Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>O1CCCC1>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]3[CH:26]=[CH:27][C:14]([C:12]4[N:13]=[C:9]([CH2:8][O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[NH:10][CH:11]=4)=[CH:15][CH:16]=3)=[CH:25][CH:24]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2ccc(Oc3ccc(-c4c[nH]c(COc5ccccc5)n4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and paramethylphenylisocyanate (0.089 g, 0.67 mmol) in 3 ml of tetrahydrofuran is stirred for 24 hours at ambient temperature. The precipitate formed is filtered then the solid is stirred in a mixture of solvents such as isopropyl ether/ethyl acetate/isopropanol (5/4/1). After filtration then drying, a solid in the form of a beige powder is obtained with a yield of 73%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([C:51](Cl)=[O:52])[CH2:47][CH2:46]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([C:51](=[O:52])[NH:25][CH:8]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[CH2:47][CH2:46]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A CH2Cl2 solution (111.0 mL) of C-(3-chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (1.9 g, 5.5 mmol) and PS-DIPEA (2.8 g, 11.1 mmol) in a round bottom flask under N2 atmosphere was charged with 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (1.4 g, 5.0 mmol) and stirred at rt for 1.5 h. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Jones Flashmaster, 20 g/70 mL cartridge, eluting with 100% CH2Cl2 to 10% CH3CN/CH2Cl2) to afford 4-{[(3-chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-piperidine-1-carboxylic acid benzyl ester as a pale yellow solid; MS (ES+): m/z 592/594 (100/50) [MH+]; HPLC: tR=3.7 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[SH:17][CH2:18][CH2:19][NH2:20].C(N(CC)CC)C>C(#N)C>[NH2:20][CH2:19][CH2:18][S:17][CH:13]1[CH2:12][C:11](=[O:16])[N:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:14]1=[O:15]
Reactant: NCCS
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCN1C(=O)CC(SCCN)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-nonyl maleimide (0.01 M) prepared as described in Example 12 above, mercapto ethylamine (0.01 M) and triethylamine (0.001 M) in acetonitrile (50 ml) was stirred for 24 hours at room temperature. Acetonitrile was evaporated in vacuo and the residue obtained was triturated with ethyl acetate (25 ml). The resultant suspension was filtered and the solid washed with ethyl acetate. The solid was then dried and characterised as the desired product, N-nonyl,3-mercapto ethylamino maleimide.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:5][N:4]=1.[N:21]1([CH2:30][C:31](O)=[O:32])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]=[CH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][N:18]([C:31](=[O:32])[CH2:30][N:21]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[CH:7][N:8]=1
Reactant: O=C(O)Cn1ccc2cccnc21
Reactant: COc1ncc(-c2ccccc2N2CCNCC2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ncc(-c2ccccc2N2CCN(C(=O)Cn3ccc4cccnc43)CC2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To 2-methoxy-5-(2-piperazin-1-yl-phenyl)-pyrimidine (7.4 g, 27.37 mmol) dissolved in dichloromethane (100 mL) is added pyrrolo[2,3-b]pyridin-1-yl-acetic acid (4.82 g, 27.37 mmol), TBTU (8.79 g, 27.37 mmol), and DIPEA (14.66 mL, 82.12 mmol). The reaction is stirred for 16 h at ambient temperature. The product is purified on a 100 g Biotage SNAP column with 40% EtOAc in hexanes to provide the title compound (8.3 g, 19.37 mmol, 71% yield).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][SH:11].C(NC(C)C)(C)C>C(Cl)Cl>[CH2:12]([C:9]1([CH3:17])[O:8][C:4](=[O:5])[CH:3]([CH2:2][C:1]([OH:6])=[O:7])[S:11][CH2:10]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(C)(O)CS
Reactant: O=C1C=CC(=O)O1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1
Reaction time: 0.25 h

Procedure:
Into a mixture consisting of 10 g of maleic acid anhydride, 8.5 g of 2-hydroxy-2-methylheptane-1-thiol and 105 ml of methylene chloride, 1 ml of diisopropylamine, dissolved in 5 ml of methylene chloride is dropped. During this step the temperature is maintained at equal to or less than 30°. An additional 8.5 g of 2-hydroxy-2-methylheptane-1-thiol, dissolved in 5 ml of methylene chloride is added. After 15 minutes the usual work-up is performed. (Usual working up refers to the following procedure throughout the examples: washing of the organic phase with 1% aqueous sulphuric acid and with water; drying of the organic phase over MgSO4 ; distilling off the solvent; and chromatographic purification of the residue on silica gel with chloroform or ether:petroleum ether = 2:8 as elution agent.) 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid is obtained: NMR: 3.88 (q), 1.54 (s), 0.9 (t).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:15]1([CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:12][CH:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 140 °C

Procedure:
A mixture of 17.3 parts of 1-(ethoxycarbonyl)-4-hydroxypiperidine, 24.7 parts of bromodiphenylmethane and 7 parts of potassium carbonate is stirred and heated in an oil-bath for 3 hours at 140° C. The reaction mixture is cooled, water is added and the product is extracted with methylbenzene. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is distilled, yielding ethyl 4-(diphenylmethoxy)-1-piperidinecarboxylate; bp. 150° C. at 0.4 mm. pressure.
Reaction SMILES: [C:1]([NH:8][CH2:9][C@H:10]1[CH2:12][C@H:11]1[CH2:13][O:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O>C(Cl)Cl>[O:14]([CH2:13][C@H:11]1[CH2:12][C@H:10]1[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[NH2:15]
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H]1CON1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H]1CON
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g (0.00433 mol) of 2-[cis-2-(N-BOC-aminomethyl)-cyclopropylmethoxy]-1H-isoindole-1,3(2H)-dione and 9 ml of hydrazinc hydrate is stirred at room temperature for 1/2 hour. 9 ml of water are then added to the reaction mixture and, after a further 1/2 hour, 50 ml of methylene chloride are added. The reaction mixture is further stirred for another 3 hours, the methylene chloride phase is then separated off and the aqueous phase is washed twice with 30 ml of methylene chloride each time. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The oily cis-2-aminoxymethyl-N-BOC-cyclopropylmethylamine thus obtained, Rf value=0.13 (silica gel/ethyl acetate:hexane (1:1)), is dissolved in 18 ml of 3M methanolic hydrochloric acid and the reaction mixture is stirred at room temperature for 1 hour. After addition of diethyl ether and cooling in an ice-bath, the title compound which has crystallized out is filtered off, washed with diethyl ether and dried, m.p. 178°-180° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:16])[N:5]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH3:1][O:2][C:3]1[C:4](=[O:16])[N:5]([CH:9]2[CH2:14][CH2:13][CH:12]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccn(C2CCC(=O)CC2)c1=O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1cccn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 3-methoxy-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: S(O[CH2:6][CH2:7][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:9])(=O)(=O)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[C:14]([O:13][C:11]([NH:10][C@@H:8]([CH3:9])[CH2:7][CH2:6][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C1COCCN1
Reactant: C[C@@H](CCOS(C)(=O)=O)NC(=O)OC(C)(C)C
Product: C[C@@H](CCN1CCOCC1)NC(=O)OC(C)(C)C
Temperature: 57 °C
Reaction time: 1 h

Procedure:
The crude product of example 22 (b) (˜5.6 mmol) was dissolved in morpholine (10 mL) and heated to 57° C. while stirring under argon for 1 h. The solvent was pumped off, and the residue was partitioned between EtOAc and water. The organic phase was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (silica gel, 2–5% MeOH/CH2Cl2) to give the title compound as a white solid. ES (+) MS m/e=259 (MH+)
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].Cl.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:26][CH:25]=1)#[N:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CNC(=NCc1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and a solution of p-nitrobenzylamine hydrochloride (0.55 g, 2.9 mmol) and triethylamine (0.32 g, 3.2 mmol) in methanol (5 ml) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.70 g, 2.5 mmol, yield: 95%) as colorless powder.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][C:25]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:26][C:21]=4[S:20][C:19]3=[N:32]C(=O)C(F)(F)F)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[ClH:1].[ClH:1].[ClH:1].[NH:32]=[C:19]1[N:18]([CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[C:22]2[CH:23]=[CH:24][C:25]([O:27][C:28]([F:29])([F:31])[F:30])=[CH:26][C:21]=2[S:20]1
Reactant: COc1ccc(N2CCN(CCn3c(=NC(=O)C(F)(F)F)sc4cc(OC(F)(F)F)ccc43)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(N2CCN(CCn3c(=N)sc4cc(OC(F)(F)F)ccc43)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 214.3 %

Procedure:
3-{2-[4-(4-Methoxyphenyl)-1-piperazinyl]ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (1.53 g), methanol (33 cc) and 7% strength potassium carbonate solution (21 cc) in a mixture of methanol (2 volumes) and water (5 volumes) are stirred for 4 hours at a temperature in the region of 20° C. The reaction medium is concentrated under reduced pressure and then extracted with ethereal sulphuric acid. The organic phase is dried over magnesium sulphate and then treated with an excess of alcoholic hydrochloric acid solution. The precipitate is drained, washed with ethereal sulphuric acid and dried at 50° C. at 20 mmHg. 2-Imino-3-{2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl}-6-trifluoromethoxybenzothiazoline trihydrochloride (1.05 g), m.p. 240° C., is obtained.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:13]([O:20][N:21]=[C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2C1=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a suspension of 5.0 g of isatin in 200 ml of ethanol was added a solution of 9.75 g of O-benzylhydroxylamine hydrochloride and 4.18 g of sodium acetate in 50 ml of water at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated. The concentrate was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. Recrystallization of the crude product from ethanol gave 6.06 g (71%) of 3-(benzyloxyimino)indolin-2-one as yellow crystals.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:17][C:18]([OH:20])=[O:19].Cl>O.CN(C=O)C>[C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([O:3][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:8]=1
Reactant: O=C(O)CBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added portionwise to a DMF (10 ml) solution of 4-hydroxybiphenyl (1.7 g) under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, to which was added bromoacetic acid (1.4 g). The reaction mixture was further stirred at room temperature for 18 hours, which was poured into water. 2N hydrochloric acid was added to the mixture to adjust the pH to 4, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1), and the crude crystals were recrystallized from IPE to obtain the entitled compound (1.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].Cl.[CH2:14]([O:16][C:17](=[O:24])[CH2:18][C:19](OCC)=N)[CH3:15]>CCO>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:24])[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccc(C(=O)OC)cc2[nH]1
Temperature: 25 °C

Procedure:
Methyl 3,4-diaminobenzoate (1 equivalent), was stirred with ethyl-3-ethoxy-3-iminopropanoate hydrochloride (2 equivalents) in EtOH at 70° C. overnight. The reaction mixture was cooled to room temperature, and the EtOH was removed under reduced pressure. The residue was taken up in water and extracted with CH2Cl2 (3×). The organic extracts were dried over Na2SO4, and the solvent was removed. The solid was triturated with Et2O to yield the desired ethyl 2-[5-(methoxycarbonyl)-benzimidazol-2-yl]acetate as an off-white solid. LC/MS m/z: 263.2 (MH+), Rt 1.80 minutes.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Cl[C:34]1[C:39]([CH:40]=[O:41])=[C:38]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])[N:37]=[CH:36][CH:35]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH3:1][N:2]1[C:3](=[O:32])[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)=[CH:5][C:6]([C:34]2[C:39]([CH:40]=[O:41])=[C:38]([N:42]3[CH2:54][CH2:53][N:45]4[C:46]5[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=5[CH:52]=[C:44]4[C:43]3=[O:55])[N:37]=[CH:36][CH:35]=2)=[CH:7]1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 100 °C
Yield: 91.4 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a condenser was charged with 111c (450 mg, 1.26 mmol), 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 103b (413 mg, 1.26 mmol), Pd(dppf)Cl2 (102 mg, 0.126 mmol), K3PO4.3H2O (85 mg, 0.352 mmol), and THF (10 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 7:1 petroleum ether/ethyl acetate to afford 111d as a yellow solid (700 mg, 63%). MS: [M+H]+ 608.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and commercially available 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (77 mg, 63%). MS (ISP) 489.3 [(M+H)+]; mp 231-233° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)CC(NC2C=CC(F)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:8][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]
Reactant: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccncc2[N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
To 4-amino-2-fluorophenol (see Step A of Example 19, 127 mg, 1.0 mmol) in DMF (5 mL) at rt under nitrogen was added sodium hydride (80 mg, 2 mmol, 60%). After stirring at rt for 10 min, 4-chloro-3-nitropyridine hydrochloride (Lancaster, 195 mg, 1.0 mmol) was added. The mixture was stirred at rt for 1 h and was then diluted with EtOAc (50 mL) and washed with water, 10% aqueous lithium chloride solution, and then brine (1×30 mL each). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc to give the title compound (150 mg, 60%) as a yellow-orange solid. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.63 (d, 1H, J=6 Hz), 7.09 (t, 1H, J=9.2 Hz), 6.92 (d, 1H, J=6 Hz), 6.55 (dd, 1H, J=13.2, 2.4 Hz), 6.45 (dd, 1H, J=9.2, 2.4 Hz), 5.61 (s, 2H); MS(ESI+) m/z 250.18 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=O)[NH2:16])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C([O:25][C:26]([C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:36][CH:35]=3)[CH:33]=2)=O)=C(F)C(F)=C(F)C=1F>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:26]([C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)=[CH:36][CH:35]=3)[CH:33]=2)=[O:25])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(N)=O)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nnc(C(=O)NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-carbamoyl-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (1.01 mmol, 0.25 g) in THF (4.0 mL), was added BH3:THF (2 mL, 1M solution in THF) and stirred for 12 h. All volatiles were removed under reduced pressure. The residue was taken in DCM (2 mL) and 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.29 mmol, 0.15 g) was added followed by TEA (0.5 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with NaOH (0.5 M) solution (2×5 mL) water (2×5 mL), brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate:hexanes (3:7) to provide 4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester.