Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4].[OH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]=2[OH:18])=[O:30])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Reaction time: 24 h

Procedure:
To a stirred solution of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester (150 mg, 0.62 mmol) and 1-hydroxy-naphthalene-2-carboxylic acid (90 mg, 0.75 mmol) in DMF (2 mL) were added HATU (285 mg, 0.75 mmol) and N,N-diisopropylethylamine (96 mg, 0.75 mmol). The mixture was stirred at room temp. for 24 h. The reaction mixture was then extracted with ethyl acetate and washed with water and brine. The organic layer was then dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C24H31N2O4 [(M+H)+] 411.0, obsd. 411.0.
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH:32]([C:37]([OH:39])=[O:38])[CH2:33][C:34]([OH:36])=[O:35])=[CH:24]1>C(O)C>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C@@H:32]([C:37]([OH:39])=[O:38])[CH2:33][C:34]([OH:36])=[O:35])=[CH:24]1.[CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: O=C(O)CC(C(=O)O)c1c[nH]c2ccccc12
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CCO
Product: O=C(O)C[C@H](C(=O)O)c1c[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 1.26 g (4.29 mmole) of cinchonidine and 1.00 g (4.29 mmole) of racemic indole-3-succinic acid in 10 mL of 96% ethanol was heated on a steam bath with magnetic stirring until all of the solid dissolved. The solution was cooled slowly to room temperature, and the white precipitate formed was collected and washed with ether. After 11 recrystallizations from 96% ethanol and one solution of 96% ethanol:methanol, 80:20 by volume, and drying, colorless fine needles of (S)-indole-3-succinic acid-cinchonidine salt was obtained. 0.296 g, yield: 13.1%, ee: 99.3%. Mp: 196-198° C. (with gas evolution). Elemental analysis: Calculated for C31H33N3O55: C=70.57%, H=6.30%, N=7.96% Found: C=70.00%; H=6.42%; N=7.84%. IR: 3500-2900, 1592, 1460 cm-1. By fractional removal of (S)-indole-3-succinic acid salt, followed by rotary evaporation of the solvent and recrystallization (supra vide), the (R)-indole-3-succinic acid-cinchonidine salt was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[CH:10][C:11]#[N:12])[CH2:3]1.[C:14](C(P(=O)(OCC)OCC)C)#N>>[CH3:1][C:2]1([CH3:13])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][C:4](=[C:10]([CH3:14])[C:11]#[N:12])[CH2:3]1
Reactant: CCOP(=O)(OCC)C(C)C#N
Reactant: CC1(C)CC(=CC#N)CC(C)(C)C1
Product: CC(C#N)=C1CC(C)(C)CC(C)(C)C1
Yield: 41 %

Procedure:
Prepared according to the procedure for compound 20 (Example 10, a) using diethyl (1-cyanoethyl)phosphonate. Nitrile 21 obtained as a colorless oil with 41% yield. 1H-NMR: (CDCl3, TMS): 0.96 and 1.00 (total 12H, both s, c-Hex-3,5-CH3); 1.34 (2H, s, c-Hex-4-CH2); 1.91 (3H, s, propionitrile-3-CH3); 2.04 and 2.28 ppm (total 4H, both s, c-Hex-2,6-CH2).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: OB(O)c1cccs1
Reactant: COc1cc(I)ccc1C(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cccs2)ccc1C(C)=O
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Ex-57a: 4′-iodo-2′-methoxyacetophenone (1.08 g, 3.9 mmol) in ethylene glycol dimethyl ether (50 ml) was degassed for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.456 g, 0.39 mmol), thiophene-2-boronic acid (0.75 g, 5.9 mmol), and sodium carbonate solution (2 m, 4 ml, 8 mmol) were added. The mixture was stirred at reflux under nitrogen for 24 hours. Upon cooling to room temperature, it was poured into water and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate, 3:1) gave 0.88 g (98%) of the desired 2′-methoxy-4′-(thien-2-yl)acetophenone.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[N:21]=2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:25]1([C:23]([NH:22][C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]([S:1][C:2]4[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=4[C:4]([O:6][CH3:7])=[O:5])=[N:18][N:17]3[CH:19]=2)=[O:24])[CH2:26][CH2:27]1
Reactant: COC(=O)c1ccccc1S
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 80 °C
Reaction time: 7 h
Yield: 17.5 %

Procedure:
A mixture of methyl 2-mercaptobenzoate (1030 mg, 6.1 mmol), N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.0 g, 3.1 mmol), potassium carbonate (1050 mg, 7.6 mmol) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 7 hr. The mixture was evaporated under reduced pressure, and ethyl acetate/tetrahydrofuran and water were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give methyl 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoate (200 mg, 18%) as a brown solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+].Cl.O>CO.C(Cl)(Cl)Cl>[Br:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(C(O)CBr)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
20.0 g (61.0 mmol) of N-[4-(2-bromoacetyl)phenyl]methanesulfonamide was suspended in 240 ml of methanol. 2.84 g of sodium borohydride was added in three portions at intervals of 5 min to the suspension cooled at -20° C. The mixture was stirred at -20° C. for 2 h. Concentrated hydrochloric acid was added dropwise to the mixture to acidify it. 300 ml of water and 500 ml of chloroform were added thereto. After extraction with chloroform, the organic layer was concentrated and a solid residue thus obtained was recrystallized from ether to give 16.4 g (yield: 82%) of the intended compound in the form of white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:15]=[C:14]([F:13])[CH:21]=[C:20]([F:22])[CH:19]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (3.3 g, 20 mmol) and 3,5-difluoro-benzaldehyde (2.84 g, 20 mmol) in ethanol (50 mL) was heated to reflux for 2 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3,5-difluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (4.27 g, 74%) as a white solid: LC/MS m/e calcd for C16H13F2NO2 (M+H)+: 290.3, observed: 290.2.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.N([O-])=O.[Na+].[I-:18].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[I:18][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1
Reactant: [I-]
Reactant: Cc1cc(N)cnc1CCCCN
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: O
Product: Cc1cc(I)cnc1CCCCN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
5-Amino-2-[4-aminobutyl]-3-methylpyridine (2.17 g) in 20% sulphuric acid (25 ml) at -5° C. was reacted with a solution of sodium nitrite (1 g) in water (5 ml) over 20 minutes. After a further 15 minutes at -9° C. the reaction mixture was added to a mixture of potassium iodide (4 g) and cuprous iodide (0.5 g) in water (65 ml) at 10° C. and then stirred at room temperature for 30 minutes. Saturated sodium thiosulphate solution (10 ml) was added and the pH was brought to 12 with sodium hydroxide. Chloroform extraction of the reaction mixture gave 5-iodo-3-methyl-2-(4-aminobutyl)pyridine as a dark oil (2.45 g). N.M.R. (CDCl3) assignment, δ (p.p.m.), multiplicity; (CH2)2CH2NH2, 1.4-2.0, m; NH2, 1.69, s; 3--CH3, 2.28, s; CH2 (CH2)2CH2NH2, 2.76, m; 4--H pyridyl, 7.75, m; 6--H pyridyl, 8.57, m.
Reaction SMILES: [O-:1][P:2]([O:5][P:6]([O:9][P:10]([O-:13])([O-:12])=[O:11])([O-:8])=[O:7])(=[O:4])[O-:3].P(O[CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[N:33]=[N+:34]=[N-:35])(O)(O)=O.[N-]1C=CN=C1.[O-]P(OP([O-])([O-])=O)(=O)[O-].C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC>CN(C=O)C>[P:10]([O:13][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[N:33]=[N+:34]=[N-:35])([O:9][P:6]([O:5][P:2]([OH:1])([OH:3])=[O:4])([OH:8])=[O:7])(=[O:12])[OH:11]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COP(=O)(O)O
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: CCCC[NH+](CCCC)CCCC
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: c1c[n-]cn1
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COP(=O)(O)OP(=O)(O)OP(=O)(O)O

Procedure:
The triphosphate can be prepared according to the procedure of Hoard et al., J. Am. Chem. Soc., 87(8), 1785-1788 (1965). For example, 3'-azido-2',3'-dideoxyuridine monophosphate is activated (by making a imidazolide, according to methods known to those skilled in the art) and treated with tributyl ammonium pyrophosphate in DMF. The reaction gives primarily 3'-azido-2',3'-dideoxyuridine triphosphate, with some unreacted monophosphate and some diphosphate. Purification by anion exchange chromatography of a DEAE column is followed by isolation of CS-87 triphosphate, e.g., as the tetrasodium salt.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:22]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:22][C:10]=3[CH:11]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(Cc2cc3cc(C4OCCO4)ccc3o2)cc1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=Cc1ccc2oc(Cc3ccc(F)cc3)cc2c1

Procedure:
Into a methylene chloride (4 mL) solution of 5-[1,3]dioxolan-2-yl-2-(4-fluoro-benzyl)-benzofuran (100 mg, 0.335 mmol) and carbon tetrabromide (222 mg, 0.67 mmol) was dropped a methylene chloride (1 mL) solution of triphenylphosphine (176 mg, 0.67 mmol), while cooling with ice.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[CH:33]=[CH:34][C:35]2[O:36][CH2:37][CH2:38][NH:39][C:40]=2[N:41]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[CH:33]=[CH:34][C:35]5[O:36][CH2:37][CH2:38][NH:39][C:40]=5[N:41]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Brc1ccc2c(n1)NCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@@H](Oc1cc(-c2ccc3c(n2)NCCO3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 135 °C
Yield: 34 %

Procedure:
In a 10 ml microwave reactor vial were placed (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (150.0 mg, 0.36 mmol), 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (172.5 mg, 0.8 mmol), and Pd(PPh3)4 (21.1 mg, 0.02 mmol) in DME (1 ml) and 2N Na2CO3 (1 ml). The mixture was sonicated and degassed for 1 min, placed in the microwave reactor, and heated at 135° C. for 15 min. Then it was directly loaded onto the pre-packed silica cartridge and purified using flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane). The fractions were collected, concentrated, and further purified by reverse phase flash chromatography. The fractions were collected, neutralized with sat. NaHCO3, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated to give 52.7 mg (34%) of (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.06 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.60 (s, 1H), 7.39 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 4.76 (m, 1H), 4.13 (m, 2H), 3.67 (m, 1H), 3.42 (m, 3H), 3.19 (m, 1H), 2.82 (m, 1H), 2.36 (m, 2H), 1.31 (d, J=5.8 Hz, 3H), 1.05 (m, 4H). MS (ESI+) m/z 420.2 (M+H).
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH2:17][F:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32].CCOC(C)=O>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH2:17][F:18])[CH2:15][N:14]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1cnn2cc(Br)cc2c1N[C@@H]1CNC[C@@H]1CF
Agent: I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1C[C@H](CF)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
A solution of 6-bromo-4-(((3S,4S)-4-(fluoromethyl)pyrrolidin-3-yl)amino) pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide salt (894 mg, 2.846 mmol) and Et3N (1.399 mL, 10.04 mmol) in DMF (10 mL) was added METHANESULFONYL CHLORIDE (0.293 mL, 3.76 mmol) and the resulting mixture was stirred at RT for 30 minutes. To the reaction mixture was then added 150 mL of EtOAc and the mixture was washed with 50 mL×2 of 10% LiCl solution, 50 mL of brine and then dried over Na2SO4. Filtration and concentration afforded a crude product which was triturated with MeOH and the resulting solid collected and dried under vacuum to afford the title compound (0.719 g, 90% yield). MS (ES+) m/z: 434.1, 436.1 (M+H); HPLC: 89.6%, retention time: 2.348 min (analytical HPLC Method H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN(C)C=O.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:24][CH:23]=1>O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:27][CH:26]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Potassium carbonate (1.38 g) and tert-butyl bromoacetate (1.07 g) were added to a dehydrated N,N-dimethylformamide (17 mL) solution of benzyl (4-hydroxyphenyl)acetate (1.21 g) at room temperature, followed by stirring for 1 hour. Thereafter, water was added to the reaction mixture on an ice bath, and extraction was performed with hexane:ethyl acetate=2:1. The resulting organic phase was washed with an aqueous saturated sodium chloride solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→8:2) to obtain the title compound (1.75 g) having the following physical property values.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]4[N:25]([CH2:35][C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=5)[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)[CH:20]=3)[CH:15]=2)[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C1COCC1.CO>O>[C:1]1([CH2:7][CH:8]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]4[N:25]([CH2:35][C:36]5[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:40][CH:41]=5)[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)[CH:20]=3)[CH:15]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 30 °C
Yield: 71.2 %

Procedure:
In a similar manner as described in step 2 of Example 6, the title compound was prepared from methyl 3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoate (0.200 g, 0.330 mmol), prepared in the previous step, and 1N NaOH (0.50 mL, 0.50 mmol) in 1.33:1.33:1 THF:MeOH:water (33 mL) with the exception that this reaction was not complete after 18 hours (overnight) at ambient temperature. The reaction was warmed to 30° C. for 1.5 hours, an additional portion of 1N NaOH (0.50 mL, 0.50 mmol) was added and the mixture maintained at 30° C. for an additional 1.5 hours. The isolated yellow amorphous solid was purified by reverse-phase (C18) HPLC using 20% water in acetonitrile with 0.1% formic acid as the eluent. Isolation of the product from the chromatography fractions gave 3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoic acid as a greenish amorphous solid (0.139 g, 71%), mp 153–155° C. Elemental Analysis for C37H28F3NO3.0.24 H2O.0.10 C6H14 Calc'd: C, 74.70; H, 4.98; N, 2.32. Found: C, 74.67; H, 5.23; N, 2.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2>C(O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc(Cl)cc2cccnc12
Agent: [Fe]
Solvent: CCO
Product: Nc1cc(Cl)cc2cccnc12
Temperature: 25 °C
Yield: 73 %

Procedure:
To a hot suspension of 6-chloro-8-nitroquinoline (Mosher, et al., Org. Syn. 27:48 (1947), 0.8 g) in a mixture of ethanol/glacial acetic acid/water (2:2:1, 25 mL) was added iron powder (0.5 g) portionwise. The resulting mixture was stirred at reflux for 1.5 hours. The reaction was the cooled to room temperature, filtered through celite and made basic by addition of solid Na2CO3. The aqueous mixture was extracted with Et2O. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give the desired product (0.5 g) as a yellow solid; MP. 70-73° C.; MS (ES) m/z (relative intensity) 179 (M+H)+ (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([OH:31])=O)([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:4]=1.[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1.CCN=C=NCCCN(C)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:48][S:45]([CH:42]5[CH2:44][CH2:43]5)(=[O:47])=[O:46])=[O:31])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[N:4]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc(-c2cc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2cc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)cc1
Yield: 44 %

Procedure:
The acid 16f (195 mg, 0.34 mmol) was reacted with cyclopropane sulfonamide (53 mg, 0.44 mmol), EDAC (85 mg, 0.44 mmol) and DBU (137 mg, 0.9 mmol) in dry DCM (3 ml) according to the procedure described in Example 13 step f. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the title compound, (100 mg, 45%), (M+H)+668.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[CH2:51][N:50]([CH3:55])[CH2:49]3)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[CH2:51][N:50]([CH3:55])[CH2:49]3)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CN1Cc2ccc(Nc3nc(Br)cn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CN(C)C4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
Following the procedures as described for compound 148h and starting with 400 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 278 mg of 5-bromo-1-methyl-3-(2-methylisoindolin-5-ylamino)pyrazin-2(1H)-one 231f, compound 231g was obtained as a yellow solid (258 mg, 51%). MS: [M+H]+ 611.