Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].C(N(S(F)(F)[F:50])CC)C.C(=O)=O.CC(C)=O>C(Cl)Cl>[F:50][C:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8]
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COCCCCC(F)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reaction time: 0.08 h
Yield: 79.5 %

Procedure:
To a 50 mL round bottom flask were added 0.0597 g (0.097 mmol, 1.0 equiv) of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate and 5 mL of CH2Cl2. The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and 0.1860 g (ca. 10 equiv) of (diethylamino)sulfur trifluoride (DAST) was added. After 5 min, the dry ice-acetone bath was replaced by an ice-MeOH bath (−10° C.). After an additional hour, the reaction mixture was quenched with 10% Na2CO3 (10 mL), extracted three times with Et2O, and dried over Na2SO4. The crude product was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 15 min, flow rate 25 mL/min) to give 0.0478 g (80%) of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-(1-fluoro-5-methoxy-1-phenylpentyl)-piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate. LC-MS tR=2.59 min in 3 min chromatography, m/z 642 (M+Na+), 620 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.83 (br s, 1H), 7.36-7.19 (m, 5H), 5.42 (br s, 0.69H), 5.00 (br s, 0.31H), 4.39-4.36 (m, 1H), 4.14-4.03 (m, 3H), 3.72-3.46 (m, 2H), 3.28-3.24 (m, 5H), 2.94-2.86 (m, 4H), 2.62-2.40 (m, 2H), 2.11-0.81 (m, 25H), 0.03 and −0.01 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.4, 157.8, 141.3, 141.0, 128.2, 128.1, 127.3, 126.9, 124.7, 124.6, 101.3, 99.5, 72.52, 72.46, 63.9, 63.8, 58.4, 58.3, 52.7, 52.6, 47.9, 47.6, 45.0, 44.82, 44.77, 44.6, 41.3, 41.1, 37.1, 36.9, 34.7, 34.6, 34.4, 34.3, 33.5, 33.4, 33.2, 29.6, 29.5, 26.4, 26.2, 26.13, 26.09, 25.1, 25.0, 24.6, 19.8, 17.7, −1.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.[CH3:30][N:31]([CH3:36])[S:32](Cl)(=[O:34])=[O:33]>>[CH3:30][N:31]([CH3:36])[S:32]([N:22]1[CH:23]=[CH:24][C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)=[N:21]1)(=[O:34])=[O:33]
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)n1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one, and dimethyl sulphamoyl chloride.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][C@H:25]([CH3:27])[CH2:24][C@H:23]([CH3:28])[CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][C@H:25]([CH3:27])[CH2:24][C@H:23]([CH3:28])[CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@@H]1C[C@H](C)CC(CNOCc2ccccc2)(C(=O)O)C1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C[C@@H]1C[C@H](C)CC(CN(C=O)OCc2ccccc2)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a cold solution of formic acid (15.5 mL, 0.40 mol) in dichloromethane (75 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (5.9 mL, 62 mmol). After 1 h, a solution of (3S,5R)-1-(Benzyloxyamino-methyl)-3,5-dimethyl-cyclohexanecarboxylic acid (1.8 g, 6.2 mmol) in dichloromethane (75 mL) was added. The reaction was stirred at room temperature for 18 h and was concentrated in vacuo. Water (150 mL) was added and the mixture was extracted with dichloromethane (75 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a yellow solid (1.59 g, 80%). MH+320.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:34][C:35]([CH3:56])([CH3:55])[CH2:36][NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[CH:43][C:42]=1[F:54])=[O:39].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH2:34][C:35]([CH3:56])([CH3:55])[CH2:36][NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH:48]2[CH2:53][CH2:52][N:51]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:20])([F:1])[F:21])=[CH:10][C:11]=3[CH2:17][CH2:18][CH3:19])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[F:54])=[O:39]
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CO
Reactant: CC(C)(N)CNC(=O)Nc1ccc(CC2CCNCC2)cc1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CN1CCC(Cc2ccc(NC(=O)NCC(C)(C)N)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 5.7 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-(hydroxymethyl)-3-propylphenyl)propan-2-ol (0.474 mmol, 150 mg) was dissolved in dichloromethane (5 mL) and triethylamine (1.423 mmol, 144 mg) added. The mixture was cooled to 0° C. before the addition of methanesulfonyl chloride (0.611 mmol, 70.0 mg). The mixture was stirred at 0° C. for 90 min. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×10 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(2-amino-2-methylpropyl)-3-(2-fluoro-4-(piperidin-4-ylmethyl)phenyl)urea (0.341 mmol, 110 mg) was added followed by potassium carbonate (1.023 mmol, 141 mg). The mixture was heated to reflux for 16 hours. The mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC and treated with strong cation exchange column chromatography to afford the title compound (12 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:15]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[N:16]2)[CH:3]=1.COC1C(C)=C2C(C(O[CH:43]3[CH2:60][CH:59]4[CH:45]([C:46](=[O:66])[N:47]([CH3:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:44]3)=CC(C3SC=CN=3)=N2)=CC=1>>[C:20]([C:17]1[CH:18]=[CH:19][N:15]([C:4]2[CH:3]=[C:2]([O:1][CH:43]3[CH2:60][CH:59]4[CH:45]([C:46](=[O:66])[N:47]([CH3:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:44]3)[C:11]3[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[N:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Reactant: COc1ccc2c(O)cc(-n3ccc(C(C)(C)C)n3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinoline (126) and intermediate 26 following the procedure (Step D-F) reported for the preparation of 17-[7-methoxy-8-methyl-2-(thiazol-2-yl)quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (29): m/z=644 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]([CH3:11])[C:9]#[N:10].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]([CH3:11])[C:9]#[N:10])[CH:6]=1
Reactant: CC(Cl)C#N
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C#N)n1cc(Cl)cn1
Temperature: 100 °C
Yield: 116.3 %

Procedure:
4-Chloro-1H-pyrazole (4.05 g, 39.5 mmol), 2-chloropropanenitrile (3.71 g, 41.5 mmol), cesium carbonate (15.6 g, 44.3 mmol) and anhydrous tetrahydrofuran (20 mL) were added into a sealed tube and the reaction mixture was heated to 100° C. for 2 h. The mixture was diluted with ether (100 mL) and filtered. The solids were rinsed with ether (30 mL×3) and the filtrate was diluted with dichloromethane (10 mL). The solution was concentrated under reduced pressure to afford the title compound as oil (7.15 g). The material was taken to the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 1.90 (d, 3H), 5.21-5.30 (m, 1H), 7.51 (s, 1H), 7.58 (s, 1H); MS (EI+) (M+) 155; GCMS retention time: 1.23 minutes (Method O).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][C@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:30](O)(=[O:32])[CH3:31].C([BH3-])#N.[Na+]>CO>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][C@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[C:16]4[CH2:22][N:21]([CH2:31][CH2:30][OH:32])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: c1ncc(-c2ccc(Nc3nc4c(c(NC[C@H]5CCCO5)n3)CNCC4)cc2)o1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: OCCN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@H]3CCCO3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.9 %

Procedure:
(R)-N2-(4-(Oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (135 mg, 0.34 mmol) was dissolved in methanol (3 mL). Acetic acid (0.020 mL, 0.34 mmol) was added followed by (R)-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (135 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (21.62 mg, 0.34 mmol) (MP—CNBH3) was added and the reaction was stirred overnight. The crude was filtered, concentrated under reduced pressure, dissolved in methanol, filtered and purified by preparative HPLC yielding (R)-2-(2-(4-(oxazol-5-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (31.0 mg, 18.15%) as acetate salt. MS (ES+) m/z 437.3 (M+H)+;
Reaction SMILES: [C:1]([NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1O
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 44 %

Procedure:
(1S,2S)-2-(N-Linoleoylamino)cyclohexanol (3.77 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 2.72 g of the title compound (yield: 44%)
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[F:26])[C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)=[O:5].[CH2:32](O)[CH:33]=C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:1][C:2]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[F:26])[C:13]([O:15][CH2:16][CH:32]=[CH2:33])=[O:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: C=CCO
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1ccc(C(=O)c2ccc(C)cc2C)n1C
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: C=CCOC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1ccc(C(=O)c2ccc(C)cc2C)n1C
Temperature: 25 °C
Reaction time: 36 h
Yield: 97 %

Procedure:
To a solution of methyl 2-[5-(2,4-dimethylbenzoyl)-1-methylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)acetate (3.51 g, 8.27 mmol) [prepared as described in Example 6, Step(c)] in 75 ml allyl alcohol was added titanium tetraisopropoxide (0.244 ml, 0.827 mmol), and the reaction mixture was heated to reflux. After 36 h, the reaction mixture was cooled to room temperature, and partitioned between ether and water. The organic layer was separated, dried over magnesium sulfate, and concentrated to dryness to give allyl 2-[5-(2,4-dimethylbenzoyl)-1-methylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)-acetate (3.60 g, 97%) as a pale yellow oil. ##STR36##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17](O)=O)[C:9]=2[F:20])[CH:5]=[CH:6][CH:7]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24].O>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[S:24][C:23]([NH2:25])=[N:22][N:21]=3)[C:9]=2[F:20])[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(N)=S
Reactant: COc1ccc(CC(=O)O)c(F)c1-c1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(Cc2nnc(N)s2)c(F)c1-c1cccc(Cl)c1
Temperature: 120 °C
Yield: 39 %

Procedure:
A mixture of (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid (I-79) (0.998 mmol, 1.0 eq.) and thiosemicarbazide (2.99 mmol; 3 eq.) in excess phosphorous oxychloride was heated to 120° C. for 45 minutes, and allowed to cool to room temperature. The resultant mixture was added to water, and extracted with 2 portions of ethyl acetate. The organics were washed with brine, and dried over magnesium sulfate. The residue was purified via flash chromatography on silica gel using 5% (1N NH3 in MeOH) in dichloromethane as eluent to afford the desired product (P-333) in 39% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:28][CH:29]([Cl:33])[C:30](Cl)=[O:31]>O1CCCC1>[Cl:28][CH:29]([Cl:33])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]3[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:19])[O:10][N:9]=2)[CH:3]=1)=[O:31]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(3-Aminophenyl)-5-(2,6-dichlorophenyl)isoxazole (60 mg, 0.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) with triethylamine (33 mL, 0.24 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (23 mL, 0.24 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give the title compound as a tan solid, 74 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[C:17]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC(C)C(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC(C)C(F)(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
129 mg of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpentanoic acid (mixture of racemic diastereomers) and 59 mg (0.31 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 51 mg (30% of theory)
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[O:9])[CH2:34][CH2:33]1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccccc2C(=O)Nc2cccc3[nH]ccc23)CC1

Procedure:
1.6 g of 2-[(2-oxiranyl)-methoxy]-N-[(1H-indol-4-yl)]-benzamide in 36 ml of ethanol as refluxed for 4 hours with 1.82 ml of (methoxyphenyl)piperazine and the solvent was eliminated under reduced pressure. The residue was purified by chromatography over silica (eluent:chloroform--ethyl acetate--triethylamine, 6-3-1) to obtain 1.85 g of 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:42]([CH:39]4[CH2:40][CH2:41][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[CH2:38]4)=[O:43])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C2CCN(C(=O)OC(C)(C)C)C2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (37 mg, 0.17 mmol). Yield 38 mg (50%).
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]2[S:15][C:16]([CH3:24])([C:20]([F:23])([F:22])[F:21])[C:17](=[O:19])[N:18]=2)[CH3:12])=[CH:7][CH:6]=1>CN(C=O)C>[CH3:24][C:16]1([C:20]([F:23])([F:22])[F:21])[S:15][C:14]([NH:13][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]#[N:2])=[CH:6][CH:7]=2)[CH3:12])=[N:18][C:17]1=[O:19]
Reactant: C[C@H](NC1=NC(=O)C(C)(C(F)(F)F)S1)c1ccc(Br)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: C[C@H](NC1=NC(=O)C(C)(C(F)(F)F)S1)c1ccc(C#N)cc1
Temperature: 150 °C

Procedure:
CuCN (140 mg, 1.6 mmol) and 2-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-5-(trifluoromethyl)thiazol-4(5H)-one (150 mg, 0.39 mmol) and 2 mL of DMF were combined in a sealed tube and heated to 150° C. for 12 h. The residue was purified by column chromatography (10 to 60% EA/Hex, 40 g) to give 4-((S)-1-(5-methyl-4-oxo-5-(trifluoromethyl)-4,5-dihydrothiazol-2-ylamino)ethyl)benzonitrile as a slightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:11][C@@H:10]2[CH3:26])=[O:8])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([N:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[C:38](=[O:40])[CH3:39])[CH2:11][C@@H:10]2[CH3:26])=[O:8])=[CH:27][CH:28]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccncc3)C[C@@H]2C)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccncc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-N-pyridin-4-yl-1,2,3,4-tetrahydroquinolin-4-amine (90 mg, 0.24 mmol, 1 equ.) in methylene chloride (0.8 mL) was added diisopropylethylamine (84 uL, 0.48 mmol, 2 equ.) followed by acetyl chloride (340 uL, 4.80 mmol, 20 equ.). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride/methanol 97/3) to afford pure N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-pyridin-4-ylacetamide (60 mg, 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:34](=[CH:35][CH:36]=3)[CH2:33][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]3=[O:32])[CH2:22]4)=[O:17])[C:13](=[O:37])[C:12]([CH3:39])([CH3:38])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:40]OS([O-])=O.[K+].O>CO>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:34](=[CH:35][CH:36]=3)[CH2:33][C@:23]3([C:31]5[C:26](=[N+:27]([O-:40])[CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]3=[O:32])[CH2:22]4)=[O:17])[C:13](=[O:37])[C:12]([CH3:39])([CH3:38])[CH2:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3c2ccc[n+]3[O-])C1=O

Procedure:
A mixture of 2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (20.0 mg, 0.038 mmol, described in Example 49) and Oxone® (70.0 mg, 0.113 mmol) in MeOH (0.5 mL) and water (0.5 mL) was stirred at ambient temperature for 3 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=547 (M+1). HRMS: m/z=547.2155; calculated m/z=547.2152 for C30H29F2N4O4.