Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C-:14]#[N:15].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:14]#[N:15])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
A mixture of 4-methyl-3-trifluorobromobenzene (33.26 g, 104.261 mmol) from step 1 above, KCN (20.43 g, 313.67 mmol) and tetrabutylammonium bromide (3.37 g, 10.45 mmol) in CH2Cl2/H2O 1:1 (300 mL) was stirred at room temperature for 4 hours. The layers were separated and the organic layer washed with H2O (100 mL) 1N HCl (100 mL), brine, dried over Na2SO4 and then concentrated to a brown oil which was purified by flash column chromatography (0% to 20% EtOAc in hexanes) to give the product as a clear oil (14.9 g, 54%). 1H NMR (400 MHz, CDCl3) δ 3.91 (s, 2H), 7.57 (d, J=8.3 Hz, 1 H), 7.75 (dd, J=8.3, 2 Hz, 1 H), 7.84 (d, J=2 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: CCNCc1cccn1C
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: CCN(Cc1cccn1C)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-(1-methyl-1H-pyrrol-2-ylmethyl)-amine
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:5]=1[C:6]#[N:7].[CH2:19]([OH:21])[CH3:20]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:5]=1[C:6](=[NH:7])[O:21][CH2:19][CH3:20]
Reactant: CCO
Reactant: COc1ccc(CN2CCOCC2)cc1C#N
Agent: Cl
Product: CCOC(=N)c1cc(CN2CCOCC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride gas was passed through a solution of 2-methoxy-5-morpholin-4-ylmethyl-benzonitrile (300 mg, 1.292 mmol) in anhydrous ethanol (30 mL) at room temperature. After 2 h, hydrogen chloride gas was stopped and the reaction vessel was sealed. After stirring at room temperature for 12 h, the reaction vessel was cooled to 0° C. and opened. The solvent was evaporated in vacuo to dryness to afford crude ethyl 2-methoxy-5-morpholin-4-ylmethyl-benzimidate hydrochloride. meso-1,2-Bis-(4-chloro-phenyl)-ethane-1,2-diamine (150 mg, 0.533 mmol), triethylamine (373 μL, 5 mmol) and ethanol (10 mL) were added and the resulting mixture was heated at reflux for 12 h. The solvent was removed and the residue was taken up in methylene chloride (2 mL) and sodium bicarbonate solution (2 mL). The product was extracted with methylene chloride (2×30 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-20% methanol in ethyl acetate to afford 4-{3-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-4-methoxy-benzyl}-morpholine (164 mg, 62%). LR-MS (APCI): 496 [(M+H)+].
Reaction SMILES: [CH2:1]([NH:6][C:7]([C@:9]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:41])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([NH:6][C:7]([C@:9]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:41])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:29])([CH3:30])[C:18]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:8])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(isopentylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.204 g, 0.318 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (0.040 g, 0.953 mmol) in H2O (1.000 mL). The resulting white slurry was stirred at rt overnight. After 15 h, TLC showed significant starting material left thus reaction was heated to 75° C. for 3 h. Reaction was treated with 1N HCl (1 mL) and concentrated to dryness. Material was absorpted onto silica gel, loaded onto a silica gel column (12 g cartridge) and was eluted with 0% B to 100% B for 180 mL and held 100% B for 600 mL (Solvents: A=100% DCM, B=90:10 DCM:MeOH). Obtained 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(isopentylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (182 mg, 0.281 mmol, 88% yield) as white solid. LCMS: m/e 628.6 (M−H)+, 2.45 min (method 5); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.0 (2H, d, J=8.2 Hz), 7.3 (2H, d, J=8.5 Hz), 5.6 (1H, t, J=5.6 Hz), 5.3 (1H, dd, J=6.1, 1.8 Hz), 4.8 (1H, d, J=2.1 Hz), 4.6-4.6 (1H, m), 3.3-3.4 (1H, m), 3.2-3.3 (2H, m), 2.5-2.6 (1H, m), 2.1 (1H, dd, J=17.4, 6.4 Hz), 1.9-2.1 (2H, m), 1.7-1.8 (2H, m), 1.7 (3H, s), 1.6-1.7 (3H, m), 1.3-1.6 (11H, m), 1.2-1.3 (2H, m), 1.0 (6H, s), 1.0 (3H, s), 1.0 (6H, s), 0.9-1.0 (6H, m) 13C NMR(CHLOROFORM-d) δ ppm 14.4, 15.6, 16.2, 19.3, 19.5, 20.8, 21.1, 22.2, 22.3, 25.5, 25.7, 29.2, 30.7, 33.4, 33.6, 36.0, 37.2, 37.7, 38.2, 38.5, 40.4, 41.5, 42.2, 46.5, 49.3, 49.9, 52.6, 55.4, 77.3, 109.0, 124.0, 126.7, 128.9, 129.9, 145.9, 149.4, 150.8, 171.1, 175.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[OH:21])=[O:6].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C1COCC1.C(N(CC)CC)C.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[O:21][C:26](=[O:28])[CH3:27])=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CCc2ccc([N+](=O)[O-])cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 113 (1.9 g, 0.005 mol) in THF (200 mL), triethylamine (1.3 mL), and a catalystic amount of 4-dimethylaminopyridine was treated with acetic anhydride (0.9 mL). After stirring over night, the solvent was evaporated and the residue treated with H2O. After 2 h, the mixture was extracted with EtOAc. The extracts were washed with 1 N H2SO4, brine, aqueous NaHCO3, and brine, then the solvent was dried and evaporated to give a floculant white solid (1.94 g) that had the appropriate nmr for the desired material.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:25]([C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=[O:35])=[O:32])=[CH:29][CH:28]=1)#[N:26]>C(#N)C>[CH2:1]([S:5]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:34]([NH:33][C:31](=[O:32])[C:30]2[CH:36]=[CH:37][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)=[O:35])=[CH:22][CH:23]=1)[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Solvent: CC#N
Product: CCCCS(=O)(=O)N[C@@H](Cc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
In a similar manner to Example 1, starting material step (c), the product of step (c) (2.59 g) and 4-cyanobenzoyl isocyanate (1.29 g) in acetonitrile (100 ml total) were reacted to give, after stirring at ambient temperature for 1 hour and storage at 10° C. overnight, a solid, which was crystallised from isopropanol to give t-butyl (2S)-2-(n-butylsulphonylamino)-3-[4-[3-(4-cyanobenzoyl)ureido]phenyl]propionate (2.32 g) as a white solid: m.p. 171°-173° C.; NMR Spectrum (CDCl3) 0.90 (3H, t), 1.37 (2H, m), 1.49 (9H, s), 1.73 (2H, m), 2.90 (2H, t), 3.11 (2H, m), 4.31 (1H, m), 5.61 (1H, d), 7.19 (2H, d), 7.42 (2H, d), 7.83 (2H, d), 8.19 (2H, d), 9.92 (1H, br s), 10.78 (1H, br s); Mass Spectrum m/Z 529 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[CH3:17][S:18]SC.O>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([S:18][CH3:17])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2scnc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2sc(SC)nc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 4-methoxybenzothiazole (495 mg, 3.0 mmol) in anhydrous THF (12 mL) at −78° C. was added BuLi (2.5 mL, 1.6M in hexanes, 4.0 mmol) dropwise. The resulting red solution was stirred at −78° C. for 2 h under N2. Methyl disulfide (0.55 mL, 6.0 mmol) was added dropwise at −78° C. and the mixture was allowed to warm to ambient temperature overnight. The reaction mixture was combined with water and then extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a yellow oil (632 mg, 100%), which solidified upon standing and was used without purification. 1H-NMR (CDCl3): δ 7.35 (1H, d), 7.24 (1H, q), 6.86 (1H, d), 4.06 (3H, s), 2.79 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]2[CH2:40][CH2:41][CH2:42][CH:36]2[CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:39][CH2:38][N:37]3[CH2:40][CH2:41][CH2:42][CH:36]3[CH2:35]2)(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCN2CCCC2C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCN4CCCC4C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic 2-((2-bromophenyl)sulfonyl)octahydropyrrolo[1,2-a]pyrazine. MS (ESI): mass calcd. for C23H24FN5O2S, 453.16; m/z found, 454.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=1.4, 1H), 8.24 (d, J=1.4, 1H), 8.17-8.13 (m, 1H), 7.99 (m, 1H), 7.78-7.73 (m, 1H), 7.68-7.63 (m, 1H), 7.48-7.45 (m, 1H), 7.36-7.30 (m, 2H), 3.89-3.35 (m, 4H), 3.26-2.53 (m, 6H), 2.18-1.97 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:16])[C:10]=2[CH:9]=[N:8]1.OS(O)(=O)=O.[Cl:27]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[Cl:27][C:12]1[CH:13]=[CH:14][C:15]2[N:7]([CH2:6][C:5]3[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)[N:8]=[CH:9][C:10]=2[C:11]=1[NH2:16]
Reactant: Nc1cccc2c1cnn2Cc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)ccc2c1cnn2Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-amine (0.056 g, 0.192 mmol) in THF (1.0 mL) was cooled to −78° C. under N2. H2SO4 (0.00512 mL, 0.0961 mmol) was added and the mixture was stirred for 5 minutes. N-chlorosuccinimide (0.0257 g, 0.192 mmol) was added in one portion and the reaction was stirred at −78° C. for 1 hour. Sodium carbonate (0.0204 g, 0.192 mmol) was added and the mixture was warmed to ambient temperature. The mixture was diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were then washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (40% EtOAc/hexane) in which two major bands were observed. The higher band was determined to be the title compound (0.028 g, 44%) and was isolated as a dark yellow/green solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:26])[C@@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1>>[NH:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:26])[C@@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH:39]=[N:38]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(Br)c1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2cn[nH]c2)c1

Procedure:
The same procedure as in example 13.0 was employed for this example, replacing tert-butyl (S)-1-(3-(1H-pyrazol-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 13.B with 1-((4-bromo-2-nitrophenoxy)methyl)benzene 33.B and replacing pyridin-4-ylboronic acid with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give tert-butyl (S)-1-(3-(1H-pyrazol-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 33.C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[C:1]1([CH2:7][CH2:8][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCc1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCc1ccccc1)OCC

Procedure:
In a manner according to Preparation 2 combine 2-phenylethyl bromide and triethyl phosphite. Distill the mixture at reduced pressure (0.15 mm Hg) and collect the fraction distilling at 115°-130° C. to obtain the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][CH2:17]2)[N:4]=1.[OH-].[Na+]>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]2)[N:4]=1
Reactant: CCOC(=O)CN1CCN(c2nc(NC)nc(N3CCN(C)CC3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CNc1nc(N2CCN(C)CC2)nc(N2CCN(CC(=O)O)CC2)n1
Temperature: 60 °C
Yield: 50 %

Procedure:
To the solution prepared in step c was added 6 N NaOH (6 mL), and the resulting mixture was heated to 60° C. overnight. The reaction mixture was cooled to room temperature, and purified directly (without concentrating or work up) using reverse-phase HPLC (Phenomenex, 2-15% CH3CN/H2O, 0.1% TFA, 6 min) to afford 0.95 g (50%) of the title compound. MS (ES+): m/e 351.1 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][C:5]1[C:10]([C:11]([O:13]C)=O)=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)C>[O:4]=[C:5]1[C:10]([C:11]([NH:2][NH2:3])=[O:13])=[CH:9][CH:8]=[CH:7][NH:6]1
Reactant: NN
Reactant: COC(=O)c1cccnc1O
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc[nH]c1=O

Procedure:
Hydrazine hydrate (0.192 mL, 3.92 mmol) was added to a solution of the methyl 2-hydroxy-3-pyridinecarboxylate (400 mg, 2.61 mmol, commercially available from e.g. Apollo or Butt Park) in ethanol (10 mL) and the reaction was heated to reflux for 16 hrs. The reaction was cooled and the solvent was evaporated to afford an off-white solid in 395 mg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][P:20]3(=[O:26])[O:25][CH2:24][CH2:23][CH2:22][O:21]3)=[CH:15][CH:14]=2)[N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH:39]2[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]2)=[C:32]2[C:36]=1[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]2>>[OH:45][C@H:42]1[CH2:41][CH2:40][C@H:39]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:2]3[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([CH2:19][P:20]5(=[O:26])[O:25][CH2:24][CH2:23][CH2:22][O:21]5)=[CH:15][CH:14]=4)[N:3]=3)=[C:36]3[C:32]=2[CH2:33][N:34]([CH3:38])[C:35]3=[O:37])[CH2:44][CH2:43]1
Reactant: O=P1(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)OCCCO1
Reactant: CN1Cc2c(C3CCC(O)CC3)ccc(N)c2C1=O
Product: CN1Cc2c(c(Nc3nc(Nc4ccc(CP5(=O)OCCCO5)cc4)ncc3C(F)(F)F)ccc2[C@H]2CC[C@H](O)CC2)C1=O

Procedure:
The title compounds were prepared according to the procedure for compound 102 using 4-chloro-N-{4-[(2-oxido-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-5-(trifluoromethyl)pyrimidin-2-amine (Compound 230A, 22.8 mg, 0.0559 mmol) and 7-amino-4-(4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (22.0 mg, 0.0845 mmol). The crude material was purified using a Teledyne/ISCO Combiflash system, eluting with 0-15% 7N NH3(MeOH):EtOAc. The collected material was a mixture of regioisomers and was purified again by Supercritical Fluid Chromatography (SFC).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:29]=2[F:36])[C:22]1=[O:37].C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:36][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:28]=1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([NH:20][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[C:22]1=[O:37]
Reactant: Cc1cc(-c2n[nH]c3ccc(C(=O)O)cc23)ccn1
Reactant: COc1cccc(F)c1CN1CCCC(N)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(F)c1CN1CCCC(NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)C1=O
Temperature: 23 °C
Reaction time: 16 h

Procedure:
3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxylic acid (50 mg, 0.154 mmol), 3-amino-1-(2-fluoro-6-methoxybenzyl)piperidin-2-one (148 mg, 0.308 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44.4 mg, 0.231 mmol) and hydroxybenzo-triazole (23.62 mg, 0.154 mmol) were combined in a sealed vial. DMF (0.8 ml) and N,N-diisopropylethylamine (0.269 ml, 1.542 mmol) were added and the reaction mixture stirred for 16 hours at a temperature of 23° C. The residue was then purified by preparative HPLC Normal phase, eluting with dichloromethane/MeOH (0-20%) to give N-(1-(2-fluoro-6-methoxybenzyl)-2-oxopiperidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide as a colorless solid. MS ESI calc'd. for C27H26FN5O3 [M+H]+488, found 488. 1H NMR (600 MHz, CDCl3) δ 10.80-10.49 (m, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.53 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=4.9 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.46 (s, 1H), 6.75-6.65 (m, 3H), 5.00 (d, J=14.1 Hz, 1H), 4.51 (d, J=14.2 Hz, 1H), 4.49-4.42 (m, 1H), 3.84 (s, 3H), 3.35-3.21 (m, 2H), 2.65 (s, 3H), 1.95-1.82 (m, 2H), 1.65-1.55 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)[C:3]#[C:4][CH3:5].[OH-].[K+].[I:17]I>CO.O>[CH3:1][N:2]([CH2:3][C:4]#[C:5][I:17])[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: II
Reactant: CC#CN(C)c1nc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CC#CI)c1nc2ccccc2s1
Yield: 99.8 %

Procedure:
Compound (d) (2.02 g) was dissolved in a mixture of methanol (35 ml), water (10 ml) and 86% potassium hydroxide (1.4 g) and then iodine (2.66 g) was added in small portions with stirring under ice-cooling. The mixture was stirred at room temperature for 1.5 hours and then water was added thereto. The resultant crystals were filtered off, washed with water and dried to give 2-(N-methyl-3-iodo-2-propynylamino)benzothiazole (No.2) (3.27 g, yield 100%): mp. 100°-101° C. (decomp.) (acetone-hexane), Hydrochloride: mp. 156°-160° C. (decomp.), Nitrate: mp. 108°-109° C. (decomp.), Hydrobromide: mp. 158°-160° C. (decomp.).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9](=O)[CH2:10][CH2:11][CH:12]=[CH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>C(O)C>[CH2:10]([C:9]1[NH:18][N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)[CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCC(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C=CCCc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylhept-6-ene-1,3-dione (3 g, 14.83 mmol) in ethanol (50 mL) was added hydrazine hydrate (2.228 g, 44.5 mmol) at room temperature. The reaction was refluxed for 10 h, cooled to room temperature and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=199.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.65-2.78 (m, 2H), 4.01-4.12 (m, 2H), 4.83-4.95 (m, 2H), 5.82-5.93 (m, 1H), 6.42 (s, 1H), 7.23-7.82 (m, 5H), 12.6 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]1[C:22]([F:23])=[C:21](F)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CC(N(C)C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:14])[C:22]=2[F:23])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#Cc1ccc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of N-Boc-piperazine (0.65 g) in DMA (20 mL) was slowly added a solution of 2,3,4-trifluorobenzonitrile (0.49 g) in DMA (10 mL). The reaction mixture was stirred for 2 hours at 80° C. After such time the solvent was removed in vacuo and purified by column chromatography (SiO2) to yield the title compound as white solid (0.76 g).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH:9]1([O:12][C:13]2[CH:21]=[CH:20][C:19]3[N:18]4[CH2:22][CH2:23][CH2:24][C:17]4=[CH:16][C:15]=3[CH:14]=2)[CH2:11][CH2:10]1>C(#N)C>[CH:9]1([O:12][C:13]2[CH:21]=[CH:20][C:19]3[N:18]4[CH2:22][CH2:23][CH2:24][C:17]4=[C:16]([I:1])[C:15]=3[CH:14]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCC(=O)N1I
Reactant: c1cc2c(cc1OC1CC1)cc1n2CCC1
Solvent: CC#N
Product: Ic1c2n(c3ccc(OC4CC4)cc13)CCC2
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
18.5 g N-iodosuccinimide at 0° C. was added to a solution of 17.55 g 6-cyclopropoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene in acetonitrile and the mixture was stirred at this temperature for 15 min. The solid was collected by filtration, washed with cold acetonitrile and dried to constant weight to yield 20.1 g 6-cyclopropoxy-8-iodo-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene as beige crystals melting at 104-105° C.