Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N+:35]([O-:37])=[O:36])(=[O:28])=[O:27])[CH2:19][CH2:20]OS(C)(=O)=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:38].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:40]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:19][CH2:20][N:50]3[CH2:51][CH2:52][CH:47]([O:46][CH2:45][C:41]4[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=4)[CH2:48][CH2:49]3)[S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N+:35]([O-:37])=[O:36])(=[O:27])=[O:28])=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:38]
Reactant: c1cncc(COC2CCNCC2)c1
Reactant: Cn1c(=O)ccc2cc(OCCCN(CCOS(C)(=O)=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)ccc2cc(OCCCN(CCN3CCC(OCc4cccnc4)CC3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Sodium iodide (2.93 g) was added to a acetonitrile solution (20 ml) of methanesulfonic acid 2-[[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)propyl]-(2-nitro-benzenesulfonyl)amino]-ethyl ester (4.37 g), and stirred at 60° C. for 1 hours. The reaction mixture was cooled to room temperature. 4-(pyridin-3-ylmethoxy)piperidine (1.87 g) and N-ethyl diisopropylamine (4.23 ml) were then added to the reaction mixture and stirred at 60° C. for 5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was washed with water, and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was concentrated under reduced pressure to give the title compound (3.48 g) as a yellow solid.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(O)=O)[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C=CN=CC=1)CCCC.[OH:26]O>C(O)(=O)C.C(Cl)Cl>[CH2:1]([C:6]1[CH:11]=[CH:10][N+:9]([O-:26])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccnc(C(=O)O)c1
Reactant: OO
Agent: CCCCCc1ccncc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCc1cc[n+]([O-])cc1
Yield: 100 %

Procedure:
4-Pentylpyridine-2-carboxylic acid (10b) (R9=pentyl) was made by employing Method P. To 4-pentylpyridine (3 g, 20 mmol) in acetic acid (30 mL), hydrogen peroxide (0.7 g, 30%, 20 mmol) was added and refluxed overnight. Removal of solvent resulted in residue which was dissolved in DCM (100 mL) dried over MgSO4 and filtered. Removal of DCM resulted in a brown liquid, 4-pentylpyridine-N-oxide, (3.3 g, 100%). To trimethylsilyl cyanide (2.37 g, 24 mmol), 4-pentylpyridine N-oxide (3.3 g, 20 mmol) in DCM (10 mL) was added followed by dropwise addition of dimethylcarbamoyl chloride (2.56 g, 24 mmol) in DCM (10 mL). After stirring at room temperature overnight, sodium bicarbonate (100 mL, 10%) was added and the organic layer was separated. The aqueous layer was extracted twice with DCM (50 mL) and the combined organic layer was dried over magnesium sulfate. Removal of solvent resulted in compound 10a (R9=pentyl) (4.1 g, 100%).
Reaction SMILES: C(O)C.[C:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:19])=[CH:13][C:14]=2[N+:16]([O-])=O)[CH2:9][CH2:8]1)(=[O:6])[CH3:5].Cl>[Fe].O>[C:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:19])=[CH:13][C:14]=2[NH2:16])[CH2:9][CH2:8]1)(=[O:6])[CH3:5]
Reactant: CC(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCc2cc(Br)cc(N)c21
Yield: 32.2 %

Procedure:
To a mixed solution of ethanol (400 ml) and water (100 ml), were added N-acetyl-5-bromo-7-nitroindoline (133.1 g), iron powder (10 mesh; 75 g) and concentrated hydrochloric acid (5 ml), and the mixture was subjected to refluxing for 5 hours with vigorous stirring. The reaction mixture was filtered by suction while hot to remove insoluble matter, and then the filtrate thereof was concentrated and cooled on standing to give the intended compound 38.3 g (32.2%) as a brown needle crystal. M.P.: 154°-155° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])#[CH:12].N>>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:11]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cccnc3)no2)c(F)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.29-7.43 (m, 1H), 7.53-7.65 (m, 2H), 7.69 (dd, J=7.5, 4.7 Hz, 1H), 8.08 (td, J=8.7, 6.3 Hz, 1H), 8.48 (dt, J=7.9, 2.0 Hz, 1H), 8.78 (dd, J=4.9, 1.5 Hz, 1H), 9.23 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=4)[CH2:21][CH2:20]3)=[N:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cn4)CC3)nc2)c1

Procedure:
6-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-nicotinic acid was synthesized from N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 6-chloro nicotinic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C26H29N5O3 (m/e) 459, obsd 460 (M+H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH-].[Na+].Br[CH2:9][CH2:10][CH2:11][Cl:12]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: ClCCCBr
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCN(CC)CCCCl
Yield: 59.2 %

Procedure:
Diethyl-amine (7.27 ml, 70 mmol), acetone (15 ml, 3 vol), 5M NaOH solution (16.8 ml, 1.2 eq.) and 1-bromo-3-chloropropane (16.5 g, 105 mmol, 1.5 eq.) were reacted together according to general procedure A to give the title compound (6.2 g, 59%) as a colourless oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[N:16]=2)[N:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[CH:23]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]3[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[N:16]=3)[N:3]=2)[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: CC(C)n1ccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)n1ccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Temperature: 105 °C
Yield: 67.2 %

Procedure:
A flask was charged with 3-bromo-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (1.8 g, 4.94 mmol), cyclopropylboronic acid (0.849 g, 9.88 mmol), potassium phosphate (3.15 g, 14.8 mmol) and 20:1 toluene/water (10.5 mL). The mixture was degassed for 30 minutes with an argon filled balloon. Palladium acetate was added (55.5 mg, 0.247 mmol) followed by tricyclohexyl phosphine (0.139 g, 0.494 mmol). The mixture was further degassed with argon and heated at 100-110° C. for 16 hours. The mixture was filtered through GF/F paper, rinsing with EtOAc, concentrated under vacuum and the residue was purified by silica gel chromatography (1-20% EtOAc in hexanes) to provide 3-cyclopropyl-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (1.08 g, 67% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(Cl)Cl.Cl>[Ti](Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21

Procedure:
In a 250 milliliter round-bottomed flask equipped with a pressure equalizing dropping funnel, there was discharged 10 grams of 1,8-dichloroanthraquinone, 16.5 milliliters of diethyl malonate, and 150 milliliters of methylene chloride under a nitrogen atmosphere. The resulting mixture was then mechanically stirred and cooled with an ice bath. Thereafter, 24 milliliters of titanium tetrachloride was added dropwise through the dropping funnel over a period of 20 minutes, followed by the addition of 45 milliliters of pyridine. The reaction mixture was then stirred at room temperature for 65 hours. Subsequently, 150 milliliters of a dilute aqueous hydrochloric acid solution was slowly added with stirring. The organic phase resulting was separated, washed twice with water, and dried with anhydrous magnesium sulfate. Evaporation of the dried organic solution yielded a yellowish solid which when recrystallized from methanol afforded 7.5 grams of the pure Compound (VIII), mp., 166°-167° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][NH:18][CH3:19])([OH:15])[CH2:6][CH2:5]2.[CH3:20][O:21][CH2:22][C:23]([CH2:32][O:33][CH3:34])([CH3:31])[C:24]([NH:26][CH2:27][CH2:28][CH:29]=O)=[O:25].C([BH3-])#N.[Na+]>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:13])[CH3:14])[C@:7]([CH2:16][CH2:17][N:18]([CH3:19])[CH2:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[C:23]([CH2:32][O:33][CH3:34])([CH3:31])[CH2:22][O:21][CH3:20])([OH:15])[CH2:6][CH2:5]2
Reactant: COCC(C)(COC)C(=O)NCCC=O
Reactant: CNCC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCC(C)(COC)C(=O)NCCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
6.55 g of (1S,2S)-6-fluoro-1-isopropyl-2-(2-methylamino-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol were dissolved in DCM (138 mL)/AcOH (15 mL). 5.36 g of 3-methoxy-2-methoxymethyl-2-methyl-N-(3-oxo-propyl)-propionamide and 6.39 g of sodium cyanoborohydride were added. The reaction mixture was stirred for 2 h at room temperature, quenched with sat.-NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using DCM/MeOH/NEt3 from 100/0/1 to 40/1/0.4 as eluant to yield 10.57 g of N-(3-{[2-((1S,2S)-6-Fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl]-methyl-amino}-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as amber resin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1
Reactant: CCOC(=O)Cl
Reactant: CCc1cc(NCCCCCCO)nc(Cl)n1
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCCCCCNc1cc(CC)nc(Cl)n1
Yield: 38.2 %

Procedure:
In 10 ml of dichloromethane were dissolved 0.70 g of dl-5-chloro-6-ethyl-4-(6-hydroxyhexyl)aminopyrimidine and 0.30 g of ethyl chloroformate, and under stirring, 0.40 g of triethylamine and a catalytic amount of 4-dimethylaminopyridine were added to the solution and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane and washed with water. Then, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=4:1) to give 0.30 g of the title compound as pale yellow oily product. nD18.7 1.5138.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=3)[C:12]#[N:13])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: N#Cc1cccc(B(O)O)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 3-(cyano)phenylboronic acid (1.26 g, 8.6 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (2.38 g, 17.2 mmol) and Pd(PPh3)4 (0.19 g, 0.172 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated and partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 3-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzonitrile (1.2 g, 4.71 mmol, yield 55%) as a brown solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>C(Cl)Cl.O>[CH:1]([NH:4][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[F:5])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)c1ccccc1F
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: To the solution of 1,082 g of isopropylamine in 2,000 ml of methylene chloride and 3,250 ml of water, that of 1,300 g of o-fluorobenzoyl chloride in 2,600 ml of methylene chloride is added during 2 hours while stirring at 2°-9°. Stirring is continued at room temperature overnight, the organic layer is separated and the aqueous phase extracted with 1,000 ml of methylene chloride. The combined organic solutions are dried, evaporated and the residue recrystallized from 1,000 ml of hexane, to yield the N-isopropyl-o-fluorobenzamide melting at 76°-78°.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[C:42]1([C:48]2[N:52]=[C:51]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[O:50][N:49]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:56]1[CH2:55][CH2:54][CH:53]([C:51]2[O:50][N:49]=[C:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:52]=2)[CH2:58][CH2:57]1)=[O:8]
Reactant: c1ccc(-c2noc(C3CCNCC3)n2)cc1
Reactant: O=C(O)CCCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCC(F)(F)F)N1CCC(c2nc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
5,5,5-Trifluoropentanoic acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.3 equiv) and diisopropylethylamine (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 4-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (8c) (0.85 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Yield 79%; 1H NMR (CDCl3) δ 8.06-8.09 (m, 2H), 7.48-7.51 (m, 3H), 4.49-4.54 (m, 1H), 3.90-3.94 (m, 1H), 3.24-3.33 (m, 2H), 2.97-3.06 (m, 1H), 2.46 (t, J=7.2 Hz, 2H), 2.17-2.24 (m, 4H), 1.93-1.98 (m, 4H). tR LCMS 6.0 min. Purity >99%; MS [M+H]+ m/z 368.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[F:16].[CH:17]1([NH:20][C:21](=[O:25])[C:22](O)=O)[CH2:19][CH2:18]1.CC1C=CC=C(C)N=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CC1CCCO1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[N:15]=[C:22]2[C:21]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:25])=[CH:4][C:3]=1[F:16]
Reactant: O=C(O)C(=O)NC1CC1
Reactant: Nc1cccnc1Nc1ccc(Cl)c(F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: Cc1cccc(C)n1
Product: O=C(NC1CC1)c1nc2cccnc2n1-c1ccc(Cl)c(F)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of the mono-tosylate salt of N2-(4-chloro-3-fluorophenyl)pyridine-2,3-diamine (C12) [prepared via treatment of C12 with p-toluenesulfonic acid monohydrate (1.5 equivalents) in ethanol at 80° C., followed by cooling to room temperature and isolation via filtration] (1.003 g, 2.447 mmol), (cyclopropylamino)(oxo)acetic acid (P2) (0.304 g, 2.35 mmol), 2,6-dimethylpyridine (0.91 mL, 0.84 g, 7.8 mmol), and 2-methyltetrahydrofuran (10 mL) was cooled to −10° C. and treated with 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 weight % solution in ethyl acetate, 4.3 mL, 4.6 g, 7.2 mmol). The reaction mixture was warmed to 0° C. and held for 1 hour, heated at reflux for 20 hours, and then cooled to 0° C. and filtered, rinsing with 2-methyltetrahydrofuran. The filtrate was sequentially washed with water (10 mL, 5 mL), with aqueous ammonium hydroxide solution (15%, 3×5 mL), with aqueous hydrochloric acid (0.1 M, 10 mL, 5 mL), and with water (10 mL). The organic layer was distilled to a volume of approximately 4 mL, diluted with 2-nnethyltetrahydrofuran (13 mL), and again distilled to approximately 4 mL, whereupon it was cooled to 50° C. and treated with heptane (3 mL). The resulting slurry was stirred at 50° C. for 2 hours, cooled to 20° C., and stirred for 12 hours. The solid was collected via filtration and washed with a mixture of heptane and 2-methyltetrahydrofuran (2:1, 5 mL). The resulting material (0.488 g) was reslurried in a mixture of 2-propanol and ethyl acetate (9:1, 4.9 mL), warmed to 40° C., cooled to 20° C., and stirred for 16 hours. Filtration and washing with 2-propanol (3 mL) afforded the product as an off-white solid. Yield: 410 mg, 1.24 mmol, 53%. LCMS m/z 330.9, 332.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J=4.8 Hz, 1H), 8.45 (d, J=4.5 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.71-7.80 (m, 2H), 7.47 (dd, J=8.0, 4.8 Hz, 1H), 7.40 (br d, J=8.5 Hz, 1H), 2.77-2.86 (m, 1H), 0.65-0.69 (m, 4H).
Reaction SMILES: [N:1]1([C:6]2[O:10][C:9]([C:11](O)=O)=[C:8]([CH3:14])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[N:1]1([C:6]2[O:10][C:9]([C:11]3[NH:15][C:16]4[CH:17]=[C:18]([C:19](=[O:20])[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:27]=[CH:28][C:29]=4[N:30]=3)=[C:8]([CH3:14])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(N2CCCC2)oc1C(=O)O
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(N2CCCC2)oc1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
5-Pyrrolidine-1-yl-methyl-furan-2-carboxylic acid (62% purity, 223 mg, 0.71 mmol) was added to a pyridine (3 ml) solution of 3,4-diaminobenzophenone (150 mg, 0.71 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol) and 1-hydroxybenzotriazole monohydrate (119 mg, 0.78 mmol) were further added, and the reaction mixture was heated to 70° C. and stirred overnight. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), and the obtained residue was dissolved in acetic acid (3 ml) and stirred at 100° C. for 8 hours. The solution was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), to afford 2-(5-pyrrolidine-1-yl-methyl-furan-2-yl)-5-benzoylbenzimidazole (143 mg, 55% in two steps) as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=[CH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].[BH3-]C#N.[Na+]>CO.CC(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCCC(=O)O
Reaction time: 0.33 h
Yield: 30.1 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (350 mg, 0.93 mmol, 1 eq) in anhydrous methanol (6.5 mL) and AcOH (65 μL) was added 4-oxobutanoic acid (15% in water, 710 mg, 1.0 mmol) at room temperature. After 20 min of stirring, NaBH3CN (130 mg, 2.0 mmol) was added in one portion and the reaction mixture was stirred for another 4 h at room temperature. The reaction mixture was quenched by addition of AcOH (0.5 mL) at 0° C. and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (5-75% ethyl acetate/hexanes) to give 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butylindolin-1-yl)butanoic acid (130 mg, 30%).