Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34](Cl)(=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)[C:34](=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)OC(C)(C)OC2=O

Procedure:
The titled compound was prepared following the procedure M using 7-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and hexanoyl chloride as all orange oil (69%). 1H NMR (CDCl3, 300 MHz) δ 7.92 (d, J=8.3 Hz, 1H), 7.41 (m, 4H), 7.14 (m, 4H), 6.78 (d, J=8.3 Hz, 1H), 6.59 (s, 1H), 4.89 (s, 2H), 2.60 (t, J=7.7 Hz, 2H), 2.14 (t, J=7.3 Hz, 2H), 1.71 (s, 6H), 1.66-1.51 (m, 4H), 1.43-1.12 (m, 8H), 0.91 (t, J=7.3 Hz, 3H). 0.84 (t, J=6.7 Hz, 3H). M+ (ESI): 538.2. HPLC, Rt: 6.34 min (Purity: 99.4%).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:22][O:21][CH2:20]5)[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>[Pd]>[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:24]=[CH:23][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:19]6[CH2:22][O:21][CH2:20]6)[CH:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:30]=[N:29]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3nccn3C3COC3)nc1-2
Agent: [Pd]
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4C4COC4)nc2-3)cn1

Procedure:
Following the procedure for 355, 8-Bromo-2-(1-oxetan-3-yl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted under Suzuki palladium conditions to give 420. MS: (ESI+)=464.1. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J=1.4 Hz, 2H), 7.47 (dd, J=8.3, 1.7 Hz, 1H), 7.28 (d, J=1.7 Hz, 1H), 7.19 (d, J=1.0 Hz, 1H), 6.38 (p, J=6.8 Hz, 1H), 5.10 (t, J=7.3 Hz, 2H), 4.86 (t, J=6.6 Hz, 2H), 4.72 (s, 1H), 4.36 (t, J=5.0 Hz, 2H), 4.04 (s, 2H), 3.38 (t, J=5.0 Hz, 2H), 1.10 (s, 6H)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]=2[CH:20]=1.O>ClCCl>[C:5]([C:12]1[C:13]2[O:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]=2[CH:20]=[C:10]([Br:9])[CH:11]=1)(=[O:7])[CH3:6]
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(Br)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A stirred, cooled (ice-bath) suspension of aluminum chloride (0.25 g, 1.7 mmol) in 3 mL of anhydrous dichloromethane was treated with acetyl chloride (0.2 mL, 2.6 mmol) under argon. A solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 2, 0.22 g) in 1.5 mL of anhydrous dichloromethane was cannulated into the clear solution, and the resulting deep red solution was allowed to warm to ambient temperature over 1 h. The reaction mixture was poured onto iced water and extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a dirty white solid. Flash column chromatography on silica gel (230-400 mesh) using 6% ethyl acetate in hexane as the eluent afforded the title compound as a white solid (0.177 g, 67%).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([CH:18]=[CH:19][C:20]3[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[NH:23][CH:24]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>[Pd]>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[NH:23][CH:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: COC(=O)c1cc(C=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)c[nH]1
Agent: [Pd]
Product: COC(=O)c1cc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)c[nH]1
Yield: 95 %

Procedure:
Upon reduction of methyl 4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]-pyrimidin-6-yl)ethenyl]pyrrole-2-carboxylate with hydrogen and palladium-on-carbon catalyst (200 mg) analogously to that described in Example 8, there is obtained methyl 4-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrole-2-carboxylate (380 mg, 95%): mp 236-238° C.: 1H NMR (DMSO-d6) δ 11.59 (s, 1H), 11.21 (s, 1H), 10.60 (s, 1H), 6.81 (s, 1H), 6.62 (s, 1H), 6.42 (s, 1H), 3.70 (s, 3H), 3.23 (br d, 1H, J=10.5 Hz), 2.82 (m, 1H), 2.57-2.43 (m, 3H), 1.87 (dd, 1H, J=15.2, 8.0 Hz), 1.68-1.43 (m, 3H), 1.18 (s, 9H).
Reaction SMILES: [N:1]1([C:6]2[N:10]3[CH:11]=[C:12]([O:15][C@H:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C@@H:19]([NH2:26])[CH2:18][CH2:17]4)[CH:13]=[CH:14][C:9]3=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:30][C:31](=O)[NH:32][C:33]1[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:38]([C:36]1[CH:37]=[C:33]([NH:32][C:31]([NH:26][C@@H:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[N:7][N:8]=4)[CH:11]=3)[CH2:17][CH2:18]2)=[O:30])[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC4)n3c2)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 20.2 %

Procedure:
A mixture of Intermediate 75b (62.0 mg, 0.18 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 78.9 mg, 0.195 mmol), DIPEA (46.3 μL, 0.27 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, then further purified by HPLC (30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as an off-white solid (22 mg, 20%). LCMS (Method 5) Rt 4.30 min, m/z 605 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.79-2.15 (8H, m), 2.36 (3H, s), 3.49 (4H, m), 4.81 (1H, m), 5.51 (1H, t, J 4.5), 6.30 (1H, s), 7.03 (1H, dd, J 10.1, 2.2), 7.09 (1H, d, J 8.5), 7.25-7.40 (8H, m), 7.51 (1H, m), 7.83 (1H, m), 8.07 (1H, s).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16](=[S:18])[NH2:17])[NH:8]2)=[CH:4][C:3]=1[O:19][C:20]1[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1.[C:30]([O:35][CH2:36][CH3:37])(=[O:34])[C:31]#[C:32][CH3:33].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:18][CH:32]([CH2:31][C:30]([O:35][CH2:36][CH3:37])=[O:34])[CH2:33][N:17]=3)[NH:8]2)=[CH:4][C:3]=1[O:19][C:20]1[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: CC#CC(=O)OCC
Reactant: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)c(F)c(OCCOC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a stirred solution of 6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (0.58 g), ethyl 2-butynoate (0.31 mL), tetrahydrofuran (10 mL) and toluene (15 mL) was added tributylphosphine (0.40 mL) at room temperature under argon atmosphere. After stirring at 40° C. for 3 h, the reaction mixture was concentrated to give a light brown oil, which was purified by silica gel chromatography (ethyl acetate:hexane=35:65 to 100:0, volume ratio) to give the title compound (525 mg, 72%) as a pale yellow oil. MS 552 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:8]([C:12]([O:14]C)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[C:16]([C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][C:10]2[C:5]([C:6]=1[OH:20])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1c(C(=O)O)nc2cc(Cl)ccc2c1O
Temperature: 60 °C
Yield: 94.5 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (1.0 g, 3.38 mmol) in water (20 mL) was added an aqueous solution of sodium hydroxide (0.27 g, 6.75 mmol). Upon addition, the suspension dissolved. The reaction mixture was warmed to 60° C. for 1 hour. After this time the reaction was cooled to room temperature and acidified with concentrated hydrochloric acid. The product was then extracted into diethyl ether and ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide the title compound as a solid (900 mg). This material was purified by recrystallization employing an ethyl acetate/hexane co-solvent system to provide the title compound (571 mg, 60%) as a white solid mp 296° C. (dec); MS (CI)=238 (M+H). Analysis for C12H8NO5Cl·0.45 CH3CO2CH2CH3·0.10 H2O: Calc'd: C, 51.30; H, 3.68; N 4.34, Found: C, 51.28; H, 3.62; N 3.97 1H NMR 8.22 (d, J=8.7 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.28 (dd, J=8.7, 1.8 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[C:13]([CH3:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Cl.[CH2:16]([N:18]([CH2:27][CH3:28])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl)[CH3:17]>O.C(O)C>[CH2:27]([N:18]([CH2:16][CH3:17])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][S:3][C:4]1[C:13]([CH3:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:28]
Reactant: CCN(CC)c1ccccc1CCl
Reactant: Cc1nc2ccccc2nc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(CC)c1ccccc1CSc1nc2ccccc2nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a solution of 0.73 g of sodium hydroxide in a mixture of 2 ml of water and 50 ml of ethanol were added successively 1.5 g of 2-mercapto-3-methylquinoxaline and 1.99 g of 2-diethylaminobenzyl chloride hydrochloride. The resulting mixture was stirred at room temperature for 3 hrs., and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to removed the solvent. The residual oil was purified by silica gel column chromatography (hexane/acetone) to give 1.74 g of 2-(2-diethylaminobenzylthio)-3-methylquinoxaline as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: C1CCNCC1
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCCCC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and piperidine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2].C(N([CH2:19][CH3:20])CC)C>CO>[CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@H:6]3[C:19]4[C:20](=[CH:1][CH:3]=[CH:4][CH:13]=4)[CH2:9][CH2:10][C@@H:11]3[OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2]
Reactant: Cc1nc2c(O)cccn2c1C=O
Reactant: CCN(CC)CC
Solvent: CO
Product: Cc1nc2c(O[C@H]3c4ccccc4CC[C@@H]3O)cccn2c1C=O
Reaction time: 8 h
Yield: 47.1 %

Procedure:
580 mg of 3-formyl-8-hydroxy-2-methyl-imidazo[1,2-a]pyridine and 580 mg of (+)-1R,2S-1,2,3,4-tetrahydro-naphthaline-1,2-oxide are reacted, analogously to the method described in Example 21, with 340 mg triethylamine in 43 ml of aqueous methanol (35 ml methanol+8 ml water) at 60° C. After 8 hours the mixture is worked up as described in Example 41. After stirring with petroleum ether and drying in high vacuum, 250 mg of the title compound is isolated. [α]D22 =+38° (c=1, chloroform).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(CC)CC)C.[CH3:54][O:55][C:56]1([CH3:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:59]1[CH2:60][CH2:61][C:56]([O:55][CH3:54])([CH3:62])[CH2:57][CH2:58]1)=[O:30]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC1(C)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1(C)CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.597 g, 1.57 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.188 g, 0.63 mmol) and triethylamine (0.193 mL, 1.39 mmol) in N,N-dimethylformamide (2 mL) at ambient temperature under an air atmosphere. The resulting solution was stirred at 25° C. for 15 minutes. A solution of 4-methoxy-4-methylpiperidine (23) (89.5 mg, 0.69 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution was stirred at 25° C. for 4 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, s), 1.25-1.34 (1H, m), 1.42 (1H, td), 1.56 (1H, d), 1.75 (1H, dd), 3.10-3.18 (4H, m), 4.09 (3H, q), 4.32 (2H, s), 7.21 (1H, t), 7.31 (1H, dd), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, dd), 8.27 (1H, dd), 12.57 (1H, s); m/z (LC-MS, ESI+), RT=1.79 (M+H 409).
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3[C:24]([Cl:28])=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([O:5]C)=[O:4]>CO.C(Cl)Cl>[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3[C:24]([Cl:28])=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([OH:5])=[O:4]
Reactant: CCCc1cc(Cn2cnc3ccnc(Cl)c32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(Cn2cnc3ccnc(Cl)c32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 82.2 %

Procedure:
A 5N sodium hydroxide solution (0.1 mL) was added to a stirred mixture of the product of Step A (25 mg, 0.0466 mmol) in methanol (1 mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo then 5% citric acid solution added. The precipitate was filtered off, washed with water and dried in vacuo to give the titled compound (20 mg).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C@@H:7]([OH:11])[C@@H:8]([NH3+:10])[CH3:9].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[C:27](=[CH:28][C:29](I)=[CH:30][CH:31]=3)[CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:2][C:3]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C@@H:7]([O:11][C:29]1[CH:28]=[C:27]2[C:32](=[CH:31][CH:30]=1)[N:24]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[N:25]=[CH:26]2)[C@@H:8]([NH2:10])[CH3:9]
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: C[C@H]([NH3+])[C@H](O)COc1ccc(F)cc1F
Agent: [Cl-]
Product: C[C@H](N)[C@@H](COc1ccc(F)cc1F)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 1a from (2S,3S)-4-(2,4-difluorophenoxy)-3-hydroxybutan-2-aminium chloride (290 mg, 1.14 mmol) and 1-(4-fluorophenyl)-5-iodo-1H-indazole (464 mg, 1.37 mmol). Yield: 90 mg (18%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1ccc2cnn(-c3ccc(F)cc3)c2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
A solution of 4-(1-(4-fluorophenyl)-1H-indazol-6-yl)butanoic acid (3, R1=4-Fluorophenyl) (13.86 g, 46.5 mmol) in DCM (225 mL) was treated with oxalyl dichloride (2M in DCM) (25.6 mL, 51.1 mmol). Two drops of DMF were added and the mixture was stirred for about 45 min at rt. A second portion of oxalyl dichloride (2M in DCM) (4.65 mL, 9.29 mmol) was added followed by 1 drop DMF. After about 15 min the solvent was removed under reduced pressure. The material was dissolved in DCM (225 mL) and the flask was fitted with a reflux condenser. Aluminum trichloride (8.2 g, 61.5 mmol) was added and the mixture was stirred for about 30 min. A second portion of aluminum trichloride (7.67 g, 57.5 mmol) was added to the mixture and stirring was continued for about 30 min. The reaction was quenched by slow addition of ice in small portions over about 30-45 min with vigorous stirring. After addition of about 50 g of ice, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (30 mL) and the combined organic solutions were washed with water (75 mL), 0.5 N aq. sodium hydroxide (100 mL) and brine (50 mL). The organic mixture was dried over MgSO4, filtered and concentrated under reduced pressure to a solid. The material was purified on silica gel (330 g) using a gradient of 0-15% EtOAc in DCM. Fractions containing >95% desired product were combined and concentrated under reduced pressure. Fractions containing desired product contaminated with the minor regioisomer [1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[g]indazol-9(6H)-one] were combined and concentrated under reduced pressure separately. The residue was purified on silica gel (80 g) using a gradient of 0-10% EtOAc in DCM. Fractions containing >95% desired product were combined with those from the first column and concentrated under reduced pressure to yield 1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[f]indazol-5(6H)-one (4, R1=4-Fluorophenyl) (8.73 g, 67%); LC/MS, method 3, Rt=2.43 min, MS m/z 281 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.52 (d, J=0.9 Hz, 1H), 8.49 (s, 1H), 7.86-7.78 (m, 2H), 7.69 (s, 1H), 7.51-7.41 (m, 2H), 3.12-3.09 (m, 2H), 2.70-2.63 (m, 2H), 2.11-2.02 (m, 2H). Note: 1H NMR shows ˜4% minor regioisomer.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH2:16][CH2:17][CH3:18].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:20]([NH:19][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[CH2:16][CH2:17][CH3:18])[CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:42])([F:41])[F:43]
Reactant: CCCc1cnn(C)c1-c1cc(C(=O)O)sc1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (206 mg, 0.78 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (300 mg, 0.78 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.68 ml, 3.90 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (400 mg, 0.86 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (283 mg, 0.46 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-fluorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 30% overall yield. FDMS m/e=369 (M+ of free base). α[D]589 =-2.49 (c=0.24, methanol).