Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[CH:19]=2)[C:15](=[O:30])[CH2:14][CH2:13][CH2:12]1.C1C(=O)N([Cl:38])C(=O)C1.O.CCOC(C)=O>CN(C=O)C>[Cl:38][C:8]1[C:3]([O:2][CH3:1])=[C:4]([CH:11]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[C:26]([CH3:29])[S:27][CH:28]=4)[CH:19]=3)[C:15](=[O:30])[CH2:14][CH2:13][CH2:12]2)[C:5]([O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)c(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 6-(2,6-dimethoxyphenyl)-1-(3-(2-methylthiazol-4-yl)benzyl)piperidin-2-one (60 mg; 0.14 mmol; compound corresponding to example 16), and NCS (21 mg; 0.15 mmol) in anh. DMF (1.5 ml) was stirred at rt, under nitrogen, for 24 h. Water (5 ml), and AcOEt (10 ml) were added, and the separated organic layer was washed with brine (5 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure.
Reaction SMILES: [Al](C)(C)C.[CH3:5]NCCNC.CO[C:13](=[O:27])[C:14]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[C:16]([C:25]#[N:26])[CH:15]=1.Cl>C1(C)C=CC=CC=1>[C:13]([C:14]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:17]=[C:16]([C:25]#[N:26])[CH:15]=1)(=[O:27])[CH3:5]
Reactant: COC(=O)c1cc(C#N)cc(NS(C)(=O)=O)c1
Reactant: CNCCNC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C#N)cc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
Al(CH3)3 (20 mmol) was added dropwise to the ice-water cooled solution of DMEDA (4.4 mmol) in dry toluene (60 mL) under nitrogen. After addition, it was continued to stir for 2 hours at room temperature. Then, methyl-3-cyano-5-(methylsulfonamido)benzoate (4 mmol) was added, and the reaction mixture was heated to reflux overnight. After cooling, it was poured into diluted hydrochloric acid, the mixture was extracted with EtOAc, the combined organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated to afford N-(3-acetyl-5-cyanophenyl)methanesulfonamide with a yield of 35%. Br2 (1.2 mmol) was added dropwise to the solution of N-(3-acetyl-5-cyanophenyl)methanesulfonamide (1 mmol) in Et2O (50 mL). After addition, it was continued to stir for 1.5 hours. Then the reaction mixture was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated to afford N-(3-(2-bromoacetyl)-5-cyanophenyl)methanesulfonamide with a yield of 85%.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][O:27][CH3:28].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][O:27][CH3:28])[CH2:14][CH2:13]1
Reactant: COCCBr
Reactant: Fc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1.1 mmol) and 1-bromo-2-methoxyethane (0.16 ml, 2.0 mmol). Yield: 0.34 g (61%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 180-181° C. MS m/z (relative intensity, 70 eV) 305 (M+, 2), 261 (14), 260 (bp), 217 (5), 177 (9).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([NH2:15])=O)[NH:7]2.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]#[N:15])[NH:7]2
Reactant: COc1c(C)ccc2[nH]c(C(N)=O)cc12
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1c(C)ccc2[nH]c(C#N)cc12
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A mixture of 79 mg of 4-methoxy-5-methyl-1H-indole-2-carboxamide (0.39 mmol), 0.19 mL of phosphorus oxychloride (2 mmol) and 1.5 mL of chloroform was refluxed for 2 hs. Then cooled solution was poured into 10 mL of water and stirred for 1 hr. After separation the organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 5:1 to afford 51 mg of 4-methoxy-5-methyl-1H-indole-2-carbonitrile.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[F:13][C:14]([F:29])([S:25](F)(=[O:27])=[O:26])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18].[OH-].[K+]>>[F:29][C:14]([F:13])([S:25]([O:4][CH2:3][C:2]([F:12])([F:1])[C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9])(=[O:27])=[O:26])[C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
2,2,3,3,4,4,4-heptafluorobutan-1-ol (200 g, 1.0 mol, obtained from 3M Company) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (300 g, 1.0 mol, obtained from 3M Company) were combined in a 1-liter, 3-necked round bottom flask. The flask was equipped with an overhead mechanical stirrer, cold water condenser, thermocouple and an addition funnel Aqueous potassium hydroxide (45 percent by weight in water, 154 g, 1.05 mol) was added dropwise via the addition funnel at such a rate that the temperature did not exceed 35° C. Once the addition of the potassium hydroxide was complete, the mixture was stirred for 16 hours at room temperature. Precipitated salts were then filtered from the mixture and the lower liquid fluorochemical product phase was separated from the upper aqueous phase and washed once with water to give 350 g crude product. The product was distilled at atmospheric pressure and the distillation cut boiling from 140-150° C. used without further purification (96.3 percent purity by GC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([C:8]#[C:9][Si](C)(C)C)=[N:6][CH:7]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[NH:14][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ncc(F)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cnc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of 5-fluoro-2-((trimethylsilyl)ethynyl)pyridin-3-amine (2.22 g, 10.7 mmol) in DMF (30 mL) at 0° C. under nitrogen was added NaH (60% in mineral oil, 1.025 g, 42.7 mmol) in several portions. After stirring at RT for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc. The extract was dried (MgSO4), filtered, and concentrated under reduced pressure to afford 1.46 g (100%) of 6-fluoro-1H-pyrrolo[3,2-b]pyridine as a brown solid. MS (ESI): m/z=137.2 [M+1]+.
Reaction SMILES: B.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][CH2:9][C:10](O)=[O:11]>O1CCCC1>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: O=C(O)CCCc1cccs1
Agent: B
Solvent: C1CCOC1
Product: OCCCCc1cccs1
Reaction time: 17 h

Procedure:
To 240 ml. of 1 M borane in tetrahydrofuran chilled in an ice bath, is added dropwise, 20.4 g. of 4-(2-thienyl)-butyric acid in 50 ml. of tetrahydrofuran. After the addition, the mixture is allowed to stand at room temperature for 17 hours and is poured onto ice. After standing, the mixture is extracted with ether, the ether extract washed with water, dried over magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:6](=[O:59])[N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]4[CH:28]=[C:29]5[C:56](=[CH:57][CH:58]=4)[C:33]4[NH:34][C:35]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:55])[CH:43]([NH:50][C:51](=[O:54])[CH2:52][CH3:53])[CH:44]6[CH2:49][CH2:48][O:47][CH2:46][CH2:45]6)=[N:36][C:32]=4[CH2:31][CH2:30]5)[CH:23]=3)[CH:18]=2)=[CH:15][N:16]=1.[C:67](Cl)(=O)CC>>[CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:6]([N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]4[CH:28]=[C:29]5[C:56](=[CH:57][CH:58]=4)[C:33]4[NH:34][C:35]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:55])[CH:43]([NH:50][C:51]([CH:52]6[CH2:67][CH2:53]6)=[O:54])[CH:44]6[CH2:49][CH2:48][O:47][CH2:46][CH2:45]6)=[N:36][C:32]=4[CH2:31][CH2:30]5)[CH:23]=3)[CH:18]=2)=[CH:15][N:16]=1)=[O:59]
Reactant: CCC(=O)Cl
Reactant: CCC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc(C6CCCN6C(=O)C(NC(=O)C6CC6)C6CCOCC6)[nH]c4-5)ccc3c2)[nH]1)c1ccccc1
Yield: 38 %

Procedure:
[2-(2-{5-[6-(2-{1-[2-(Cyclopropanecarbonyl-amino)-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-carbamic acid methyl ester (0.01 g, 38%) was prepared following the procedure for [2-Oxo-1-phenyl-2-(2-{5-[6-(2-{1-[2-propionylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamic acid methyl ester, substituting Cyclopropanecarbonyl chloride for Propionyl chloride. LCMS-ESI+: calc'd for C53H56N8O6: 900.43 (M+); Found: 902.07 (M+H+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl:37][C:38]1[C:39]([C:48]([F:51])([F:50])[F:49])=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([C:48]([F:50])([F:49])[F:51])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[O:46])[C:42]=1[CH3:43]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccccc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-Phenylpiperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.32 (m 4H), 7.02 (m, 1H), 5.40 (s, 2H), 3.74 (m, 4H), 3.39 (m, 2H), 3.29 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) expect M+H=387.1, found 387.1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]([CH2:23][O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([NH:35]C(=O)OC(C)(C)C)=[CH:27][CH:26]=3)[CH:20]=[CH:19][N:18]=2)[CH:13]=[N:12][CH:11]=1)[CH3:9]>C(Cl)Cl>[NH2:35][C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([O:24][CH2:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:14]3[CH:13]=[N:12][CH:11]=[C:10]([CH2:8][CH3:9])[N:15]=3)[CH:22]=2)=[CH:26][CH:27]=1
Reactant: CCc1cncc(Nc2cc(COc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)ccn2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cncc(Nc2cc(COc3ccc(N)c4ccccc34)ccn2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
TFA (1.485 mL, 19.09 mmol) was added to a solution of tert-butyl (4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (Intermediate D (protected)) (360 mg, 0.763 mmol) in DCM (15 mL), and the reaction mixture stirred at room temperature for 4 h, then concentrated in vacuo. The residue was combined with sat. sodium hydrogencarbonate solution and stirred at room temperature for 16 h. The solid was filtered, washing with acetonitrile, and dried under vacuum to give the subtitle compound N-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amine as a beige solid (200 mg, 69%); Rt 2.14 min (Method 2); m/z 372 (M+H)+ (ES+); 1H NMR δ: 1.20 (3H, t), 2.64 (2H, q), 5.18-5.24 (4H, overlapping m), 6.59 (1H, d), 6.82 (1H, d), 7.03 (1H, d), 7.41-7.51 (2H, overlapping m), 7.98-8.01 (2H, m), 8.04 (1H, m), 8.22-8.29 (2H, overlapping m), 8.91 (1H, s), 10.04 (1H, s).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:43][C@@H:44]([F:51])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])(=O)=O)=CC=1.F[C@@H](CCCCCC)CO.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>CN(C)C=O.N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:43][CH:44]([F:51])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C@@:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH:15]=1
Reactant: CCCCCC1(c2ccccc2)C=CC(c2ccc(O)c(F)c2F)=CC1
Reactant: CCCCCC[C@H](F)COS(=O)(=O)c1ccc(C)cc1
Agent: CCCCCC[C@H](F)CO
Agent: Cc1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCC(F)COc1ccc(C2=CC[C@](CCCCC)(c3ccccc3)C=C2)c(F)c1F

Procedure:
0.02 mol of 2,3-difluoro-4-hydroxy-4'-pentyl-p-terphenyl, 0.02 mol of potassium carbonate and 0.2 mol of (S)-2-fluorooctyl p-toluenesulfonate (prepared from (S)-2-fluorooctan-1-ol and toluenesulfonyl chloride in the presence of pyridine) are stirred at 60° for 15 hours in 25 ml of dimethylformamide. The undissolved salts are filtered off with suction, and water is added to the filtrate. Extractive work-up and subsequent column chromatography give the pure (S)-2,3-difluoro-4-(2-fluorooctyloxy)-4'-pentyl-p-terphenyl.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.CC(C)=O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1/[CH:14]=[CH:13]/[CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)C(=O)c1ccc(OC/C=C/c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: O=C(O)C(=O)c1ccc(OC/C=C/c2ccc3ccccc3c2)cc1
Yield: 92 %

Procedure:
A mixture of (E)-4-[[3-(2-naphthalenyl)-2-propenyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.85 g) in methanol (20 mL), acetone (5 mL), and 0.5N sodium hydroxide (6 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from dichloromethane-hexane to give 0.75 g of colorless (E)-4-[[3-(2-naphthalenyl)-2-propenyl]oxy]-alpha-oxobenzeneacetic acid, mp 142°-143° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:9])=[CH:4][C:3]=1[O:27][CH3:28].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:28][O:27][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: COc1cc(C(=O)c2c(-c3ccccc3)c(OC)c3ccccn23)ccc1N
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CNc1ccc(C(=O)c2c(-c3ccccc3)c(OC)c3ccccn23)cc1OC

Procedure:
This compound was obtained according to the method described in Example 192, by alkylating (4-amino-3-methoxyphenyl)(1-methoxy-2-phenylindolizin-3-yl)methanone, a compound of Example 95, with ethyl bromoacetate. A yellow powder is obtained.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]([C:18]1[N:19]=[N:20][C:21]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[CH:33]=[C:32]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[N:31]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:29]=4[N:30]=3)=[CH:22][CH:23]=1)=[O:17])[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][N:35]([CH3:37])[C:34]([C:32]1[N:31]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:29]2[N:30]=[C:25]([NH:24][C:21]3[N:20]=[N:19][C:18]([C:16]([N:11]4[CH2:10][CH:9]5[NH:8][CH:13]([CH2:14][CH2:15]5)[CH2:12]4)=[O:17])=[CH:23][CH:22]=3)[N:26]=[CH:27][C:28]=2[CH:33]=1)=[O:38]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)nn3)nc2n1C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)nn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of 3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (110 mg, 0.187 mmol) in DCM (1 ml) at −78° C. was added TFA (1 mL, 13.0 mmol). After warming to room temperature and stirring for 1 h, the reaction was concentrated under reduced pressure. The resulting oily residue was dissolved in 2 mL MeOH, flushed through a PL-HCO3 MP-Resin cartridge to remove TFA, then purified by HPLC which gave a white solid (55 mg, 0.112 mmol). 1H NMR (400 MHz, DMSO): δ, 10.71 (s, 1H), 8.88 (s, 1H), 8.60 (d, J=8 Hz, 1H), 7.82 (d, J=8 Hz, 1H), 6.68 (s, 1H), 4.81-4.72 (m, 1H), 4.22 (d, J=12 Hz, 1H), 3.53 (d, J=12 Hz, 1H), 3.48 (br s, 1H), 3.29 (br s, 1H), 3.27 (d, J=12 Hz, 1H), 3.06 (s, 3H), 3.05 (s, 3H) 2.93 (d, J=12 Hz, 1H), 2.42-2.33 (m, 2H), 2.01-1.96 (m, 4H), 1.72-1.58 (m, 6H); HRMS calcd for C25H31N9O2. H+ (M+H)+ 490.2679. Found 490.2676 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([S:24][C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:38])OC(C)(C)C)[CH:28]=[CH:29][CH:30]=4)[C:18]4[S:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:40][N:41]([CH3:48])[CH2:42]/[CH:43]=[CH:44]/C(O)=O.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.C(Cl)(Cl)Cl.CC(O)C>[CH3:40][N:41]([CH3:48])[CH2:42]/[CH:43]=[CH:44]/[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([S:24][C:17]2[C:18]3[S:23][CH:22]=[CH:21][C:19]=3[N:20]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:13][CH:12]=3)[N:16]=2)[CH:26]=1)=[O:38]
Reactant: CN1CCN(c2ccc(Nc3nc(Sc4cccc(NC(=O)OC(C)(C)C)c4)c4sccc4n3)cc2)CC1
Reactant: CN(C)C/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CN(C)C/C=C/C(=O)Nc1cccc(Sc2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3ccsc23)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
40 mg (0.09 mmol) of the compound obtained in Step 2 of Example 223 was dissolved in 1.5 mL of pyridine, and 22 mg (0.14 mmol) of (E)-4-(dimethylamino)-2-butenoic acid hydrochloride and 35 mg (0.18 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added thereto, and stirred for 30 minutes at 80° C. Upon the completion of the reaction, the resulting mixture was diluted with mixed solvent of chloroform:2-propanol (3:1(v/v)) and washed with saturated saline. The organic layer was separated, dried over anhydrous Na2SO4, and filtered and distilled under a reduced pressure. The resulting residue was separated by column chromatography (dichloromethane:methanol=6:1 (v/v)) to obtain 2 mg of the title compound (yield: 4%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[C:16]([Br:21])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[S:10])[CH3:8].Cl>CO>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:9](=[S:10])[N:7]([CH3:8])[CH2:6][C:5]([OH:22])=[O:4]
Reactant: COC(=O)CN(C)C(=S)c1cccc2c(Br)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(=O)O)C(=S)c1cccc2c(Br)cccc12
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A 1N aqueous NaOH solution (25 ml) was added to a suspension of N-[(5-bromo-1-napthalenyl)thioxomethyl]-N-methylglycine methyl ester (7.3 g, 20.7 mmoles; described in Example 3) in methanol (75 ml). The mixture was stirred at 20° to 22° C. for 21/2 hr, neutralized to pH 7 with aqueous HCl and concentrated under reduced pressure to remove methanol. The residual solution was rendered acidic (pH=2) with the addition of aqueous HCl solution and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated to dryness. The residue was crystallized from ethyl acetate-hexane to give 5.3 g of the title compound; mp 181° C.; NMR (DMSO-d6) δ 2.95 (s, 3H), 4.65 & 5.2 (2d, J=16.8, 2H), 7.85 (m, 6H), UVλmax (EtOH) 285 nm (ε12,300), 280 (12,400), 221 (42,600); IR(Nujol™) 2900, 1720 cm-1 ; Anal Calcd: C, 49.72% H, 3.58% N, 4.14%; Found: C, 49.63% H, 3.63% N, 4.18%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Method 76; 1.0 g, 3.6 mmol), (S)-1-(4-fluorophenyl)ethanamine (0.5 g, 3.6 mmol), and DIEA (0.6 g, 4.6 mmol) in n-BuOH (15 ml) was stirred at 25° C. for 1 hour and then concentrated. The resulting oil was purified by column chromatography (DCM:MeOH=50:1) to give the title compound (0.8 g, 60%). MS: Calcd.: 383; Found: [M+H]+ 384.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:25])([CH3:26])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[C@@H:4]([OH:32])[CH2:3][C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:46](=[O:47])[C@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[NH:44][C:42](=[O:43])[O:41][CH3:40]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
A solution of the product from Example 23S (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 1F (0.010g, 0.053 mmol), DEPBT (0.020 g, 0.067 mmol), and N,N-diisopropylethylamine (0.040 mL, 0.229 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.015 g, 45% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.77 (s, 9 H), 0.83 (s, 9 H), 1.48 (m, 2 H), 2.74 (m, 3 H), 3.50 (s, 3 H), 3.54 (s, 3 H), 3.64 (m, 1 H), 3.79 (d, J=9.19 Hz, 1 H), 3.93 (d, J=956 Hz, 1 H), 4.09 (m, 2 H), 4.85 (d, J=5.88 Hz, 1 H), 6.60 (d, J=9.93 Hz, 1 H), 6.75 (d, J=9.93 Hz, 1 H), 7.11 (m, 5 H), 7.31 (m, 3 H), 7.59 (d, J=9.19 Hz, 1 H), 7.74 (d, J=8.82 Hz, 1 H), 7.86 (m, 4 H), 8.63 (d, J=4.41 Hz, 1 H).