Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]2.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]2[N:57]=[C:56]([CH2:58]O)[CH:55]=[CH:54][N:53]=2)=[CH:47][CH:46]=1>C1COCC1.O>[Cl:44][C:45]1[CH:46]=[CH:47][C:48]([NH:51][C:52]2[N:57]=[C:56]([CH2:58][O:32][C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]4)[CH:55]=[CH:54][N:53]=2)=[CH:49][CH:50]=1
Reactant: OCc1ccnc(Nc2ccc(Cl)cc2)n1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccc2cc(OCc3ccnc(Nc4ccc(Cl)cc4)n3)ccc2[nH]1
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
A solution of triphenylphosphine (0.145 g, 0.552 mmol) in THF (2.0 mL) was cooled to 0° C. under N2 and DEAD (0.087 mL, 0.552 mmol) was added dropwise. The mixture was stirred for 10 min, then 6-hydroxyquinolin-2(1H)-one (0.068 g, 0.424 mmol) was added. After stirring for 5 min, a solution of (2-((4-chlorophenyl)amino)pyrimidin-4-yl)methanol (0.1 g, 0.424 mmol) in THF (2.0 mL) was added. The reaction was stirred for 18 h at room temperature. The mixture was diluted with water and filtered. The beige filter cake was stirred in methanol and filtered to give 6-((2-(4-chlorophenylamino)pyrimidin-4-yl)methoxy)quinolin-2(1H)-one as a beige solid (0.03 g, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (s, 1H), 9.91 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 7.95-7.72 (m, 3H), 7.44-7.16 (m, 5H), 6.98 (d, J=5.0 Hz, 1H), 6.51 (d, J=9.5 Hz, 1H), 5.16 (s, 2H). LCMS: R.T.=3.74; [M+H]+=379.09.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:10][C:4]1[C:5]([O:9][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=2)=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(Cl)c(O)cc1F
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Yield: 29.7 %

Procedure:
A solution of 4-amino-2-chloro-5-fluorophenol (6.0 g, 37 mmol), 2,4-dichloro-pyridine (5.3 g, 37 mmol) and K2CO3 (5.2 g, 37 mmol) in DMSO (100 mL) was heated at 80° C. under nitrogen overnight. The mixture was cooled to RT, poured into water (300 mL), and extracted with EtOAc (3×200 mL). The combined organics were washed with brine (3×100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/petroleum ether) to give 5-chloro-4-(2-chloro-pyridin-4-yloxy)-2-fluoro-phenylamine as a white solid (3.0 g, 32% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.33 (d, J=5.7 Hz, 1H), 7.34-7.31 (m, 1H), 7.01-6.82 (m, 3H), 5.63 (br s, 2H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][CH:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=1[CH3:14].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>>[Br:3][C:4]1[N:8]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=1[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1c[nH]c(Br)c1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c(Br)c1C
Yield: 85.5 %

Procedure:
Using sodium hydride (60% in oil, 620 mg), ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (3.0 g) and tosyl chloride (2.95 g), a procedure as in Reference Example 41 was performed to give the title compound as pale-yellow crystals (yield 4.27 g, 86%).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17]OS(C)(=O)=O)(=O)=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([N:30]1[CH2:17][CH2:16][C:8]2[C:7](=[CH:12][C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=2)[CH2:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)OCCc1ccc([N+](=O)[O-])cc1COS(C)(=O)=O
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
A solution of [2-[2-[(methylsulfonyl)oxy]ethyl]-5-nitrophenyl]methyl methanesulfonate (Step 1, 1.75 g, 4.95 mmol) in CH2Cl2 (25 mL) under N2 is treated with benzylamine (2.70 mL, 24.75 mmol), and the resulting mixture is stirred at ambient temperature for 24 hrs and then washed with water (20 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product is then chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with EtOAc/heptane (10/90), and those fractions with an Rf=0.32 by TLC (EtOAc/hexane, 25/75) are pooled and concentrated to give 1.33 g (100%) of the title compound as an orange solid, mp 85-86° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[O-:20][CH2:21][CH3:22].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([O:20][CH2:21][CH3:22])=[N:4][CH:5]=[C:6]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: CC[O-]
Reactant: CCN1CCN(S(=O)(=O)c2cnc(Cl)c(Br)c2)CC1
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1Br
Yield: 94.7 %

Procedure:
A mixture of 3-bromo-2-chloro-5-(4-ethylpiperazin-1-ylsulfonyl)pyridine (Preparation 9; 6.60 g, 17.9 mmol) and sodium ethoxide (6.09 g, 89.55 mmol) in ethanol (100 mL) was heated under reflux for 18 hours, then cooled. The reaction mixture was concentrated under reduced pressure, the residue partitioned between water (100 mL) and ethyl acetate (100 mL), and the layers separated. The aqueous phase was extracted with ethyl acetate (2×100 mL), the combined organic solutions dried (MgSO4) and evaporated under reduced pressure to afford the title compound as a brown solid (6.41 g, 95%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C@H:13]([CH:17]([CH3:19])[CH3:18])[C:14](O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>CCOCC>[C:7]1([C@H:13]([CH:17]([CH3:19])[CH3:18])[CH2:14][OH:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)[C@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)[C@H](CO)c1ccccc1
Yield: 105.3 %

Procedure:
A suspension of 19.5, g (0.51 mol) of lithium aluminium hydride in 750 ml of absolute ether was heated to reflux. Within 4 hours there was added, dropwise, a solution of 54.5 g (0.307 mol) of (S)-(+)-2-phenyl 3-methylbutyric acid in 250 ml of absolute ether. After heating to reflux for a further 2 hours, the suspension was treated carefully with 1N hydrochloric acid and the ether phase was washed with water, dilute sodium bicarbonate solution, and once more with water. After drying the organic phase over sodium sulfate and evaporation under reduced pressure, there were obtained 53.1 g of (S)-(+)-2-phenyl-3-methylbutanol as a thick oil which was used directly in the next step.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16](Cl)=[O:17])=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>CO.O>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][OH:17])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2c1CCCc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: OCc1cccc2c1CCCc1ccccc1-2

Procedure:
The reaction of 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carbonyl chloride (3.5 grams, 0.014 mole), lithium aluminum hydride (0.6 grams, 0.016 mole), and diethyl ether (100 ml) gave a yellow oil. The oil was dissolved in methanol/water, and the solution was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-methanol as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:27])=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2s1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)NCC(=O)O)ccc2s1
Yield: 70.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-5-carboxylic acid (310 mg, 0.686 mmol), DMAP (167 mg, 1.37 mmol), EDC (197 mg, 1.03 mmol), and glycine methyl ester hydrochloride (172 mg, 1.37 mmol) are reacted and hydrolyzed in a sequence analogous to Example 5 to afford the title compound (246 mg, 70%).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:28])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH3:20]/[C:21](/[CH2:28][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:11][CH:10]=1)=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C=C(C)CBr
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C(/C)COc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4-(1-methylpropoxy)phenol (0.84 g, 5.06 mmol) and potassium carbonate (0.66 g, 0.48 mmol) in 10 ml of dimethylformamide (DMF) at 5° is added ethyl 4-bromo-3-methyl-2-butenoate (1.0 g, 0.48 mmol). The mixture is allowed to warm to RT and is stirred at RT for 20 hours. The reaction mixture is poured into water and extracted with ether. The organic layer is washed with 10% sodium hydroxide to remove any starting phenol, dried and the solvent removed. The product is purified by preparative thin layer chromatography (prep. TLC). The second main band is collected to give ethyl (Z)-3-methyl-4-[4-(1-methylpropoxy)phenoxyl]-2-butenoate, MS m/e 292 (M+).
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]OC(C1CCCC1)=O>CCOCC>[CH3:16][O:14][C:13]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:15]
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Reactant: COC(=O)C1CCCC1
Solvent: CCOCC
Product: COC(=O)C1(c2ccccc2)CCCCC1

Procedure:
This compound was prepared (1.91 g, 8.76 mmol, 89%) from the product of Step A (2.00 g, 9.8 mmol) following the procedure for synthesis of methyl-1-cyclopentanecarboxylate as set forth in Step A, Example 1. The product of this step was homogeneous by TLC (ether:C2Cl2, 2:1) and used in the next step without further purification. CIMS 219 m/z (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.58 g, 10.00 mmol, 1.00 equiv), pyrrolidine (710 mg, 10.00 mmol, 1.00 equiv) and potassium carbonate (2.76 g, 20.00 mmol, 2.00 equiv) in CH3CN (20 mL) was stirred at 60° C. in an oil bath. After 2 h, the reaction mixture was allowed to reach ambient temperature. The solids were filtered off and the filtrate was concentrated under reduced pressure. The residue was triturated with 1×20 mL of petroleum ether to yield 1.8 g (93%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
A solution of 60.0 g of 2-phenylcyclohexanone in 400 ml of ethanol is stirred and treated with 160 ml of 15% aqueous sodium hydroxide and 53.0 g of benzaldehyde. The solution is stirred at room temperature and the product begins to separate from the solution as an oil after 30 minutes. The mixture is seeded with crystalline material and allowed to stand for about 16 hours at room temperature. The resulting slurry is poured onto 1.5 l. of ice-water, allowed to stand at room temperature for 2 hours, filtered and washed with cold water to yield 81.2 g of material, melting point 75°-78° C. After crystallization from 200 ml of isopropanol, the product weighs 62.1 g, melting point 85°-87° C. A small sample, recrystallized from ethanol, melts at 86°-88° C.
Reaction SMILES: C1[C@H]2CN[C@H](CO)CN2CCO1.C1[C@@H]2CN[C@H](CO)CN2CCO1.CCN(CC)CC.[CH3:32][C:33]([Si:36]([CH3:50])([CH3:49])[O:37][CH2:38][C@@H:39]1[CH2:48][N:47]2[C@H:42]([CH2:43][O:44][CH2:45][CH2:46]2)[CH2:41][NH:40]1)([CH3:35])[CH3:34]>ClCCl>[CH3:35][C:33]([Si:36]([CH3:50])([CH3:49])[O:37][CH2:38][C@@H:39]1[CH2:48][N:47]2[C@@H:42]([CH2:43][O:44][CH2:45][CH2:46]2)[CH2:41][NH:40]1)([CH3:32])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Agent: OC[C@@H]1CN2CCOC[C@@H]2CN1
Agent: OC[C@@H]1CN2CCOC[C@H]2CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@H]2CN1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(7S, 9aR)-octahydropyrazino[2,1-c][1,4]oxazin-7-ylmethanol and (7S, 9aS) -octahydropyrazino[2,1-c][1,4]oxazin-7-ylmethanol (D21) (315 mg,1.83 mmol) was dissolved in 10 mL of anhydrous dichloromethane and treated with Et3N (600 μL, 4.30 mmol) and TDBMSCI (590 mg, 3.91 mmol). The reaction was stirred overnight at room temperature (17 h). It was diluted with dichloromethane (30 mL) and extracted with sat. NaHCO3 (2×20 mL). TLC analysis (EtOAc: MeOH 95:5) showed 2 main products. The organics were dried and the solvent removed leaving an oil, which was purified by flash chromatography (silica, EtOAc→EtOAc:MeOH 90:10). Isolated two products: (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D22), 253 mg. Direct MS: m/z=287 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:10]C(=O)OC(C)(C)C)[C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1.[ClH:18].O1CCOCC1>CO>[ClH:18].[NH2:10][C@H:3]([C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1)[CH2:2][OH:1]
Reactant: Cn1nnc([C@H](CO)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1nnc([C@@H](N)CO)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 106 mg of tert-butyl [(1R)-2-hydroxy-1-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate in 3 ml of methanol was added to 1.5 ml of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 78 mg of (2R)-2-amino-2-(2-methyl-2H-tetrazol-5-yl)ethanol hydrochloride.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f18) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)c1ccc(=O)[nH]c1C
Product: CCC(=O)c1ccc(=O)[nH]c1C=CN(C)C

Procedure:
The process according to claim 9 which comprises reacting 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone with dimethylformamide dimethyl acetal to produce 6-(2-dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone.
Reaction SMILES: [ClH:1].Cl.[N+](OC[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:41])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:40])[C@H:19]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[NH:20][C@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-])=O.Cl.[N+:43]([O:46]CCCOC(=O)[C@@H]1CCCN1)([O-:45])=[O:44]>>[ClH:1].[ClH:1].[N+:43]([O:46][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:41])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:40])[C@H:19]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[NH:20][C@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-:45])=[O:44]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)OCCCCO[N+](=O)[O-]
Reactant: O=C(OCCCO[N+](=O)[O-])[C@@H]1CCCN1
Agent: Cl
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)OCCCO[N+](=O)[O-]

Procedure:
Starting from N2-[(1S)-ethoxycarbonyl-3-phenylpropyl]-N6-BOC-L-lysine (obtained as described in Example 6) and L-proline 3-nitrooxypropyl ester hydrochloride (obtained as described in Example 3) applying the same procedure described in Example 6) the title compound was obtained as a highly hygroscopic white powder (0.85 g, 28%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:23]1([NH:26][C:27]([C:29]2[S:42][C:32]3=[N:33][C:34](S(C)=O)=[C:35]([Cl:38])[C:36]([CH3:37])=[C:31]3[C:30]=2[NH2:43])=[O:28])[CH2:25][CH2:24]1>C1COCC1>[CH:23]1([NH:26][C:27]([C:29]2[S:42][C:32]3=[N:33][C:34]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]4[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)=[C:35]([Cl:38])[C:36]([CH3:37])=[C:31]3[C:30]=2[NH2:43])=[O:28])[CH2:25][CH2:24]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCOCCN1CCNCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCOCCN2CCNCC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
To a solution of 1-[2-(2-hydroxyethoxy)ethyl]piperazine (1.061 g, 6.09 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl) amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate forms. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.078 g, 17%). Mass (m/z): 454.2 (M++1), 452.2 (M+−1).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.CS([Cl:35])(=O)=O>ClCCl.N1C=CC=CC=1>[Cl:35][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3ccccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(Cl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.57 g) is dissolved in dichloromethane (30 ml) and pyridine (1.1 ml), and thereto is added dropwise methanesulfonyl chloride (0.9 ml) in small portions at 0° C. Then, the mixture is stirred at room temperature for 3 days. The solvent is distilled off and the resulting residue is poured into ice-water. The precipitated crystal is collected by filtration, washed with water, and dried to give 5-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.10 g) as light yellow powder.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:20]1([C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=C(\NC(=O)C3C=CC(OCCC4C=CC(OC)=CC=4)=CC=3)/C(NCCO)=O)=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O.CCCCCC>[CH:20]1([C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[C:14]3\[N:13]=[C:11]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:19][CH:18]=4)[O:17][C:15]\3=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: COc1ccc(CCOc2ccc(C(=O)N/C(=C\c3ccc(C4CC4)cc3)C(=O)NCCO)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: O=C1OC(c2ccc(OCCC3CC3)cc2)=N/C1=C\c1ccc(C2CC2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A mixture of N-[4-(2-cyclopropylethoxy)benzoyl]glycine (184 mg, 0.699 mmol) prepared in Example 9 (9b), 4-cyclopropylbenzaldehyde (113 mg, 0.769 mmol) prepared in Example 5, sodium acetate (75 mg, 0.909 mmol), and acetic anhydride (660 μL, 6.99 mmol) was stirred at 120° C. for 30 minutes and was then allowed to cool to room temperature. Hexane (2 mL) and water (4 mL) were added to the resulting solidified product which was washed by ultrasonic vibration. The precipitate was collected by filtration, washed with water and hexane, and dried by heating under reduced pressure to give 196 mg of the title compound (white powder, yield: 74%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:10])[N:6]([CH3:9])[C:7]=1[CH3:8])=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1c(C=O)c(C)n(C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1c(CO)c(C)n(C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 10.9 g of ethyl 4-formyl-1,2,5-trimethylpyrrole-3-carboxylate in 40 ml of methanol is added dropwise under nitrogen 5.6 g of sodium borohydride in methanol while maintaining the reaction temperature below 50° C. After total addition the reaction mixture is stirred at ambient temperature for 4 hours, then 90 ml of water introduced and the reaction mixture saturated with potassium carbonate and extracted with ether. The combined ether extracts are dried and concentrated in vacuo leaving a yellow solid which is recrystallized from cyclohexane to give ethyl 4-(hydroxymethyl)-1,2,5-trimethylpyrrole-3-carboxylate, mp 184°-186° C.