Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:27]3[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]3)=[CH:14][N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C1CNCCN1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CCN1
Yield: 39.7 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (40 mg, 0.12 mmol), 2-piperazinone (18 mg, 0.18 mmol), acetic acid (7 μL, 0.12 mmol) and sodium triacetoxyborohydride (38 mg, 0.18 mmol) to afford 20 mg (40%) of the desired product after purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([P:9]([CH2:16][CH:17]([C:19]#[N:20])[CH3:18])(=[O:15])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8].O>C(OCC)C>[CH2:7]([P:9]([CH2:16][CH:17]([CH3:18])[CH2:19][NH2:20])(=[O:15])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8]
Reactant: CCCCOP(=O)(CC)CC(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCOP(=O)(CC)CC(C)CN
Yield: 85 %

Procedure:
At room temperature, 2.3 g (0.06 mol) of lithium aluminum hydride in 100 ml absolute diethyl ether in a three-neck flask equipped with stirrer, dropping funnel and high-performance condenser are, while continuously stirring, admixed with a solution of 21.7 g (0.1 mol) of butyl ethyl(2-cyano-2-methylethyl)phosphinate (produced similarly to Example 10) in 100 ml of diethyl ether added dropwise at such a rate that there is a moderate boil of the diethyl ether. This is followed by refluxing for 1 hour and admixing of the reaction solution with 1.8 g (0.1 mol) of water, and the insoluble salts are filtered off, the solvent is removed in vacuo and the product is purified by chromatography to obtain 18.8 g (85% of theory) of butyl ethyl(2-methyl-3-aminopropyl)phosphinate as colorless oil.
Reaction SMILES: CS(Cl)(=O)=O.[Si]([O:13][CH2:14][C:15]([CH3:45])([CH3:44])[CH2:16][N:17]1[CH:26]=[C:25]([CH2:27]O)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:29]3[CH:30]=[C:31]([CH:38]=[C:39]([F:42])[C:40]=3[CH3:41])[C:32]([NH:34][CH:35]3[CH2:37][CH2:36]3)=[O:33])[CH:23]=2)[C:18]1=[O:43])(C(C)(C)C)(C)C.C(N(CC)CC)C.[CH3:53][C@H:54]1[NH:59][CH2:58][CH2:57][N:56](C(OC(C)(C)C)=O)[CH2:55]1>C(Cl)Cl>[CH:35]1([NH:34][C:32](=[O:33])[C:31]2[CH:30]=[C:29]([C:22]3[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:43])[N:17]([CH2:16][C:15]([CH3:44])([CH3:45])[CH2:14][OH:13])[CH:26]=[C:25]4[CH2:27][N:59]3[CH2:58][CH2:57][NH:56][CH2:55][C@H:54]3[CH3:53])[C:40]([CH3:41])=[C:39]([F:42])[CH:38]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(CO)c2c1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCNC[C@H]3C)c2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 22.2 %

Procedure:
Methanesulfonyl chloride (0.55 mL) was added to a solution of 3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 26 g, 3.65 g) and triethylamine (1.79 mL) in DCM (10 mL) at −20° C. After 30 min the solution was warmed to 0° C. and tert-butyl (3R)-3-methylpiperazine-1-carboxylate (2.58 g) was added. The reaction was stirred for 18 h at room temperature, evaporated and the residue purified (SiO2 chromatography, elution with 20 to 80% ethyl acetate in isohexane). Fractions containing product were evaporated, dissolved in THF (100 mL) and treated with 4 M HCl in dioxane (5 mL), stirred at room temperature for 60 h, evaporated to dryness and the residue purified (SiO2 chromatography, elution with 5 to 10% 7N NH3/methanol in DCM) to give the title compound (1.53 g) as a solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[CH3:16][O:17][C:18]1[C:19]([C:28](O)=[O:29])=[CH:20][C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1>>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:28]([C:19]3[C:18]([O:17][CH3:16])=[CH:27][C:22]4[O:23][CH2:24][CH2:25][O:26][C:21]=4[CH:20]=3)=[O:29])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: COc1cc2c(cc1C(=O)O)OCCO2
Agent: Cl
Product: COc1cc2c(cc1C(=O)Nc1cnn(Cc3c(C)noc3C)c1)OCCO2
Yield: 50 %

Procedure:
Prepared as in Example 4-73 from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 4-1a) and 7-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (example 4-95a). Yield 50%. MS M+H calculated 385.1, found 385.1. 1H NMR (400 MHz, DMSO): 2.136 (s, 3H), 2.410 (s, 3H), 3.851 (s, 3H), 4.214 (bs, 2H), 4.296 (bs, 2H), 5.120 (s, 2H), 6.688 (s, 1H), 7.290 (s, 1H), 7.6006 (s, 1H), 8.069 (s, 1H), 9.856 (s, 1H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H:9]1([NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:15].Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>[Cu]I.O1CCOCC1>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH2:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(Br)cc1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(N[C@@H]2CCCC[C@H]2N)cc1
Temperature: 110 °C
Reaction time: 70 h
Yield: 63.6 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (190 mg, 0.998 mmol), K3PO4 (2.10 g, 9.89 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (0.60 mL, 5.00 mmol), 4-bromotoluene (0.70 mL, 5.69 mmol) and dioxane (3.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 70 h. The resulting dark brown suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The black filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane saturated with aq NH3-methanol 50:1; 15 mL fractions). Fractions 9–11 provided 650 mg (64% yield) of the product as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.00–6.95 (m, 2H), 6.62–6.57 (m, 2H), 3.30 (br s, 1H), 2.96–2.86 (br m, 1H), 2.49 (td, J=10.4, 3.6, 1H), 2.23 (s, 3H), 2.17–2.08 (m, 1H), 2.02–1.94 (m, 1H), 1.79–1.66 (m, 2H), 1.44 (br s, 2H), 1.38–1.17 (m, 3H), 1.07–0.95 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 145.9, 129.7, 126.6, 113.9, 60.5, 56.1, 35.2, 32.4, 25.3, 25.0, 20.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH2:9]([O:11][C:12]([CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[C:15]1=[O:20])=[O:13])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(O)(=O)C>[CH2:9]([O:11][C:12]([C:14]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:17][N:16]([CH3:19])[C:15]1=[O:20])=[O:13])[CH3:10]
Reactant: Fc1ccc(Br)cn1
Reactant: CCOC(=O)C1CCN(C)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1(c2ccc(Br)cn2)CCN(C)C1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-fluoro-pyridine (3.45 g), 1-methyl-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester (5.00 g), cesium carbonate (12.77 g), and dimethyl sulfoxide (10 mL) was stirred at 100° C. overnight. After cooling to room temperature, acetic acid (4.5 mL) was added and the resulting solution was extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane/ethyl acetate 1:0→1:1) to give the title compound as an oil. Yield: 3.92 g (61% of theory); Mass spectrum (ESI+): m/z=327/329 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=[O:5])=[O:4].[C:20](Cl)(=[O:22])[CH3:21].N1C=CC=CC=1>C(Cl)Cl>[C:20]([O:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][S:3]([C:2]([F:18])([F:1])[F:19])(=[O:4])=[O:5])=[CH:8][C:9]=1[CH:15]([CH3:17])[CH3:16])(=[O:22])[CH3:21]
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1CO
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(OS(=O)(=O)C(F)(F)F)cc1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-hydroxymethyl-3-isopropylphenyl 1,1,1-trifluoromethanesulfonate (Intermediate 149, 190.0 mg, 0.64 mmol) in 5 mL CH2Cl2 was added acetyl chloride (75.0 mg, 0.96 mmol) and pyridine(101.0 mg, 1.38 mmols). After stirring for 3 hours at 25° C. the reaction was quenched by the addition of H2O and the resulting mixture extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The title compound, 182 mg (84%), was isolated from the residual oil by column chromatography (5-10% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19](Cl)(Cl)Cl)=[C:11]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:10]=1)=[O:7].[N+:35]([C:38]1[CH:43]=[CH:42]C(O)=[CH:40][CH:39]=1)([O-:37])=[O:36].[O-2].[Mg+2]>C(OCC)(=O)C>[N+:35]([C:38]1[CH:43]=[CH:42][C:19]([O:18][C:17](=[O:23])[NH:16][CH2:15][CH2:14][O:13][C:12]2[CH:24]=[CH:25][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:32]=[CH:33][CH:34]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:10][C:11]=2[C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:40][CH:39]=1)([O-:37])=[O:36]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(Cl)(Cl)Cl)c(-c3ccnn3C)c2)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)Oc3ccc([N+](=O)[O-])cc3)c(-c3ccnn3C)c2)c1
Temperature: 22 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
Trichloromethyl 2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (50.0 g, 94.74 mmol), 4-nitrophenol (14.50 g, 1.1 eq) and magnesium oxide (1.067 mL, 1.0 eq) were taken up in 2 mL of ethyl acetate in a round bottomed flask and stirred at 22° C. for 3 hr. The magnesium oxide was filtered off. The solvent was then evaporated and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 39.1% yield. LCMS m/z (%)=532 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[OH-:11].[K+].Cl>CS(C)=O.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1c(O)cccc1Cl
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of 2-chloro-6-fluorobenzaldehyde (2.44 g, 15.4 mmol) in DMSO (20 mL) at 0° C. was added potassium hydroxide (2.23 g, 33.8 mmol) slowly. The reaction mixture was allowed to stir and warm to rt overnight and then diluted with water (65 mL). The mixture was acidified to pH<1 with conc. HCl. A white solid formed and was filtered, washed with water, and dried to give 2-chloro-6-hydroxybenzaldehyde (1.48 g, 61%). LCMS: (FA) ES-155.0.
Reaction SMILES: [C:1]1([N:11]=[C:12](Cl)[C:13]([F:16])([F:15])[F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:18]=[N+:19]=[N-:20].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([N:11]2[C:12]([C:13]([F:16])([F:15])[F:14])=[N:20][N:19]=[N:18]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C(Cl)=Nc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Four grams (15.5 mmol) of N-(naphthalen-1-yl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 13, 1.84 g (27.9 mmol) of sodium azide, 1.08 g (7.76 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 14 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was precipitated for 1 hour in 18 ml of n-hexane while being cooled using an ice bath, followed by filtration and drying, thereby giving 3.86 g of 1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-tetrazole as a white powder (yield: 94.1%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1COCCN1
Product: Brc1ccc(-c2nsc3cc(OCCCCN4CCOCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and morpholine were converted to yield 3-(4-Bromo-phenyl)-6-(4-morpholin-4-yl-butoxy)-benzo[d]isothiazole, MS: 448 (MH+, 1Br).
Reaction SMILES: C(OC([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH: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)[C:12](=[O:17])[CH2:13]2)=O)(C)(C)C.C(OCC)(=O)C.Cl>O1CCOCC1>[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[CH:22]=[CH:23][C:18]([N:11]4[C:12](=[O:17])[CH2:13][CH:14]5[NH:8][CH:9]([CH2:16][CH2:15]5)[CH2:10]4)=[CH:19][N:20]=3)[N:26]=[CH:27][C:28]=2[CH:33]=1)=[O:38]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Yield: 45 %

Procedure:
To 0.55 grams (0.96 mmoles) of 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester was added 15 ml of ethyl acetate. The mixture was stirred at room temperature under N2 and cooled to ice bath temperature. To this mixture was added 5 mls 4N HCl in dioxane. The resultant mixture was allowed to stir until all starting material was consumed. The resultant mixture was stirred until all starting material was consumed as determined by HPLC-MS. To this mixture was added 50 ml of a 1:1 mixture of ethyl acetate/diethyl ether to precipitate solids. The solids were filtered and washed with excess 1:1 mixture of ethyl acetate/diethyl ether and dried under vacuum to a constant weight to yield 7-Cyclopentyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as the di-hydrochloride salt, 0.213 grams (45% yield). MS m/z 489 (M+H)+. 1H NMR (400 MHz, D6 DMSO) δ 10.2 (s, 1H, broad), 9.05 (s, 1H, broad), 8.35 (s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 6.9 (s, 1H), 4.82 (m, 1H, broad), 4.6 (d, 1H), 4.25 (s, 1H, broad), 4.15 (s, 1H, broad), 3.82 (m, 1H, broad), 3.5 (d, 1H), 3.05 (s, 6H), 2.82 (m, 1H), 2.3 (m, 2H), 2.2-1.95 (m, 10H, broad), 1.89 (m, 1H), 1.65 (m, 2H).
Reaction SMILES: C(=O)(O)[O-].[K+].Cl.[C:7](=[NH:10])([NH2:9])[CH3:8].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Br:22])[CH:16]=1)=O>O1CCCC1.O>[Br:22][C:17]1[CH:16]=[C:15]([C:13]2[NH:9][C:7]([CH3:8])=[N:10][CH:12]=2)[CH:20]=[CH:19][C:18]=1[CH3:21]
Reactant: CC(=N)N
Reactant: Cc1ccc(C(=O)CBr)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(-c2ccc(C)c(Br)c2)[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 4.2 %

Procedure:
Potassium bicarbonate (2.10 g, 20.7 mmol) was added portionwise to a solution of acetimidamide hydrochloride (1.06 g, 11.2 mmol) in tetrahydrofuran (20 mL) and water (5 mL). The resulting mixture was heated to reflux and 2-bromo-1-(3-bromo-4-methylphenyl)ethanone (preparation 58a, 2.74 g, 9.4 mmol) was added dropwise over a period of 20 minutes. After 3 hours, further acetamidamide hydrochloride (1.06 g, 11.2 mmol) and potassium bicarbonate (1.03 g, 10.1 mmol) were added and the was mixture refluxed overnight. The mixture was evaporated to dryness and partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The acidic aqueous layer was bascified with solid sodium hydroxide and extracted with ethyl acetate. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give a semi solid. This semi solid was heated in vacuo at 70° C. for one hour in order to remove excess acetamidamide to give the pure title compound (0.10 g, 5%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH:8]2[C:12](=[O:13])[N:11]([CH:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)[C:10](=[O:21])[NH:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:52]([O:59][NH2:60])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.Cl>CN(C=O)C>[CH2:52]([O:59][NH:60][C:15](=[O:17])[CH:14]([N:11]1[C:12](=[O:13])[CH:8]([CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:23][CH:22]=2)[NH:9][C:10]1=[O:21])[CH:18]([CH3:20])[CH3:19])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C(C(=O)NOCc1ccccc1)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of the compound obtained in step h above (22h) (300 mg, 0.782 mmol), NMM (0.19 mL, 1.72 mmol) and HOBt (179 mg, 1.329 mmol) in DMF (11 mL) were stirred at 0° C. for 10 minutes, then the reaction was cooled to −15° C., and EDCI (165 mg, 0.860 mmol) was added. The reaction was stirred for 30 minutes at −15° C. and then allowed to warm to room temperature, BnONH2HCl (137 mg, 0.860 mmol) was added. After being stirred overnight, the reaction mixture was concentrated under vacuum, and the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the residue was purified by silica gel column chromatography which gave the title compound as colorless oil (426 mg, 83% yield).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])[CH:22]=1>>[CH:1]1([NH:5][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[N:21]2[CH:22]=[C:18]([C:8]3[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:10][O:11][C:7]=3[CH3:6])[N:19]=[CH:20]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)NC2CCC2)cn1
Yield: 46 %

Procedure:
As described for Example 71, cyclobutylamine was converted, using 2-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (53 mg, 46%) which was obtained as an off-white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].S(C1C=CC(C)=CC=1)(O[CH2:15][C@H:16]1[CH2:19][CH2:18][N:17]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O>CN(C=O)C>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:16]1[CH2:15][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: Oc1cncc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCN2C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cncc(Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
To a solution of 5-chloro-3-hydroxypyridine (0.3 g, 2.6 mmol) in DMF was added KOH (0.2 g, 3.8 mmol) at room temperature. 1-t-Butoxycarbonyl-2-(R)-azetidinylmethyl tosylate (0.8 g, 2.4 mmol, from example 10d) was then added, and the reaction mixture was stirred at 80° C. for 16 hours. The DMF was removed by washing with H2O/brine (1:1) in EtOAc. The organic layer was dried, concentrated and chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (0.6 g, 87%): 1H NMR (CDCl3, 300 MHz) δ1.43 (s, 9H), 2.21-2.40 (m, 2H), 3.89 (t, 2H, J=8 Hz), 4.12 (m, 1H), 4.36 (m, 1H), 4.52 (m, 1H), 7.29 (m, 1H), 8.20 (d, 1H, J=2 Hz), 8.25 (d, 1H, J=3 Hz); MS (CI/NH3) m/z 299 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[C:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)([CH3:8])[CH3:7].C[N:21](C=O)C>>[CH3:3][O:4][C:5](=[O:19])[C:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11]([NH2:21])[CH:10]=1)([CH3:8])[CH3:7]
Reactant: COC(=O)C(C)(C)c1c[nH]c2ccc(F)cc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C)(C)c1cn(N)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (1.02 g, 25.5 mmol, 60% in mineral oil) in DMF (25 mL) at 0° C. is treated with 2-(5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (400 mg, 1.7 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (960 mg, 8.5 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: COC(=O)c1ccc2occ(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1coc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 95.9 %

Procedure:
Methyl 3-methyl-1-benzofuran-5-carboxylate (365 mg, 1.9 mmol) is dissolved in MeOH (7 mL), diluted with H2O (3.5 mL) and treated with 3N NaOH (1.41 mL, 4.2 mmol). The mixture is diluted with MeOH (3.5 mL) to homogeneity, stirred at RT for 2.5 days then concentrated to dryness. The residue is dissolved in H2O (5 mL) and acidified to pH 2 with concentrated HCl. The resulting solid is filtered and dried in a vacuum oven at 40° C. for 18 h to afford 321 mg (95%) of 3-methyl-1-benzofuran-5-carboxylic acid as a white solid. HRMS (FAB) calcd for C10H8O3+H: 177.0552, found: 177.0553 (M+H)+.