Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[NH:4][CH:5]([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1.O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[N:4]([CH:5]([CH3:7])[CH3:6])[C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)Nc1cc(F)ccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)N(C(=O)C1CC1)c1cc(F)ccc1Br
Temperature: 20 °C
Reaction time: 24 h

Procedure:
2-Bromo-5-fluoro-N-(propan-2-yl)aniline E-1.7′″″ (2.20 g; 9.48 mmol) is suspended in 5 ml DCM and DIPEA (8.2 ml; 47.40 mmol) is added. Afterwards cyclopropanecarbonyl chloride (3.44 ml; 75.84 mmol) is added and the reaction mixture is stirred for 24 h at 20° C. The reaction mixture is poured into water and extracted with DCM. The combined organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.[CH2:17](Br)[CH:18]=[CH2:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:19]([N:8]1[CH:7]2[C:16]3=[C:3]([O:2][N:1]=[C:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=3)[CH2:4][CH2:5][CH2:6]2)[CH:18]=[CH2:17]
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1c2ccccc2-c2noc3c2C1CCC3
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In 20 ml dry dimethylformaldehyde (DMF) were combined 4.00 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 3.26 ml allyl bromide and 8 g milled K2CO3. The mixture was heated at 90° C. and mechanically stirred. Every hour 2 ml more allyl bromide was added. After 3 hours, the reaction was complete as observed by TLC. The mixture was partitioned between water and EtOAc. The EtOAc layer was concentrated to a solid which was purified by passing over a silica column (flash chromatography). The product obtained in this manner was recrystallized twice from 20% EtOAc/hexanes to yield 2.99 g solid which was dried in vacuo, m.p. 114°-117° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[Na].[C:11]([O:15][CH2:16][CH:17]([OH:30])[CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+]>COCCO.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:18][CH:17]([OH:30])[CH2:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)COC(C)(C)C)cc1
Reactant: N#Cc1ccccc1O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: CC(C)(C)OCC(O)COc1ccccc1C#N
Reaction time: 0.08 h

Procedure:
o-Cyanophenol (5.95 g.) is added to a solution of sodium (1.15 g.) in 2-methoxyethanol (20 ml.), the mixture is stirred for 5 minutes, and a solution of 3-t-butoxy-1-toluene-p-sulphonyloxypropan-2-ol (15.1 g.) in 2-methoxyethanol (30 ml.) is added. The mixture is heated under reflux for 90 minutes, cooled and poured into a mixture of ice and water (150 ml.), and the mixture is basified with aqueous 2 N-sodium hydroxide solution and extracted twice with chloroform (100 ml. each time). The combined extracts are washed with water, dried and evaporated to dryness and the residue is chromatographed on a slica gel column using chloroform as eluant. The appropriate fractions of the eluate are evaporated to dryness and there is thus obtained as oily residue 1-o-cyanophenoxy-3-t-butoxypropan-2-ol, the structure of which is confirmed by proton magnetic resonance spectroscopy.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:19]
Reactant: CCI
Reactant: O=Cc1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(O)cccc1C=O
Yield: 54.9 %

Procedure:
2,3-Dihydroxybenzaldehyde (1.12 g, 8.11 mmol), potassium carbonate (1.12 g, 8.11 mmol) and iodoethane (0.65 mL, 1.26 g. 8.11 mmol) in dry DMF (10 mL) were stirred at ambient temperature for 21 h. The reaction mixture was poured into water and extracted with diethyl ether. The ether layer was washed with water (2×), and extracted with 1N sodium hydroxide solution (3×). The basic extracts were combined and acidified by addition of 3N hydrochloric acid, then extracted with diethyl ether. The ether layer was washed with water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-ethoxy-3-hydroxybenzaldehyde (0.74 g, 55%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)CCc4ccccc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-propionamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.96 mmol) and 3-phenyl-propionic acid chloride (157 μl, 1.06 mmol). The title compound was obtained as yellow powder (201 mg, 47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.ClC[CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(Cl)[Cl:21]>N1C=CC=CC=1>[Cl:21][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:9])=[O:18]
Reactant: O=C(Cl)CCCCCCl
Reactant: ClCCl
Reactant: CC(N)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CC(NC(=O)CCCCCl)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluorophenyl)ethanamine 15b (5.0 g, 35.9 mmol) in a mixture of 10 mL of DCM and 14.5 mL of pyridine, with ice cooling, was added dropwise a solution of 6-chlorohexanoyl chloride 15a in 20 mL of DCM. After the addition was compete, cooling was removed and the resulting precipitate was stirred overnight. The reaction mixture was diluted with 100 mL of ther and washed with 100 mL of 1M HCl. The organic phase was dried over MgSO4 and concentrated to furnish 9.2 g of crude 5-chloro-N-(1-(4-fluorophenyl)ethyl)pentanamide 15c which was used in the next step without purification.
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9](=O)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)CCC>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=c1nc(C2CCCCC2)c2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(O)c1ccc(Nc2nc(C3CCCCC3)c3ccccc3n2)cc1
Temperature: 140 °C
Yield: 48.4 %

Procedure:
A mixture of 4-cyclohexylquinazolin-2(1H)-one (500 mg, 2.2 mmol) and phosphorous oxychloride (10 mL, 111 mmol) was heated to reflux for 1 h. The volatiles were removed under reduced pressure, and then the residue was treated with ice water and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride and dried over sodium sulfate. The solvent was removed on a rotary evaporator, and to this residue was added 4-aminobenzoic acid (300 mg, 2.2 mmol), triethylamine (435 μL, 3.0 mmol) and n-butanol (5 mL). This mixture was heated to 140° C. for 25 min. The mixture was cooled to rt and triturated with ether. The residual solid was collected via vacuum filtration, washed with ether and dried to afford 4-(4-cyclohexylquinazolin-2-ylamino)benzoic acid (370 mg, 48%) as an off white solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.ClC1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][CH3:24])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+].[O:34]1CCC[CH2:35]1>>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:1]([Cl:4])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([CH3:24])[C:35]1=[O:34]
Reactant: O=C(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1c(Cl)cccc1Cl
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1c(Cl)cccc1Cl)C2
Reaction time: 1 h
Yield: 89 %

Procedure:
A stirred solution, cooled in ice, of 12 ml of phosgene (20% solution in toluene; 23 mmol) in 100 ml of tetrahydrofuran was treated dropwise with a solution of 5 g (15.2 mmol) of 5-(2,6-dichlorophenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 4 ml (29 mmol) of triethylamine in 80 ml of tetrahydrofuran. After stirring for 1 hour the mixture was treated with 100 ml of saturated aqueous ammonium chloride solution and the phases were separated. The aqueous phase was extracted with 100 ml of tetrahydrofuran and the combined organic solutions were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 4.8 g (89%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(NCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(NCc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
To a solution of 4-(benzylamino)phenol (200 mg, 1 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (48 mg, 1.2 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (356 mg, 1 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (169 mg, 44%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][C:12](=O)[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].N1(CC([O-])=O)CCCCC1>C(O)C.O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH3:13])[NH:20][C:18](=[O:19])[C:17]=1[C:15]#[N:16])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C#CCO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])CN1CCCCC1
Solvent: O
Solvent: CCO
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(=O)[nH]1
Yield: 32.4 %

Procedure:
To a stirred solution of compound 5-((tert-butyldimethylsilyl)oxy)pent-3-yn-2-one (13.0 g, 61.0 mmol) and cyanoacetamide (6.2 g, 73.2 mmol) in a mixture of ethanol and water (9:1) (270 mL) at room temperature was added piperidineacetate (catalytic) and the reaction mixture was heated to reflux for 5 h. After removal of solvent water was added and the solid product was filtered. The solid product on washing with water followed by ether and hexane afforded the desired compound (5.5 g, 32%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][N:11](C(OCC2C=CC=CC=2)=O)[C:12]([NH:14]C(OCC2C=CC=CC=2)=O)=[NH:13])[CH2:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[NH:13])[CH2:6][CH2:7]1
Reactant: CN1CCC(CCCN(C(=N)NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(CCCNC(=N)N)CC1
Temperature: 50 °C

Procedure:
To a 1-L round bottom flask were added N-[3-(1-methyl-piperidin-4-yl)-propyl]-N,N′-di-cbz-guanidine (140.6 g, 0.301 moles) and ethanol (500 mL, 200 proof). The flask was equipped with a heating mantle and warmed to 50° C. Once a yellow homogeneous solution was obtained, the heating mantle was exchanged for an ice bath and the mixture cooled to an internal temperature of 10° C. The resultant cold mixture was transferred to a 2.25 liter Parr bottle equipped with a thermocouple probe, and 10% Pd on Carbon (10 wt. %) in one portion. The bottle was charged with H2(g) (60 psi). The Parr bottle was kept pressurized with hydrogen gas for 15 minutes, then evacuated, re-pressurized with H2(g) (60 psi) and allowed to shake for an additional hour. The catalyst was removed by filtration (Zap-Cap) and washed with ethanol (300 ml, 200 proof). The solvent was removed under pressure to yield the title compound.
Reaction SMILES: C([Li])CCC.Br.[CH2:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])[CH3:8].[CH2:18]([N:20]([C:29]#[N:30])[C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])[CH3:19].C1COCC1>CCCCCC>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[N:9]([CH2:7][CH3:8])[C:29]([N:20]([C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:18][CH3:19])=[NH:30]
Reactant: CCNc1c(C)cccc1C
Reactant: CCN(C#N)c1c(C)cccc1C
Agent: Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(C(=N)N(CC)c1c(C)cccc1C)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (20.5 mL, 1.6 M in hexane, 32.8 mmol) was added dropwise to a stirred suspension of N-ethyl-2,6-dimethylaniline hydrobromide (3.8 g, 16.5 mmol) in hexane (40 mL) at 0° C. The reaction mixture was stirred for 1 h at room temperature and cooled subsequently to −80° C. N-Ethyl-N-cyano-2,6-dimethylaniline (2.92 g, 16.8 mmol) was added drop wise at −80° C. after which the reaction mixture was allowed to slowly warm up to room temperature. The resulting reaction mixture was stirred for 2 h at room temperature, during which hexane (60 mL) and THF (20 mL) were added to form a homogeneous solution. The reaction mixture was quenched and washed with water (100 mL). The organic layer was separated, the aqueous layer was extracted with diethyl ether (100 mL) and the combined organic layers were dried with Na2SO4. Filtration and rotatory evaporation of the volatiles yielded the desired guanidine as a yellow waxy material. Yield: 5.3 g (99%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[S-:15][C:16]#[N:17].[NH4+].BrBr>CO>[C:1]([C:5]1[C:6]([S:15][C:16]#[N:17])=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])c(N)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)c1cc(N)c([N+](=O)[O-])cc1SC#N

Procedure:
The title compound was prepared according to the General Method 13 using 5-tert-butyl-2-nitro-phenylamine (prepared in Example PP-2; 170 g, 876 mmol), ammonium thiocyanate (400 g, 5260 mmol), bromine (140 g, 876 mmol), and MeOH (500 mL). The crude reaction mixture was purified by flash silica gel chromatography (5%-50% EtOAc in hexanes as eluents). MS(APCI): 252 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:22])[CH2:15][NH:16][S:17]([CH:20]=[CH2:21])(=[O:19])=[O:18])=[CH:10][CH:9]=1.[OH-:23].[NH4+].[CH3:25]O>N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:22])[CH2:15][NH:16][S:17]([CH2:20][CH2:21][O:23][CH3:25])(=[O:19])=[O:18])=[CH:10][CH:9]=1
Reactant: C=CS(=O)(=O)NCC(C)c1ccc(-c2ccccc2F)cc1
Reactant: CO
Reactant: [OH-]
Agent: N
Agent: [NH4+]
Product: COCCS(=O)(=O)NCC(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 5 h
Yield: 5 %

Procedure:
A solution of 0.5 g (1.6 mmol) of material from Example 8 in 5 mL of 2M ammonia in methyl alcohol was stirred at room temperature for 18 h. To the solution was added 2 mL of concentrated ammonium hydroxide and stirring was continued for 5 h. The mixture was concentrated in vacuo. Chromatography (25 g of silica gel, 50% ethyl acetate/hexane with 2% methyl alcohol) of the residue afforded 0.03 g (5%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([NH2:32])[N:23]=1.Cl.[OH-].[Na+]>O.CO.C(O)C>[NH2:32][C:24]1[N:23]=[C:22]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([CH2:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:25]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: N#Cc1c[nH]c2nccc(Cc3ccc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: N#Cc1c[nH]c2nccc(Cc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12

Procedure:
82 mg (0.31 mmol) of 4-(4-amino-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 67 mg (0.34 mmol) of 4-chloro-6-trifluoromethylpyrimidine-2-amine are suspended in 3 ml of water, 1.5 ml of ethanol and 0.15 ml of 4N hydrochloric acid. The reaction mixture is heated at reflux for 2 hours. After cooling, the mixture is made alkaline using dilute aqueous sodium hydroxide solution, a little methanol is added, the mixture is extracted with ethyl acetate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC. This gives crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:21]=[CH:20]C2C(=O)CCCS[C:12]=2[CH:11]=1.C[Mg]I>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:11]([CH3:12])[CH2:10][CH2:21][CH2:20][S:8][C:4]=2[CH:3]=1
Reactant: Sc1cccc(Br)c1
Reactant: O=C1CCCSc2cc(Br)ccc21
Agent: C[Mg]I
Solvent: CCOCC
Product: CC1CCCSc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, m-bromothiophenol was converted into 8-bromo-3,4-dihydro-1-benzothiepin-5(2H)-one. This ketone was methylated with MeMgI in ether and the resulting tertiary alcohol was deoxygenated as follows: 22.85 g were placed in 250 ml of hexane under argon and treated in succession with 75.1 g of sodium iodide (NaI), 26.4 ml of acetonitrile and 63.5 ml of Me3SiCl. The mixture was stirred at room temperature overnight, poured on to ice, extracted with ether, washed with bisulfite solution and water, dried and evaporated. Chromatography on silica gel with petroleum ether gave 18.1 g of 8-bromo-2,3,4,5-tetrahydro-5-methyl-1-benzothiepine as a pale yellow oil.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.O.[OH-].[Li+].CO>C1COCC1>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(-c2ccccc2)cc1

Procedure:
The title compound was synthesized from methyl 4-(biphenyl-4-ylmethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (118 mg, 0.36 mmol) and lithium hydroxide monohydrate (60 mg, 1.42 mmol in 5 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (15 mL) was used. The resulting product was purified by flash chromatography (Isco CombiFlash) eluting with a gradient of 0-70% EtOAc/Heptane to give the title compound: 60 mg, 53%. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.06-2.18 (m, 1H), 2.48-2.62 (m, 1H), 2.62-2.75 (m, 2H), 2.78-2.89 (m, 2H), 3.28-3.37 (m, 1H), 6.37 (d, J=1.76 Hz, 1H), 7.29-7.37 (m, 3H), 7.41-7.48 (m, 2H), 7.57-7.63 (m, 2H), 7.63-7.69 (m, 2H), 10.38 (s, 1H); LCMS-MS (ESI−) 316.2 (M−H); HPLC (UV=99.4%), (ELSD=100%).
Reaction SMILES: CN1CCOCC1.[Cl:8]C1N=C(OC)N=C(OC)N=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([OH:31])=O)=[CH:20]1.[CH3:32][N:33]([CH3:47])[C:34]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1>C1COCC1>[ClH:8].[CH3:32][N:33]([CH3:47])[C:34]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:39][CH2:38][CH:37]([NH:40][C:29](=[O:31])[CH2:28][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[CH2:36][CH2:35]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Reactant: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)Cc2c[nH]c3ccccc23)CC1
Product: Cl
Reaction time: 1 h

Procedure:
N-Methylmorpholine (235 μl, 2.1 mmol.) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (371 mg, 2.11 mmol.) were added to a solution of indol-3-ylacetic acid (257 mg) in abs. THF (10 ml). Stirring was then carried out for one hour at RT. The polar diastereomer of N,N-dimethyl-1-phenylcyclohexane-1,4-diamine (320 mg) was then added to the batch, and stirring was carried out for 12 hours at RT. For working up, the mixture was concentrated, the batch was adjusted to pH 11 with 5M NaOH, the phases were separated, and the aqueous phase was diluted with water (10 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried with Na2SO4 and concentrated. The amide obtained was purified by column chromatography with ethyl acetate/ethanol (1:1) and (120 mg) dissolved in 2-butanone (3 ml) and converted with chlorotrimethylsilane (61 μl) into the corresponding hydrochloride (white solid; 128 mg; 100-102° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[N+:10]([CH:13]([CH:16]=O)[CH:14]=[O:15])([O-:12])=[O:11]>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:16]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: COc1cccc(NC=C(C=O)[N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To the HCl salt of 3-methoxy-phenylamine (4.6 g, 289 mmol) in 1N HCl (300 mL) was added a solution of 2-nitro-malonaldehyde (2.7 g, 19.3 mmol) in 150 mL water. After 30 min, the precipitate was filtered and rinsed with 0.1 N HCl. Air-drying in a Büchner funnel for 18 h gave 3.36 g (78%) of a light yellow/green powder. LC/MS (m/z): 245.1 (MH++Na), Rt 2.21 minutes.