Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[C:12]([NH:16][C:17]([CH:19]1[CH2:21][C:20]1([CH3:23])[CH3:22])=[O:18])[C:13]([OH:15])=[O:14]>O>[CH3:22][C:20]1([CH3:23])[CH2:21][CH:19]1[C:17]([NH:16]/[C:12](=[CH:11]\[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:3][C:2]([NH2:4])=[NH:1])/[C:13]([OH:15])=[O:14])=[O:18]
Reactant: CC1(C)CC1C(=O)NC(=CCCCCCBr)C(=O)O
Reactant: N=C(N)N
Solvent: O
Product: CC1(C)CC1C(=O)N/C(=C\CCCCCNC(=N)N)C(=O)O
Temperature: 70 °C
Yield: 34.5 %

Procedure:
To a solution of 2 mmoles of guanidine (prepared from 432 mg of guanidine sulfate and 630 mg of barium hydroxide octahydrate) in 7 ml of water was added 332 mg (1 mmole) of 8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)octenoic acid, and the solution was heated at 70° C. in a nitrogen atmosphere for 1 hr. The reaction mixture was applied to a 2×25 cm column of Dowex 50W-X8 (H +, 100-200 mesh). After elution with water the fractions containing the product were pooled and evaporated under reduced pressure. The residue was dissolved in several ml of warm ethanol and added dropwise to 100 ml of ether with rapid stirring. Filtration and washing with ether gave 107 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-guanidino-2-octenoic acid as an amorphous electrostatic powder. Homogeneous by TLC (n-BuOH, HOAc, H2O; 4:1:1). NMR (D2O, NaOD): ##STR9##
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:19]([OH:21])=O)[N:8]=[C:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:4][CH:3]=1.[CH2:22]([N:24](CC)[CH2:25][CH3:26])[CH3:23].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:22]([N:24]([CH2:25][CH3:26])[C:19]([C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)=[O:21])[CH3:23]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccc(Cl)cc2c(-c2ccccc2Cl)n1
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc2ccc(Cl)cc2c(-c2ccccc2Cl)n1
Yield: 59 %

Procedure:
Operations are carried out as for Example 7, starting from 3.18 g of 7-chloro 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.16 g of triethylamine, 1.25 g of ethyl chloroformate and 0.95 g of diethylamine in 100 ml of chloroform. 2.2 g of N,N-diethyl 7-chloro 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 145° C., are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=O)[CH2:8][O:9][N:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2].Cl.[O:30]([NH2:32])[CH3:31].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][C:7](=[N:32][O:30][CH3:31])[CH2:8][O:9][N:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(=O)CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CC(CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1)=NOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
3.85 g of the 4,4'-dimethoxybenzophenone O-(3-ethoxycarbonyl-2- oxopropyl)oxime as obtained in Example 1 was dissolved in 5 ml of pyridine and 1 g of methoxylamine hydrochloride was added thereto. Then the obtained mixture was stirred at room temperature. After two hours, the reaction mixture was poured into ethyl acetate, washed with diluted hydrochloric acid and then with a saturated saline solution and purified by silica gel chromatography. Thus 4 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(#N)C.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:4][C:3]5[C:28](=[CH:29][CH:30]=[CH:20][CH:2]=5)[CH2:27]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and αα'-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>C1COCC1>[CH2:3]([O:10][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([Cl:11])[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cncc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a cooled mixture of sodium hydride (60%, 300 mg, 7.5 mmol) in THF (20 mL) at 0° C. was added dropwise benzyl alcohol (0.75 mL, 7.24 mmol). After 30 minutes, 2,6-dichloropyrazine (999 mg, 6.71 mmol) was added and mixture was warmed to room temperature and stirred overnight. After quenching with sat. NH4Cl(aq), mixture was extracted with ethyl acetate and combined organics were washed with water then brine. Organics were dried, filtered, and concentrated under reduce pressure to yield 2-(benzyloxy)-6-chloropyrazine 5.33 (1.45 g), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].[CH3:32][C:33]1[C:37]([NH2:38])=[CH:36][NH:35][N:34]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:38][C:37]2[C:33]([CH3:32])=[N:34][NH:35][CH:36]=2)=[O:20])[CH:8]=1)=[O:5]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: Cc1n[nH]cc1N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]cc1NC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 210 mg, 0.46 mmol), 3-methyl-1H-pyrazol-4-amine (68 mg, 0.69 mmol) and DIPEA (0.32 mL, 1.85 mmol) in anhydrous DMF (4 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (264 mg, 0.69 mmol). The reaction was stirred at room temperature for 1 hour under nitrogen. The reaction was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was collected, washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by elution through an SCX-2 column using MeOH followed by 7N ammonia in MeOH, followed by purification using silica gel column chromatography eluting with EtOAc followed by 10% MeOH in DCM to afford the title compound (170 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]=[CH:8][C:7]=2[CH:12]=1.[N+](=[C:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[N-]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C@@H:9]3[C:15]([C:20]([O:22][CH3:23])=[O:21])([C:16]([O:18][CH3:19])=[O:17])[C@@H:8]3[C:7]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C=CCO2
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C1(C(=O)OC)[C@@H]2c3cc(OC)ccc3OC[C@@H]21
Reaction time: 1.5 h

Procedure:
To stirred solution of 79 g of 6-methoxy-2H-[1]benzopyran (J. Org. Chem. 1973, 38, 3832) and 17.6 g of cuprous iodide-trimethyl phosphite (Synthesis 1971, 658) in 400 ml toluene, is added at 103° 125 g dimethyl diazomalonate (Synthesis 1971, 658) over a period of 30 min. After stirring 1.5 h, the reaction mixture is cooled, filtered through Celite, concentrated under reduced pressure and flash chromatographed with ethyl acetate/hexane (3:7) to give cis-(±)-dimethyl 1,1a,2,7b-tetrahydro-6-methoxybenzo[b]cyclopropa[d]pyran-1,1-dicarboxylate.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[C-:13]#[N:14].[Na+].CS(C)=O>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:6][C:13]#[N:14])[CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cccc(C(F)(F)F)c1
Yield: 107.1 %

Procedure:
A mixture of 12.0 g (61.5 mmole) m-trifluoromethylbenzyl chloride, 9.56 g (195 mmole) sodium cyanide and 60 ml dimethylsulfoxide was heated at 50° to 80° C. for four hours and poured into water. The aqueous mixture was extracted with methylene chloride, the extracts dried over sodium sulfate and the solvent evaporated in vacuo to give 12.2 g of yellow oil which was used in the next step. 1H-NMR(CDCl3)ppm(delta): 3.80 (s, 2H), 7.60 (s, 4H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10]([OH:12])=O)=O)(C)(C)C.[ClH:20].[CH3:21][NH:22][CH3:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[ClH:20].[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10]([N:22]([CH3:23])[CH3:21])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H](N)Cc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-pyridin-3-ylpropionic acid (500 mg, 1.88 mmol) in DMF (10 mL) was added dimethylamine hydrochloride (153 mg, 1.88 mmol), DIPEA (1.2 mL, 6.57 mmol) and TBTU (602 mg, 1.88 mol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue dissolved in methanol (20 mL). To this was added 4M hydrochloric acid in dioxane (20 mL) and the reaction was stirred for 16 h at rt. The solvent was removed in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (2×100 mL). The aqueous layer was evaporated to dryness and the residue recrystallised from ethanol/ethoxyethanol (9:1), to give the title compound as a white solid. δH (CD3OD): 2.99 (3H, s), 3.06 (3H, s), 3.35-3.42 (1H, m), 3.45-3.53 (1H, m), 4.87-4.94 (1H, m), 8.04-8.10 (1H, m), 8.48-8.53 (1H, m), 8.84-8.90 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>ClCCl.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(N)ccc21

Procedure:
To a solution of 2-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (79.0 g, 0.339 mol) in dichloromethane as added 1 g of 10% palladium on carbon and the mixture was hydrogenated at 40–50 psi of hydrogen for 20 hrs. The catalyst was removed by filtration and the organic and the aqueous layers were separated. The aqueous layer was made alkaline by addition of 1N NaOH and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated to give 2-amino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene as a red-orange solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([C@@H:14]([OH:28])[CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.N1C(=O)CC[C@H]1C(O)=O>CS(C)=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:28])[CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[O:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc2nccc(C[C@H](O)[C@@H]3CC[C@@H](NC(=O)OC(C)(C)C)CO3)c2n1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc2nccc(CC(=O)[C@@H]3CC[C@@H](NC(=O)OC(C)(C)C)CO3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of {(3R,6S)-6-[(1S)-1-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester (prepared as described in WO 2006/032466, 0.78 g, 1.73 mmol) cooled to −10° C. was added dropwise DIPEA (1.03 mL, 5.90 mmol). A solution of Pyr.SO3 (0.684 g, 48%, 1.1 eq.) in DMSO (2 mL) was added dropwise. The reaction mixture was stirred for 1 h 45 at 0° C. The volatiles were removed under reduced pressure and water (20 mL) was added. The resulting precipitate was filtered and further dried under HV to give a yellow solid (0.518 g, 66% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[ClH:13].[Br:14][C:15]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:16]=1[NH2:17]>ClC1C=CC=CC=1>[ClH:13].[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([NH:17][C:16]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:15]=2[Br:14])=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(N(C)C#N)c1
Reactant: Nc1cc(Br)ccc1Br
Agent: Cl
Solvent: Clc1ccccc1
Product: CCc1cccc(N(C)C(=N)Nc2cc(Br)ccc2Br)c1

Procedure:
A mixture of N-(3-ethylphenyl)-N-methylcyanamide (520 mg, 3.3 mmol), 2,5-dibromoaniline hydrochloride (861 mg, 3 mmol), and chlorobenzene (2 mL) were combined in a dry round bottom flask equipped with water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 3 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine hydrochloride, as a white solid (780 mg, 59% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:18][C:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OC(=Cc1ccncc1)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 152.9 %

Procedure:
To a suspension of NaH (0.81 g, 18.6 mmol) in DMF (30 mL) under argon atmosphere and cooled to 0° C., a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (2.00 g, 9.3 mmol, obtained in reference example 1) in DMF (15 mL) was added and stirred to room temperature for 30 minutes. It was then cooled to 0° C. and a solution of 4-fluorobenzoyl chloride (2.95 g, 1.9 mmol) in DMF (10 mL) was added. It was stirred at room temperature overnight. Water was added and the solvent was evaporated off. The residue was dissolved in a mixture of CHCl3 and water and the phases were separated. The aqueous phase was extracted with CHCl3 (×3). The organic phase was washed with water (×2), dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.98 g of the desired compound as a yellow solid (yield: 31%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28]([OH:30])=O)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][O:33][NH:34][CH3:35].N=C=N.C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1>ClCCCl>[CH3:32][O:33][N:34]([CH3:35])[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([S:15](=[O:17])(=[O:16])[NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)=[CH:19][CH:20]=1)=[O:30]
Reactant: O=C(O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Reactant: CNOC
Agent: Cl
Agent: N=C=N
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CON(C)C(=O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid 34 (212 mg, 0.5 mmol) in DCE (5 mL), was added O,N-dimethyl-hydroxylamine hydrochloride (59 ul, 0.6 mmol), PS-carbodiimide (1.9 g, 2.5 mmol), triethyl amine (140 uL, 1 mmol) and HOAt (102 mg, 0.75 mmol). After stirring at 50° C. overnight, the resultant solution was filtered and concentrated in vacuo to give the crude product 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid methoxy-methyl-amide 35. LCMS showed m/z: 468 (M+H)+. This material was used without further purification.
Reaction SMILES: [C:1]([O:4][CH:5]([C@@H:7]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:10]2[NH:11][C:12](=O)[O:13][C@H:9]2[CH2:8]1)[CH3:6])(=[O:3])[CH3:2].F[B-](F)(F)F.C[O+](C)C.[CH3:42][NH:43][CH3:44]>C(Cl)Cl>[C:1]([O:4][CH:5]([C@@H:7]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:10]2[N:11]=[C:12]([N:43]([CH3:44])[CH3:42])[O:13][C@H:9]2[CH2:8]1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)OC(C)[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC(=O)OC(C)[C@H]1C[C@@H]2OC(N(C)C)=N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 5 (0.90 g, 2.0 mmol), trimethyloxonium tetrafluoroborate (1.5 g, 10 mmol) and 4 Å Molecular sieves (0.5 g) in DCM (5 mL) was stirred overnight at room temperature, followed by addition of dimethylamine (20 mL, 1 M in THF, 20 mmol). The reaction mixture was stirred for 12 h at room temperature, then quenched with saturated aqueous NaHCO3 (20 mL), extracted with DCM (4×50 mL). The organic layer was washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give crude product 6, which was used in the next step directly. (ES, m/z): [M+H]+ 467.1.
Reaction SMILES: [C:1]([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([C:13]#[N:14])[C:7]=2[CH:6]=[CH:5]1)(=[O:3])[CH3:2].CCN(CC)CC.[C:22](OC(=O)C)(=[O:24])[CH3:23]>[Pd].CCOC(C)=O>[C:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:22](=[O:24])[CH3:23])=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1ccc2c(C#N)ccnc21
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccnc2c1CCN2C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.691 g, example 15, step D), 10% Pd/C (0.702 g), 5 mL of Et3N, and 20 mL of EtOAc was added acetic anhydride (1.0 mL). The mixture was stirred at RT under balloon pressure of H2 for overnight. Solid was removed by filtration through a pad of Celite® and the filtrate was concentrated to yield a white residue, which was purified by chromatography through silica gel (150 g, 1 to 5% MeOH/CHCl3 with 1% NH4OH, stepwise gradient) to afford N-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide (0.50 g) as white solid.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[OH:10])(C)(C)C.Cl[CH2:20]Cl>FC(F)(F)C(O)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]2[O:10][CH2:20][CH2:6][NH:7][CH2:8]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(F)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A solution of [2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (90 mg) in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous potassium carbonate (5 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and redissolved in dry tetrahydrofuran (3 mL) and triethylamine (54 μL). Chloroacetyl chloride (31 μL) in dry tetrahydrofuran (1 mL) was added dropwise at 0° C. After 30 minutes the reaction was diluted with ethyl acetate (10 mL) and washed with water/brine (1:1.3×10 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and redissolved in tert-butanol (5 mL). Potassium tert-butoxide (79 mg) was added and the reaction stirred at 25° C. for 1.5 hour. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and co-evaporated with toluene (2×5 mL). The residue was dissolved in dry toluene (5 mL) under argon and treated with sodium bis(2-methoxyethoxy)aluminium hydride (70% in toluene, 205 μL) dropwise and stirred at 25° C. for 5 hours. The reaction was quenched at 0° C. with 10% aqueous sodium hydroxide (5 mL), and the mixture was extracted with diethyl ether (2×15 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to furnish 60 mg (94%) of the title compound as a colorless oil. LC-MS (m/z) 182 (MH+); tR=1.06, (UV, ELSD) 78%, 98%.
Reaction SMILES: [CH:1]1([CH:4]([OH:7])[CH:5]=[CH2:6])[CH2:3][CH2:2]1.N#N.CCN(CC)CC.[Si:17](OS(C(F)(F)F)(=O)=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:7][C@@H:4]([CH:1]1[CH2:3][CH2:2]1)[CH:5]=[CH2:6])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CC(O)C1CC1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C[C@@H](O[Si](C)(C)C(C)(C)C)C1CC1
Reaction time: 1 h
Yield: 76.9 %

Procedure:
R)-3-Cyclopropyl-3-hydroxy-1-propene (150 mg, 1.53 mmole) was dissolved in anhydrous CH2Cl2 (5 ml) and the mixture was stirred at 0° C./N2. Then Et3N (248 mg, 341 μL, 2.45 mmole) and t-butyl(dimethyl)silyl-trifluoromethane-sulfonate (525 mg, 456 mL, 1.99 mmol) were added. After 1 h 10% aq. KHCO3 (5 mL) was added and the mixture was stirred at room temp. for 1 h. CH2Cl2 (5 mL) was added, the phases were separated, the organic phase was washed with 10% aq. KHCO3 solution (3×8 mL). The combined organic phases were dried over anhydrous K2CO3, filtered and concentrated in vacuo. The crude product was purified on the column with silica gel (230-400 mesh, 10 g, hexane). After drying the product under vacuum (0° C., 10 mm Hg), (3R)-3-t-butyl(dimethyl)silyloxy-3-cyclopropyl-1-propene as a colourless oil (250 mg, 77%) was obtained; C12H24OSi; E1 MS m/z 212 (M+, 3%); [α]D=+8.0° (20° C., c=1, CHCl3); 1H-NMR (200 MHz, CDCl3) δ 5.89 (1H, ddd: 16.9, 10.4, 5.6 Hz), 5.16 (1H, ddd: 17.2,2.0, 1.2 Hz), 5.02 (1H, ddd: 10.4, 1.8, 1.2 Hz), 3.65 (1H, bt: 6.3 Hz), 0.90 (9H, s), 0.89 (1H, m), 0.43 (2H, m), 0.30 (1H, m), 0.26 (1H, m), 0.05 (3H, s), 0.03 (3H, s) ppm.