Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[CH3:21].C(Cl)(Cl)Cl.C1(C)C=CC(S(ON=C(C#N)C(OCC)=O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:21]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: CCOC(=O)C(C#N)=NOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.1 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g) and L-leucine ethyl ester hydrochloride (1.0 g) are suspended into chloroform (10 ml), and therein is dissolved triethylamine (1.4 ml). To the solution is added ethyl 2-(p-toluenesulfonyloxyimino)-2-cyanoacetate (1.5 g) and the mixture is stirred at room temperature for 16 hours. After reaction, the reaction mixture is extracted with ethyl acetate. The exatract is washed with water, 1 N aqueous sodium hydrogen carbonate, water, 1 N hydrochloric acid and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the residual oily substance (1.6 g) is dissolved in chloroform and then the mixture is subjected to a silica gel column chromatography (developer: chloroform). The first fraction thus obtained is concentrated and the resulting residue is crystallized from ether-petroleum ether to give N-(N-benzyloxycarbonyl-L-prolyl)-L-leucine ethyl ester (80 mg), melting point: 60°-64° C. The product is identified with an authentic sample by infrared spectrum.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([OH:15])[CH3:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[N+:23]([C:26]1[CH:33]=[CH:32][C:29](CBr)=[CH:28][CH:27]=1)([O-:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:6][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH:13]([OH:15])[CH3:14])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(O)C1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-Hydroxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.6 mmol) in CH2Cl2 is cooled to 0° C. and TFA (2.5 mL) is added dropwise. The mixture is allowed to stir at room temperature overnight. All the volatiles were removed and CH3CN (20 mL) is added. After addition of 4-nitrobenzyl bromide (1.25 g, 5.78 mmol) and K2CO3 (2.0 g, 14.4 mmol), the mixture is stirred at room temperature for 5 hours.
Reaction SMILES: O=[C:2]1[CH:10]([C:11]([O:13]CC)=O)[CH2:9][CH:8]2[N:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3]1.[Br:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1>ClCCCl.O>[Br:16][C:17]1[CH:22]=[CH:21][N:20]2[C:11](=[O:13])[C:10]3[CH2:9][CH:8]4[N:4]([CH2:5][CH2:6][CH2:7]4)[CH2:3][C:2]=3[N:23]=[C:19]2[CH:18]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CCOC(=O)C1CC2CCCN2CC1=O
Solvent: O
Solvent: ClCCCl
Product: O=c1c2c(nc3cc(Br)ccn13)CN1CCCC1C2
Yield: 19.9 %

Procedure:
A solution of ethyl 6-oxooctahydroindolizine-7-carboxylate (230 mg, 1.1 mmol), 4-bromopyridin-2-amine (188 mg, 1.1 mmol) and excess PPA (2 g) in 1,2-dichloroethane was stirred at 80° C. overnight. After the suspension was diluted with water (20 mL) and adjusted to pH 8. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were concentrated to give the crude product. 70 mg of the desired product was obtained after column chromatography. MS (ESI): 320, 322 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)C)[CH2:21]4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1.Cl.O1CCNC1=O.Cl[C:38]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[O:39]>>[CH3:44][O:43][CH2:42][CH2:41][O:40][C:38]([NH:25][C@H:22]1[CH2:23][CH2:24][N:20]([C:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:9][C@H:8]([CH2:7][NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)[O:12][C:11]3=[O:13])=[CH:15][C:16]=2[F:29])[CH2:21]1)=[O:39]
Reactant: COCCOC(=O)Cl
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Agent: Cl
Agent: O=C1NCCO1
Product: COCCOC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4(3(S)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (419 mg, 0.73 mM) and 2-methoxyethyl chloroformate (450 mg, 3.27 mM) gave the title compound (442 mg).
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]2[CH2:16][CH2:15]2)=[C:9]([N+:11]([O-])=O)[CH:10]=1>C(O)C.O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]2[CH2:16][CH2:15]2)=[C:9]([CH:10]=1)[NH2:11]
Reactant: O=[N+]([O-])c1cc(Br)ccc1C1CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)ccc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tin (II) chloride (16.0 g, 0.10 mol) is added in one portion to a solution of crude 5-bromo-2-cyclopropylnitrobenzene (8.68 g) in ethanol (190 ml) and water (1.9 ml). The reaction mixture is stirred at room temperature overnight, followed by addition of further tin (II) chloride (28 g, 0.175 mol) and additional stirring overnight. After concentration in vacuo ice is added, and the solution is basified with 2M aqueous sodium hydroxide. After extraction with ethyl acetate (×2) the organic phase is washed again with 2M aqueous sodium hydroxide, then also distilled water and brine. After drying over magnesium sulfate the solution is concentrated in vcauo to give a brown oil which is purified by flash column chromatography on silica gel (9:1 isohexane/ethyl acetate eluant) to afford 5-bromo-2-cyclopropylaniline as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2OC)=[O:7])=[CH:4][CH:3]=1.[CH3:20]OC1C=C([N+]([O-])=O)C=CC=1N.CC1C=C([N+]([O-])=O)C=CC=1N>>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: COc1cc(N)ccc1NC(=O)c1ccc(N)cc1
Agent: Cc1cc([N+](=O)[O-])ccc1N
Product: Cc1cc(N)ccc1NC(=O)c1ccc(N)cc1

Procedure:
By operating as described under (a) above, but using, instead of 202 parts of 2-methoxy-4-nitro-aniline, 183 parts of 2-methyl-4-nitro-aniline, high yields of 4,4'-diamino-2'-methyl-benzanilide were obtained (melting point: 111°-115° C.).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:31]=[CH:30][C:15]([O:16][S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:29])[CH:21]=2)(=[O:19])=[O:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:36](OC(=O)C)(=[O:38])[CH3:37].O>CCOC(C)=O.CN(C)C1C=CN=CC=1>[C:36]([O:29][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:9]3[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[O:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:31][CH:30]=2)(=[O:18])=[O:19])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(OC(C)=O)c2)cc1
Reaction time: 24 h
Yield: 76 %

Procedure:
At ambient temperature, to a stirred solution containing 4-{4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.298 g, 0.602 mmol) and acetic anhydride (1 mL) In EtOAc (2 mL) was added 4-(dimethylamino)pyridine (3.7 mg, 0.0301 mmol). The reaction was refluxed for 72 h. The reaction was cooled to ambient temperature, hydrolyzed with H2O (5 mL) and stirred for 24 h. The reaction was diluted with EtOAc and the organic phase washed sequentially with H2O (2×), brine (2×), dried (MgSO4) and concentrated. Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 10 & 20% EtOAc/pet ether step gradient gave 0.122 g (76%) of the title compound as a yellow solid, mp 54-57° C. 1H NMR consistent. IR (KBr) 3400, 2900, 1700, 1380 and 1190 cm−1. mass spectrum (−ESI) m/z 535 (M−H).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[N:22]1([C:28]2[CH:29]=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:34][C:31]3[N:30]=[CH:29][C:28]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:33][CH:32]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: Nc1ccc(N2CCCCC2)cn1
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCCCC4)cn3)ncc12
Temperature: 25 °C
Yield: 27.4 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 6-bromo-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a brown solid (0.358 g, 27.3%). 1H NMR δ(400 MHz, CDCl3) 8.79 (s, 1H), 8.27 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.01 (s, 1H), 7.38 (d, J=6.8 Hz, 1H), 5.98 (m, 1H), 3.1 (m, 4H), 2.60 (s, 3H), 2.30 (m, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.57-1.75 (m, 8H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.Cl.[CH3:26][O:27][NH:28][CH3:29].Cl>ClCCl.O1CCOCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:28]([O:27][CH3:26])[CH3:29])=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CNOC
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(C)=O)CC1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 1-acetylpiperidine-4-carboxylic acid (58.50 g, 342 mmol) in dichloromethane (700 mL) was added di(1H-imidazol-1-yl)methanone (58.18 g, 359 mmol). After the addition the mixture was agitated for two hours and N-methoxymethanamine hydrochloride (35.00 g, 359 mmol) was added at once. The mixture was allowed to agitate overnight at ambient temperature and 4M HCl in dioxane (75 mL) was added slowly. The slurry was agitated for 30 minutes and then filtered. Filtrate was washed twice with sodium bicarbonate solution, dried and concentrated to give the title compound (59.10 g, 80.72% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:35](OC)(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:8]1([C:5]2[N:6]=[CH:7][C:2](/[CH:37]=[CH:36]/[CH:35]=[O:38])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Brc1ccc(-n2cccn2)nc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C/C=C/c1ccc(-n2cccn2)nc1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
A solution of the compound from step A (450 mg, 2.01 mmol) and tri(o-tolyl)phosphine (123 mg, 0.40 mmol) in DMF (8 mL) was cooled to 0° C. and purged with nitrogen for 15 min. TEA (0.56 mL, 4.02 mmol) and methyl acrylate (0.36 mL, 4.00 mmol) were added and purging was continued for 5 min. Palladium acetate (45 mg, 0.20 mmol) was added and the flask was stoppered and heated to 120° C. for 24 h. The cooled reaction mixture was diluted with ether (50 mL) and washed with water (2×25 mL) and brine (25 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 356 mg (77%) of the title compound. MS 230 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:11]([CH3:12])=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[CH3:13].C1C=CC=CC=1.[Cl:25]N1C(=O)CCC1=O>C(OCC)(=O)C>[Cl:25][C:10]1[C:11]([CH3:12])=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[C:6]([CH3:13])=[CH:7][C:8]=1[NH2:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(N)c(Cl)c(C)c1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Into a 200 milliliter three-necked, round bottom reaction flask was charged 6.76 grams (24.0 mmol) of 4-(2,4-dichlorophenoxy)-3,5-dimethyl aniline and 48 milliliters of benzene. N-chlorosuccinimide (3.85 grams, 28.8 mmol) was then added and the resultant heterogeneous mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed (2x) with saturated Na2SO3 solution and dried over Na2SO4. Concentration under reduced pressure afforded the crude product as a dark oil. This material was filtered through a short column of silica gel using 9:1 hexane: ethyl acetate as an eluant. Solvent removal under reduced pressure afforded 2-chloro-4-(2,4-dichlorophenoxy)-3,5-dimethylaniline (6.5 grams) contaminated with at least three other products. This material was placed in a Parr bottle and dissolved in toluene (50 milliliters). The Parr bottle was purged with nitrogen, 5% platinum on carbon (650 milligrams) was added and the mixture was hydrogenated for 1 hour at 40-50 psi and room temperature on a rocking Parr hydrogenator. Filtration through a pad of celite, solvent removal and flash chromatography (9:1 hexane: ethyl acetate afforded pure 2-chloro-4-(2,4-dichlorophenoxy)-3,5-dimethyl aniline (3.1 grams, 9.8 mmol, 41%) as a crystallized solid having a melting point of 89° C.-93° C. Elemental analysis of the crystalline solid indicated the following:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[F-:10].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2]
Reactant: [F-]
Reactant: N#Cc1ccc(Cl)cn1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(F)cn1
Yield: 48.2 %

Procedure:
A mixture of 2-cyano-5-chloropyridine (1 g, 7.22 mmol) and potassium fluoride (1.26 g, 21.68 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. The organic solvents were then removed in vacuo. Silica gel chromatography of the residue afforded 425 mg (48%) of 2-cyano-5-fluoropyridine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C@@H:53]([CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:54][OH:55]>CN(C=O)C>[OH:55][CH2:54][C@@H:53]([NH:52][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:56][CH:57]([CH3:59])[CH3:58]
Reactant: O=C(O)c1cnc(N2CCCCC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO)NC(=O)c1cnc(N2CCCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A mixture of 11 mg (0.04 mmol) 6-cyclopropylmethoxy-5-piperidin-1-yl-pyrazine-2-carboxylic acid, 15.3 mg (0.048 mmol) TBTU, 15.3 mg (0.119 mmol) DIPEA and 7 mg (0.059 mmol) (S)-2-amino-4-methyl-pentan-1-ol (commercially available) in 1 mL DMF was shaken at room temperature for 16 h. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The combined product fractions were evaporated to yield 10.5 mg (70%) of the title compound. m/z (ES+): 377.5 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:12])=[CH:7][C:6]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH3:2].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=1[N:29]=[C:30]=[S:31]>C(#N)C>[NH2:12][C:8]1[C:9]([NH:11][C:30]([NH:29][C:22]2[C:23]([F:28])=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=2[Cl:20])=[S:31])=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:19])=[C:6]([O:13][CH2:14][C:15]([F:16])([F:18])[F:17])[CH:7]=1
Reactant: Fc1ccc(Cl)c(Cl)c1N=C=S
Reactant: CCOC(=O)c1cc(N)c(N)cc1OCC(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1cc(NC(=S)Nc2c(F)ccc(Cl)c2Cl)c(N)cc1OCC(F)(F)F

Procedure:
Prepared analogously to example 583h from ethyl-4,5-diamino-2-(2,2,2-trifluoro-ethoxy)-benzoate (synthesis described at example 575) and 2,3-dichloro-6-fluoro-1-isothiocyanato-benzene in acetonitrile.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[C:28]([O:18][C:17]1[C:9]([Br:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:12]=[CH:11]2)(=[O:30])[CH3:29]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)c(O)ccc21
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
Triethylamine (0.29 g, 2.8 mmol) was added to a solution of 4-bromo-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 21, 0.67 g, 1.9 mmol) and acetyl chloride (0.22 g, 2.8 mmol) in THF (10 mL). The mixture was stirred for 10 minutes at room temperature and evaporated. The residue was partitioned between DCM and saturated aqueous NaHCO3. The reaction mixture was washed with saturated aqueous NaHCO3, and the organic phase was dried (MgSO4) and evaporated to give the title compound (0.6 g) as a red solid. MS m/z 394/396 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([CH3:14])[CH2:7][C:8]2=[O:13].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=O.C1(S(O)(=O)=O)C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:15](=[O:18])[CH:16]=[C:7]1[CH:6]([CH3:14])[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:8]1=[O:13])[CH3:21]
Reactant: CCOC(=O)C=O
Reactant: COc1cccc2c1CC(C)CC2=O
Agent: O=S(=O)(O)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1C(=O)c2cccc(OC)c2CC1C
Temperature: 25 °C
Yield: 51 %

Procedure:
In a heavy walled sealed tube, 5-methoxy-3-methyl-3,4-dihydro-2H-naphthalen-1-one (1.3 g, 6.8 mmol), ethyl glyoxylate (3 mL, 50% solution in toluene), benzenesulfonic acid (100 mg), magnesium sulfate (5 g), and toluene (30 mL) were heated to 120° C. for 13 hours. The reaction was cooled to room temp, filtered, diluted with water, and extracted with ethyl acetate. The extracts were washed with brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography to yield the desired product (960 mg, 51% yield). LCMS-ESI+ (m/z): [M+H]+ calcd for C16H19O4: 275.13. Found: 275.26.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:20].[CH3:30][N:31]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[C:32]1[C:39](Cl)=[O:40]>CO.C(Cl)Cl.[Pd]>[CH3:30][N:31]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[C:32]1[C:39]([NH:15][C:13]1[CH:14]=[C:10]([C:8]([NH:7][C:5]2[CH:4]=[C:3]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:20])[N:2]([CH3:1])[CH:6]=2)=[O:9])[N:11]([CH3:18])[CH:12]=1)=[O:40]
Reactant: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)NCCN1CCOCC1
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)cc1C(=O)NCCN1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Methyl-4-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-N-[2-(4-morpholinyl)ethyl]-1H-pyrrole-2-carboxamide (0.343 g, 0.85 mmol; see Preparation 1(iv) above) was dissolved in methanol (10 mL) and cooled to 0° C., Pd/C (200 mg) was then added in small portions and the solution stirred under H2 for 3 h. The solution was then filtered and the solvent removed under reduced pressure. A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (160 g, 0.85 mmol) in DCM (10 mL) was then added and allowed to stir for 1 h at RT, the solvent was removed under reduced pressure, the crude product obtained was separated on basified silica using a 1:1 solution of methanol ethyl acetate to yield the sub-title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl.Cl.Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Reactant: Cc1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 1.64 parts of 2-methyl-1H-imidazole, 9.2 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride, 6.4 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 60° C. The reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.6 parts (30% of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 170.5° C. (compound 20).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[N+:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[C-:12]>C1COCC1>[CH2:17]([O:16][C:14]([C:13]1[N:11]=[CH:12][O:7][C:6]=1[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)=[O:15])[CH3:18]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 4-iodobenzoyl chloride (14.0 g, 0.052 mol) in 100 ml THF was added TEA (15.6 g, 0.156 mol) in a dropwise manner and the mixture was stirred for 10 minutes before slowly adding ethyl 2-isocyanoacetate (6.5 g, 0.058 mol). The reaction mixture was stirred at room temperature for 16 hours, the solvent was removed and the residue was treated with EtOAc and water. The organic layer was separated, dried over Na2SO4 and the solvent was removed. The crude product was purified by column to give the title compound (11.0 g, 61.7%) as an orange solid.