19 mmol) was added in one portion, and the reaction was stirred for an additional 16 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) and saturated aqueous sodium chloride solution (50 mL), then dried over magnesium sulfate and concentrated in vacuo. Purification was carried out twice using silica gel chromatography (Gradient #1: 0% to 20% methanol in dichloromethane; Gradient #2: 0% to 70% [10% 2 N ammonia in methanol/90% ethyl acetate] in ethyl acetate) to afford the title compound as a white solid. Yield: 268 mg, 0.595 mmol, 82%. LCMS m/z 451.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.24 (d, J=0.9 Hz, 3H), 3.90-3.95 (m, 2H), 4.01 (dd, J=5.1, 5.1 Hz, 2H), 4.32-4.37 (m, 4H), 7.21-7.26 (m, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.30-7.32 (m, 1H), 7.32-7.39 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 8.30 (d, J=1.3 Hz, 1H).
Reaction SMILES: ClCC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35](O)[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1.[NH:40]1[CH:44]=[C:43]([CH2:45][O:46]C2C=C(N3CCOCC3)C=CC=2)[N:42]=[CH:41]1>>[NH:40]1[CH:44]=[C:43]([CH2:45][O:46][C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[N:42]=[CH:41]1
Reactant: c1cc(OCc2c[nH]cn2)cc(N2CCOCC2)c1
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: c1ccc(N2CCOCC2)c(OCc2c[nH]cn2)c1

Procedure:
In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 3-morpholinophenol and converted to 4-[3-(1H-imdazol-4-ylmethoxy)-phenyl]-morpholine as a white solid. MS (ISP): 260.3 ([M+H]+)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[S:10]([O:15]C)([O:13][CH3:14])(=[O:12])=[O:11].[C:17](OCC)(=O)C>C(#N)C>[CH3:14][O:13][S:10]([O-:15])(=[O:12])=[O:11].[C:1]([C:4]1[CH:9]=[CH:8][N+:7]([CH3:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)c1ccncc1
Solvent: CC#N
Product: CC(=O)c1cc[n+](C)cc1
Product: COS(=O)(=O)[O-]

Procedure:
2.0 g 4-Acetylpyridine were dissolved in 10 ml acetonitrile and 2.0 g dimethyl sulfate were added. After refluxing for 5 h, the solution was added dropwise to 40 ml ethyl acetate and the precipitate was filtered, washed with ethyl acetate and dried in vacuo.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](O)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B.CC(C)=O.O>O1CCCC1>[CH2:1]([O:17][CH2:18][CH2:19][OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOCCO
Yield: 92.6 %

Procedure:
A solution of 80 g of (hexadecyloxy) acetic acid in 350 ml of tetrahydrofuran was stirred at 0° C. while 798.71 ml of 1M borane in tetrahydrofuran was added dropwise over one hour. When addition was complete the mixture was stirred 2 hours than 50 ml of acetone was added followed by 60 ml of water dropwise. The tetrahydrofuran was allowed to evaporate overnight, then the residue was mixed with water and chloroform and heated to dissolve the solid. The organic layer was separated, dried and the solvent removed. The residue was recrystallized from cold methanol, giving 70.6 g of the desired compound as a white solid, mp 42°-44° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][O:9][C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][O:9][C:10]1[C:15]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)CCOc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)CCOc1nc(Cl)ncc1-c1cccs1

Procedure:
Preparation according to procedure 11a with the use of 3-(5-Bromo-2-chloro-pyrimidin-4-yloxy)-propionic acid tert-butyl ester and 2-thienyl-boronic-acid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][C:17]3=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([S:27]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36]([CH2:40][NH2:41])=[CH:35][CH:34]=[CH:33]3)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.[CH3:43][C:44]1([CH3:52])[CH2:49][NH:48][CH:47](SC)[NH:46][CH2:45]1>C(Cl)Cl>[C:21]1([S:27]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36]([CH2:40][NH2:41])=[CH:35][CH:34]=[CH:33]3)(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:40][NH:41][C:47]3[NH:46][CH2:45][C:44]([CH3:52])([CH3:43])[CH2:49][N:48]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSC1NCC(C)(C)CN1
Reactant: O=C1CCCc2ccc(S(=O)(=O)c3ccccc3)cc21
Agent: Cl
Agent: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Solvent: ClCCl
Product: CC1(C)CN=C(NCc2cccc3ccc(S(=O)(=O)c4ccccc4)cc23)NC1
Temperature: 150 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine is prepared from 7-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one following the procedures of Examples 1 and 2. C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine and 5,5-dimethyl-2-methylsulfanyl-hexahydro-pyrimidine hydrochloride are added to methylene chloride, and the reaction mixture is heated to gentle reflux until all of the solvent is evaporated. The reaction mixture is heated to 150° C. and then cooled. The resulting mixture is basified by dropwise addition of aqueous NaOH solution, and then purified by preparative liquid chromatography to give (7-benzenesulfonyl-naphthalen-1-ylmethyl)-(5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-yl)-amine.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].N.[C-:23]#[C-:24].[K+].[K+]>CC(C)=O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:23]#[CH:24])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: [C-]#[C-]
Agent: N
Agent: [K+]
Solvent: CC(C)=O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
500 Mg. of 13β-ethyl-gon-4-en-3,17-dione produced in Example 135, was dissolved in 10 ml. of a benzene-ether solvent mixture (1:1) and added to a solution of 50 ml. of liquid ammonia containing 0.1 ml. of acetone and 0.5 g. of potassium acetylide. The reaction mixture was agitated at the ammonia boiling point for 2 hours and then the ammonia was evaporated at room temperature. The organic materials were extracted with ether and then the solvent was evaporated in vacuo. The residue was purified by chromatography over 50 g. of silica gel and on elution with a benzene-ethyl acetate mixture, afforded 13β-ethyl-17α-ethynyl-17-hydroxy-gon-4-en-3-one.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[CH:42]=[CH:41][C:33]5[C:34]([C:37]([O:39]C)=[O:38])=[N:35][S:36][C:32]=5[CH:31]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:17])([F:19])[F:18])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[CH:42]=[CH:41][C:33]5[C:34]([C:37]([OH:39])=[O:38])=[N:35][S:36][C:32]=5[CH:31]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1nsc2cc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nsc2cc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)ccc12

Procedure:
Methyl 6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]isothiazole-3-carboxylate (37 mg, 0.062 mg) in a 3:2:1 THF-MeOH—H2O solution (1 mL) was treated with a 6N LiOH solution (85 μL, 0.49 mmol) at rt for 12 hours. After this time the organic was removed in vacuo and the residue was diluted with water (1 mL.) and cooled in ice. 3N NaOH was added dropwise until pH 7. The solid that separated was collected by filtration, washed with additional water and dried in vacuo to afford the 6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]isothiazole-3-carboxylic acid as off white solid. 1H NMR (400 MHz, DMSO) δ 8.31 (d, J=8.0 Hz, 1H), 7.68-7.62 (m, 2H), 7.57-7.52 (m, 2H), 7.18 (bs, 1H), 6.90 (d, J=9.2 Hz, 1H), 4.31 (s, 2H), 4.18 (bs, 2H), 3.42 (m, 1H), 1.88-1.84 (m, 2H), 1.80 (1.78 (m, 4H), 1.53-1.49 (m, 2H), 1.15-1.03 (m, 5H). MS m/z 586.2 (M+1).
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@@H:5]([CH:17]=O)[C@H:4]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:3]1.[CH3:26][C@@H:27]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][C:29](=[O:37])[CH2:30]P(=O)(OC)OC>>[Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@@H:5](/[CH:17]=[CH:30]/[C:29](=[O:37])[CH2:28][C@@H:27]([CH3:26])[CH2:38][CH2:39][CH2:40][CH3:41])[C@H:4]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:3]1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@H]1Cl
Reactant: CCCC[C@H](C)CC(=O)CP(=O)(OC)OC
Product: CCCC[C@H](C)CC(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1OC1CCCCO1

Procedure:
By the same procedure as the reaction of Example 6 using methyl (5Z)-7-[(1R,2R,3R,5R)-5-chloro-2-formyl-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate (Reg. No. 261772-21-8) instead of the compound 5 and using dimethyl [(4S)-4-methyl-2-oxooctyl]phosphonate instead of dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate, the title compound (360 mg) having the following physical data was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:15][CH:16]([OH:18])[CH3:17]>>[Cl:1][C:2]1[N:7]=[C:6]([O:18][CH:16]([CH3:17])[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of 2,4-dichloropyrimidine (5.0 g, 34 mmol) in 2-propanol (84 mL) was added Cs2CO3 (12 g, 37 mmol) and the mixture was stirred at rt for 16 h. The reaction was then heated to 65° C. for 3 h, after which time the reaction was filtered and concentrated. Purification on silica using a gradient solvent system of 0-10% EtOAc/Hexanes furnished 2-chloro-4-(propan-2-yloxy)pyrimidine (2.4 g, 41%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J=5.7, 1H), 6.56 (d, J=5.7, 1H), 5.38 (hept, J=6.2, 1H), 1.34 (d, J=6.2, 6H).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1NN=[CH:8]2.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([NH:28][CH3:29])=[CH:21]2.O.O.[OH-].[Li+].[CH3:34]O>>[CH3:29][NH:28][C:22]1[N:23]=[CH:24][C:11]2[C:7]([CH:8]=1)=[CH:6][C:5]([C:12]([O:14][CH3:34])=[O:13])=[CH:4][CH:3]=2.[CH3:29][NH:28][C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:12]([OH:14])=[O:13])=[CH:27][CH:26]=2
Reactant: CNc1cc2cc(Br)ccc2cn1
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CNc1cc2cc(C(=O)O)ccc2cn1
Product: CNc1cc2cc(C(=O)OC)ccc2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Methyl 3-(methylamino)isoquinoline-6-carboxylate was prepared by a method analogous to that described in Step 3 of Intermediate 21, using 6-bromo-N-methylisoquinolin-3-amine. To the crude material (580 mg, 2.7 mmol) was added water (5 mL), methanol (5 mL), and lithium hydroxide monohydrate (300 mg, 7 mmol). The mixture was stirred at room temperature overnight. The reaction was concentrated and the residue was acidified to pH=5 with 1 N aqueous hydrochloric acid. The resulting residue was dried under vacuum and purified by reversed-phase HPLC to give the title compound (512 mg, 89%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.81 (s, 1H), 8.23 (s, 1H), 7.80 (d, 1H), 7.72 (d, 1H), 6.70 (s, 1H), 2.93 (s, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.Cl.NC[C:49]([NH2:51])=[O:50].O[N:53]1[C:57]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:49]([N:53]([CH3:57])[C:40]([CH2:39]/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:45])[CH3:44])=[CH:32][CH:33]=1)=[O:42])(=[O:50])[NH2:51]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: On1nnc2ccccc21
Reactant: NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(/C=C/CC(=O)N(C)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}-methyl)-5-isopropyl-1H-pyrazole (0.34 g) in N,N-dimethyl-formamide (1 mL) were added glycinamide hydrochloride (0.12 g), 1-hydroxybenzotriazole (0.09 g), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.15 g) and triethylamine (0.27 g), and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration. To the filtrate was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/acetonitrile=90/10-10/90) to give 4-({4-[(1E)-3-(carbamoyl-methylcarbamoyl)prop-1-enyl]phenyl}methyl)-3-(β-D-gluco-pyranosyloxy)-5-isopropyl-1H-pyrazole (0.03 g). This material was dissolved in methanol (1 mL). To the solution was added 10% palladium-carbon powder (0.01 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.02 g).