Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30]([OH:32])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH2:33][C:34]1[C:35]([N:52]2[CH2:57][CH2:56][CH2:55][C@H:54]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:53]2)=[C:36]2[CH:42]=[CH:41][N:40]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(=[O:45])=[O:44])[C:37]2=[N:38][CH:39]=1.N1C=CC=CC=1>C1COCC1>[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30]([NH:33][C:34]1[C:35]([N:52]2[CH2:57][CH2:56][CH2:55][C@H:54]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])[CH2:53]2)=[C:36]2[CH:42]=[CH:41][N:40]([S:43]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)(=[O:45])=[O:44])[C:37]2=[N:38][CH:39]=1)=[O:32])=[O:15])([CH3:11])([CH3:10])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (115.7 mg, 0.8659 mmol) in THF (1.0 mL) was added slowly to a solution of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, Step 6, 120.4 mg, 0.3379 mmol) in THF (1.0 mL). The mixture was stirred at room temperature for 5 h. A solution of tert-butyl {(3S)-1-[5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (127.3 mg, 0.2699 mmol) in THF (2.0 mL) was then added, followed by pyridine (227.6 mg, 2.877 mmol) and the mixture was stirred at room temperature for a further 12 h. The mixture was then concentrated and the residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (194.4 mg, 89%). LCMS calc. for C38H42F2N2O2S2 (M+H)+: m/z=810.2. found 810.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=O)C(F)(F)F)[CH2:14][C@H:13]2[O:24][CH2:25][CH:26]([F:28])[F:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.BrC1[S:43][C:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][N:46]=1>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:43][C:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][N:46]=3)[CH2:14][C@H:13]2[O:24][CH2:25][CH:26]([F:28])[F:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)C(F)(F)F)C[C@H]2OCC(F)F)nc1Cl
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC(F)F)C2)s1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 73.9 %

Procedure:
cis(±)-4-Chloro-N-{3-(2,2-difluoroethoxy)-1-(trifluoroacetyl)piperidin-4-yl}-5-ethyl-1H-imidazole-2-carboxamide obtained in Example (121f) (144 mg, 0.33 mmol) was dissolved in methanol (4 mL). A 2 N aqueous lithium hydroxide solution (0.4 mL) was added, and the mixture was stirred at 40° C. for 40 minutes. The pH was adjusted to 4 by adding a 1 N aqueous hydrochloric acid solution, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMA (5 mL). Diisopropylethylamine (130 mg, 1 mmol) and ethyl 2-bromo-1,3-thiazole-5-carboxylate (155 mg, 0.66 mmol) were added, and the mixture was stirred at 75° C. for one hour. Dilution with ethyl acetate, washing with water and brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure gave a residue, which was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.12 g of the title compound as a colorless amorphous solid (74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH2:24][CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH2:24][CH3:25])[N:9]=3)[CH:5]=2)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-ethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.89) (0.30 g, 0.739 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.209 g, 0.813 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 25%) and additional off-white solid (0.20 g, 50%). MS (ISP) 539.3 [(M+H)+]; mp 169° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22]([CH2:23][N:45]6[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]6)=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)c(C(F)(F)F)c4)cnc32)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a solution of 4-[3-(1H-indol-5-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-trifluoromethyl-benzaldehyde (0.12 g, 0.214 mmol) in CH2Cl2 (3 mL) was added 1-methylpiperazine (32 mL, 0.32 mmol) and sodium triacetoxyborohydride (136 mg, 0.64 mmol). The reaction mixture was stirred for 1 hr at room temperature, after which it was partitioned between CH2Cl2 and 1 M NaOH. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in 3:2 MeOH:acetone (5 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to provide a residue that was subjected to silica gel column to yield 3-(1H-indol-5-yl)-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-1H-pyrrolo[2,3-b]pyridine (0.024 g, 24% yield). 1H NMR (CDCl3, 400 MHz): δ 11.89 (s, 1H), 11.07 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.46 (dd, J=1.8, 6.4 Hz, 2H)), 7.34 (d, J=2.4 Hz, 1H), 6.46 (s, 1H), 3.63 (s, 2H), 3.32 (s, 3H), 2.49-42 (m, 8H), 2.14 (s, 3H); MS ESI (m/z) 490 (M+1)+, calc. 489.53.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[CH:5][C:6]([CH2:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]#[N:21])[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:26][NH:25][C:20](=[NH:21])[CH2:19][N:16]1[C:17]([CH3:18])=[C:13]([CH2:12][C:6]2[CH:5]=[C:4]([CH3:23])[C:3]([O:2][CH3:1])=[C:11]3[C:7]=2[CH2:8][CH2:9][CH2:10]3)[C:14]([CH3:22])=[N:15]1
Reactant: COc1c(C)cc(Cc2c(C)nn(CC#N)c2C)c2c1CCC2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1c(C)cc(Cc2c(C)nn(CC(=N)NO)c2C)c2c1CCC2
Temperature: 70 °C
Reaction time: 33 h
Yield: 81.2 %

Procedure:
To a stirred solution of [4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile (2.0 gm 0.00647 mole) in methanol (50 ml), A suspension of Hydroxylamine hydrochloride (2.29 gm, 0.033 mole) and Potassium carbonate (4.37 gm, 0.0317 mole) in water (20 ml) was added. The reaction mixture was stirred for 30-36 hours at 70° C., cooled and then was filtered. The obtained solid was washed with water (10 ml) and finally with Hexane and dried under vacuum to give 1.8 gm of desired product
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:10][C:11]1[CH:26]=[CH:25][C:14]([CH2:15][CH:16]([C:22]([CH3:24])=O)[C:17](OCC)=[O:18])=[CH:13][CH:12]=1.Cl>C(O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[C:17](=[O:18])[O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[C:3]=3[C:22]=2[CH3:24])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: Cc1c(Cc2ccc(Cl)cc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (1.57 g) and ethyl 2-(4-chlorobenzyl)-acetoacetate (3.18 g) in ethanol (25 ml) was treated with dry HCl at 0° C. for 1.5 hours and the solution was kept at that temperature overnight. Solvent was evaporated and the precipitate triturated with water. Yield 3.87 g (98%). Melting point 270-278° C.
Reaction SMILES: [C:1]1([C:15]([OH:17])=O)[C:10]2[C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][CH2:5][C:4]=2[NH:3][N:2]=1.[N:18]1([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]2)[CH2:21][CH2:20][CH2:19]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.C(Cl)Cl>[N:18]1([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH:30][C:15]([C:1]3[C:10]4[C:9]5[N:11]=[CH:12][CH:13]=[CH:14][C:8]=5[CH2:7][CH2:6][CH2:5][C:4]=4[NH:3][N:2]=3)=[O:17])=[N:26]2)[CH2:19][CH2:20][CH2:21]1
Reactant: Nc1ccn(CCCN2CCC2)n1
Reactant: O=C(O)c1n[nH]c2c1-c1ncccc1CCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1ccn(CCCN2CCC2)n1)c1n[nH]c2c1-c1ncccc1CCC2
Yield: 8.8 %

Procedure:
7.8 mL of 1.7 M of t-BuLi in pentane is added dropwise under argon to a stirred solution of 1-bromo-3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene (1.4 g) in 75 mL of anhydrous THF at −78° C. After addition, dry carbon dioxide is bubbled into the mixture at the same temperature for 2 hours. The reaction mixture is allowed to warm to room temperature, quenched with 1N HCl solution, and diluted with water. The mixture is basified with 1N NaOH to pH 8-9, and then extracted with EtOAc. The aqueous layer is then acidified with HOAc to pH 4-5 and extracted with CH2Cl2 eight times. The combined extracts are washed with water, dried, and concentrated to give 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid as a tan solid. 1H NMR(DMSO): 1.95(m, 2H), 2.96(m, 2H), 3.07(t, 2H), 7.45(m,1H), 7.97(d,1H), 8.52(d, 2H). LR-MS: MW 229.23, Found: 230.2(M+1). Step 6: A mixture of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid (80 mg), 1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-ylamine (68 mg), EDCI(85 mg) and DMAP(55 mg) in 10 mL of 1,2-dichloroethane is refluxed overnight, cooled and diluted with CH2Cl2. The mixture is washed with aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated under vacuum. Purification on a silica gel plate, eluting with 10% MeOH in CH2Cl2 yields 12 mg of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amide as a colorless foam. 1H NMR (CDCl3): 2.01-2.31(m, 6H), 2.67-2.92(m, 8H), 3.63(m, 2H), 4.17(t, 2H), 6.65(d, 1H), 7.23(m, 1H), 7.33(d, 1H), 7.65(d, 1H), 8.62(d, 1H), 14.13(bs, 1H). LR-MS: MW 391.48, Found: 392.2 (M+1).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH2:18][CH:19]([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:22]([CH3:24])[CH3:23])[S:14]2)[C@H:10]1[O:25]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[F:21][CH:19]([F:20])[CH2:18][C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:22]([CH3:24])[CH3:23])[S:14]2)[C@@H:10]([OH:25])[C@@H:9]1[OH:8]
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CC(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CC(F)F)O[C@@H]2S1
Yield: 24.2 %

Procedure:
A solution of 109 (270 mg, 0.6 mmol) in dichloromethane (20 mL) was treated with BCl3 (6 mL, 6 mmol, 1M in dichloromethane) for 2 hours at −60° C., then the reaction was quenched with methanol (20 mL). Volatiles were distilled out under vacuum to give a residue, which was dissolved into methanol (5 mL) and neutralized by Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give the title compound as a white solid (41 mg, 25%); (ES, m/z) [M+H]+ 283.0; 1HNMR (300 MHz, D2O) δ 6.17 (d, J=6.3 Hz, 1H), 5.77-6.14 (m, 1H), 4.12 (t, J=6.0 Hz, 1H), 3.93 (t, J=5.1 Hz, 1H), 3.68-3.73 (m, 1H), 3.43-3.48 (m, 1H), 2.91 (s, 6H), 1.99-2.35 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH2:31])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH:31][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:21][CH:22]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OC)cc3)ccnc2n1

Procedure:
The product from Example 2g (275 mg, 1.33 mmol) was reacted with the product from Example 50b (326 mg, 1.33 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (392 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H) 1.85 (m, 2H) 2.34 (s, 3H) 3.00 (t, J=7.54 Hz, 2H) 3.72 (s, 3H) 6.27 (d, J=6.99 Hz, 1H) 6.84 (d, J=8.82 Hz, 2H) 7.11 (d, J=7.72 Hz, 1H) 7.27 (m, 4H) 7.83 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 9.02 (d, J=8.46 Hz, 1H) 11.06 (br. s., 1H) 14.37 (br. s., 1H); MS (ESI+) m/z 416 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][C:3]1=[O:15].C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:4]1[C:3](=[O:15])[C:2]([CH3:16])([CH3:1])[O:6][C:5]=1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(Br)C1=O
Reaction time: 3 h
Yield: 30.6 %

Procedure:
To a stirred solution of 4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.2 g, 5.60 mmol) in CHCl3 (12 mL), NBS (1.1 g, 6.00 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (100 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (0.50 g, 31%) as an off white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.Br[C:13]1[N:14]=[CH:15][S:16][CH:17]=1>>[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][O:10][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH2:6][O:5]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Brc1cscn1
Agent: [H-]
Agent: [Na+]
Product: CC1(C)OCC(COc2cscn2)O1

Procedure:
NaH (60% dispersion in mineral oil, 12.19 g, 305.3 mmol) was added portionwise to DL-1,2-isopropylideneglycerol (16.11 g, 1218 mmol) and the mixture was stirred until gas evolution had ceased (ca. 30 min RT, followed by 2 h at 60° C.). Subsequently, 4-bromothiazole (20.00 g, 121.9 mmol) was added and the mixture was stirred at 140° C. for 45 min. Subsequently, the reaction mixture was quenched with aq. sat. NH4Cl and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was subjected to distillation and the volatiles (HV, 60° C.) were removed. The residue was purified by means of CC (5-40% EtOAc/Hept) to provide a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)[O:8][CH2:9][C@@H:10]1[C@:19]2([CH3:20])[C@H:14]([C:15]([CH3:22])(C)[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12][C@@:11]1([CH3:24])O)[CH3:3].Cl[Sn](Cl)(Cl)Cl.[CH2:37](Cl)Cl>>[CH3:24][C@@:11]12[CH2:12][CH2:13][C@@H:14]3[C@:15]([CH3:22])([CH2:16][CH2:17][CH2:18][C:19]3([CH3:20])[CH3:37])[C@H:10]1[CH2:9][O:8][C:7]1[C:25]2=[C:26]([O:28][CH:29]([CH3:30])[CH3:31])[CH:27]=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:6]=1
Reactant: CC(C)Oc1cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)cc(OC(C)C)c1
Reactant: ClCCl
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CC(C)Oc1cc2c(c(OC(C)C)c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CO2
Temperature: -78 °C
Yield: 23 %

Procedure:
To a solution of (1S,2R,4aS,8aS)-1-[3,5-bis(propan-2-yloxy)phenoxy-methyl]-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (48) (0.90 g, 2.1 mmol) in CH2Cl2 (20 mL), cooled to −78° C., a solution of SnCl4 (0.97 mL, 8.3 mmol) in CH2Cl2 (10 mL) was added dropwise. The temperature was maintained at −78° C. for 4 h, after which the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with water (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/toluene, 1:1) gave (1R,10R,11S,16S)-1,11,15,15-tetramethyl-3,5-bis(propan-2-yloxy)-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 49) (0.20 g, 23%) as a tan solid. 1H NMR (CDCl3): δ 5.95 (d, 1H), 5.87 (d, 1H), 4.50 (m, 1H), 4.40 (m, 1H), 4.22 (m, 1H), 3.95 (t, 1H), 3.10 (m, 1H) 1.78-1.40 (m, 7H), 1.37 (m, 15H), 1.25-1.00 (m, 4H) 0.92 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:26])[N:15]([CH3:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]=1[S:19][CH3:20])[CH3:2].C(=O)([O-])[OH:28].[Na+].ClC1C=C(C=CC=1)C(O)=O.S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:26])[N:15]([CH3:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]=1[S:19]([CH3:20])=[O:28])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCc1cc(CC)c(-c2c(SC)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1cc(CC)c(-c2c(S(C)=O)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Yield: 97.3 %

Procedure:
To a 100 ml volume four-necked flask, 4-(2,4,6-triethylphenyl)-2-methyl-5-methylsulfanyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-46)-(1)-40) (0.683 g) and chloroform (24 ml) were added at room temperature, and stirred. Sodium hydrogen carbonate (0.597 g), and meta-chlorobenzoic acid (0.615 g) was added and the resulting mixture was stirred at room temperature for 4 hours. Then, the reaction mixture was poured into water (30 ml), added sodium sulfite (0.4 g), and extracted with t-butyl methyl ether (30 ml) 4 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane: ethyl acetate=5:1 to hexane: ethyl acetate=1:1) to give 0.692 g of 4-(2,4,6-triethylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-40).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(-c2ccc(CCCO)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc(-c2ccc(CCCOS(C)(=O)=O)cc2)cc1
Reaction time: 8 h

Procedure:
3-[4′-(3-Hydroxy-propyl)-biphenyl-4-yl]-propan-1-ol (intermediate 14) (5.0 g,18.5 mmol) was dissolved in dichloromethane (100 mL) and triethylamine (6.0 g, 59 mmol) and subsequently methanesulfonyl chloride (4.6 g, 40 mmol) were added dropwise. The mixture was stirred overnight, washed with water (30 mL), evaporated in vacuo and the residue crystallized from benzene giving 4,4′-biphenyidipropanol bismethanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:26][CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28](Cl)=[O:29]>C1COCC1>[Cl:26][CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 15 (0.10 g, 0.39 mmol) in THF (10 mL), was added triethylamine (0.059 g, 0.58 mmol) and 2-chloro-2-phenylacetyl chloride (0.110 g, 0.58 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5 methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6([C:32]([O:34]C)=[O:33])[CH2:31][CH2:30]6)[CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.O[Li].O.Cl>CC(C)=O>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]6)[CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)C1(c2cccc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)ccc3C)c2)CC1
Agent: Cl
Agent: [Li]O
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C2(C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropanecarboxylate (−0.26 mmol) was dissolved in acetone (3 mL) and water (3 mL) in a reaction tube. LiOH.H2O (25 mg, 60 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was acidified with 1N HCl until pH 1-2. The volatiles were removed under reduced pressure. The residue was taken up in methylene chloride and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The solid was triturated with Et2O, then hexanes to 1-(3-(6-(1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-methylpyridin-2-yl phenyl)cyclopropanecarboxylic acid. ESI-MS m/z 493.2 (M+1)+. Retention time 1.80 minutes.