Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH2:4][C@H:5]([CH3:13])[CH2:6][CH2:7][C@@H:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1.[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH3:11][CH:10]([C@H:8]1[NH:9][C:3](=[NH:15])[CH2:4][C@H:5]([CH3:13])[CH2:6][CH2:7]1)[CH3:12]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1=N[C@H](C(C)C)CC[C@@H](C)C1
Solvent: CO
Product: CC(C)[C@@H]1CC[C@@H](C)CC(=N)N1
Product: Cl
Yield: 73.3 %

Procedure:
The product of EXAMPLE 135 (690 mg, 3.8 mmol) in 20 mL of MeOH was reacted with ammonium chloride (201 mg, 3.8 mmol) by the method of EXAMPLE 27 to yield 570 mg (73%) of the white solid title material.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:6][N:7]=1.[CH3:11][I:12]>C(O)C>[I-:12].[CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:6][N+:7]=1[CH3:11]
Reactant: CI
Reactant: CC1=NCCn2cccc21
Solvent: CCO
Product: CC1=[N+](C)CCn2cccc21
Product: [I-]

Procedure:
A solution of 3,4-dihydro-1-methylpyrrolo(1,2-a)pyrazine (4.5 g, described in Example 2) and methyl iodide (9 ml) in ethanol (60 ml) is refluxed for 15 hr and evaporated. The residue is crystallized from methanol-diethyl ether to obtain 3,4-dihydro-1,2-dimethylpyrrolo(1,2-a)pyrazinium iodide (6.0 g), mp 166°-168° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.II.[C:14]([CH:17]1[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>O1CCCC1.C(#N)C.O>[S:10]1[C:6]2[CH:5]=[CH:4][C:3]([C:14]([CH:17]3[CH2:19][CH2:18]3)([OH:16])[CH3:15])=[CH:11][C:7]=2[CH:8]=[CH:9]1
Reactant: Brc1ccc2sccc2c1
Reactant: CC(=O)C1CC1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(O)(c1ccc2sccc2c1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.60 g (24.64 mmol) of magnesium turnings were dried by heating under argon and, after cooling to RT, 30 ml of tetrahydrofuran were added. 5.00 g (23.46 mmol) of 5-bromo-1-benzothiophene in 30 ml of tetrahydrofuran, and traces of iodine, were added to the mixture, which was stirred at RT for 30 min. Addition of 2.17 g (25.81 mmol) of acetylcyclopropane in 30 ml of tetrahydrofuran was followed by stirring for 2 h. The reaction solution was mixed with water and acetonitrile, and the mixture was filtered through kieselguhr. The organic solvents were removed in a rotary evaporator, and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). The acetonitrile was removed from the combined product phases in a rotary evaporator, and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were again washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. 2.39 g (46% of theory) of the title compound were obtained.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].CS(CCO)(=O)=[O:15]>CN(C=O)C>[F:12][C:11]1[C:4]([OH:15])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cccc(F)c1F
Reactant: CS(=O)(=O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(F)c1O
Temperature: 25 °C

Procedure:
Sodium hydride was added to a DMF solution of 2,3-difluorobenzonitrile and 2-(methylsulfonyl)ethanol, followed by stirring at room temperature to obtain 3-fluoro-2-hydroxybenzonitrile. FN: 136.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:46]1N=N[C:48]2[CH:49]=CC=C[C:47]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:46][CH2:47][CH2:48][CH3:49])=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and propylamine (6.78 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16.1 mg, 53%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: C(S[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]=[C:12]2[CH3:40])=[CH:7][CH:6]=1)(C)C.Cl[C:42]1[CH:43]=C(C(OO)=O)C=C[CH:47]=1.C(OCC)(=O)C.[S:58]([O-:62])([O-])(=[O:60])=S.[Na+].[Na+]>C(#N)C.O>[CH:42]([S:58]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]=[C:12]2[CH3:40])=[CH:7][CH:6]=1)(=[O:62])=[O:60])([CH3:43])[CH3:47]
Reactant: O=S([O-])([O-])=S
Reactant: CCCc1nc(C)n(-c2ccc(SC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(S(=O)(=O)C(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of 3-[4-(isopropylthio)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.28 g) in acetonitrile (3 mL) was added 3-chlorobenzenecarboperoxoic acid (0.26 g), and the mixture was stirred at 0° C. for 3 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]([O:28][C:29](C)(C)[CH3:30])=[O:27])[CH2:20][CH2:19]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:33])[CH:3]=1.Cl.CCOC(C)=O>CCO>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:19][CH2:20][CH:21]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:23]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:33])[CH:3]=1
Reactant: CC(C)(C)OC(=O)COC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)COC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 157.1 %

Procedure:
A mixture of 1.07 g of tert-butyl ({1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}oxy)acetate, 20 ml of 4M HCl-EtOAc solution and 20 ml of EtOH was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the obtained residue was recrystallized from EtOH-ether to give 855 mg of ethyl ({1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}oxy)acetate hydrochloride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([NH:12][C:13](=[O:38])[NH:14][C:15]2[CH:37]=[CH:36][C:18]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[O:29][CH:30]=[C:31]([C:33]([OH:35])=O)[N:32]=4)[CH2:23][CH2:22]3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.[C:39]([NH2:43])([CH3:42])([CH3:41])[CH3:40].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:39]([NH:43][C:33]([C:31]1[N:32]=[C:28]([CH2:27][N:24]2[CH2:25][CH2:26][N:21]([C:19]([C:18]3[CH:36]=[CH:37][C:15]([NH:14][C:13]([NH:12][CH:8]4[CH2:9][CH2:10][CH2:11]4)=[O:38])=[CH:16][CH:17]=3)=[O:20])[CH2:22][CH2:23]2)[O:29][CH:30]=1)=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C(Nc1ccc(C(=O)N2CCN(Cc3nc(C(=O)O)co3)CC2)cc1)NC1CCC1
Reactant: CC(C)(C)N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1coc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
To a solution of 2-((4-(4-(3-cyclobutylureido)benzoyl)piperazin-1-yl)methyl)-oxazole-4-carboxylic acid 2,2,2-trifluoroacetate (8 mg, 15 μmol) in N,N-dimethyl-acetamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uronium hexafluorophosphate (5.7 mg, 154 μmol; HATU), tert-butylamine (1.6 μL, 15 μmol) and N,N-diisopropylethylamine (3.9 μL, 23 μmol). The reaction mixture was stirred at room temperature for 20 hours and was then concentrated under vacuum. The crude residue was purified by acidic reverse phase HPLC to give the title compound (5.6 mg). MS (ESI) m/z 483.1 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1>>[OH:7][C:3]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[C:4]=1[CH:15]([C:25]1[NH:26][C:27]2[C:32]([C:24]=1[CH3:23])=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Product: Cc1ccc(C2(C)C(=O)C(C(c3ccccc3)c3[nH]c4ccccc4c3C)=C2O)cc1

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione (from Example 4.1) was reacted with benzaldehyde and 3-methyl-1H-indole to give the title compound as a colorless solid. MS: 406.6 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]3[N:24]([CH:32]([CH3:34])[CH3:33])[C:23]2=[O:35])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[CH3:31][C:29]1[CH:30]=[C:25]2[N:24]([CH:32]([CH3:33])[CH3:34])[C:23](=[O:35])[N:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:21][CH:20]=3)[C:26]2=[N:27][CH:28]=1
Reactant: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(O)cc1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(Oc2nc3cccnc3n2C)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (198 mg) and 3-(4-hydroxyphenyl)-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (177 mg) in DMF (1.5 ml) was added NaH (40.0 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (125 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5](F)=[CH:4][C:3]=1[F:10].O.FC1C=C(F)C=C(F)C=1.[NH3:21]>[Cu].CO>[F:10][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([F:8])[CH:2]=1)[NH2:21]
Reactant: N
Reactant: Fc1cc(F)c(Cl)c(F)c1
Agent: [Cu]
Agent: Fc1cc(F)cc(F)c1
Solvent: O
Solvent: CO
Product: Nc1cc(F)cc(F)c1

Procedure:
EP 460 639 describes a three-stage preparation of 3,5-difluoroaniline. Starting from 5-chloro-2,4,6-trifluoroisophthalic acid, this is decarboxylated to give 2-chloro-1,3,5-trifluorobenzene. By reaction of the 2-chloro-1,3,5-trifluorobenzene with copper and water at 300° C., 1,3,5-trifluorobenzene can be prepared. According to Example 6 of EP 460 639, 1,3,5-tri-fluorobenzene is reacted with methanol saturated with ammonia at 200° C. for 60 hours and 3,5-difluoroaniline is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.O1CCOCC1.C(OCC)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Cl)cc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)—N—((R)-1(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (14.6 g, 44.5 mmol) in methanol (25 mL) was added a solution of hydrochloric acid in p-dioxane (4.0 M in p-dioxane, 22.3 mL, 89.1 mmol), and the reaction was stirred at room temperature for 30 min. Diethyl ether was then added (400 mL) and the slurry was stirred for 10 min. The solid was collected by filtration, and washed with diethyl ether (2×200 mL). The solid was then dissolved in 5 M aqueous sodium hydroxide solution, and extracted with dichloromethane (2×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was used without further purification (7.8 g, 34.9 mmol, 79%, >96% ee, determined by Mosher's method).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:11][OH:12])[CH3:10].[OH-].[K+]>CO.O>[CH3:10][C:9]1[C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[O:12][N:11]=1
Reactant: CC(=NO)c1ccc(O)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc2cc(O)ccc12
Yield: 22 %

Procedure:
1.98 g of 1-(2,4-dihydroxyphenyl)ethanone oxime (12 mM) and 1 g of potassium hydroxide (18 mM) are refluxed for 4 days in a methanol/water mixture (100 ml/100 ml). The reaction medium is subsequently concentrated under reduced pressure, acidified to pH=1 with 1N HCl, and then extracted with ethyl acetate. The organic phase obtained is dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by silica gel chromatography (methylcyclohexane/ethyl acetate gradient of 70/30 to 30/70; v/v). The expected product is obtained in the form of a white solid (0.39 g) with a yield of 22%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][N:7]=1.[NH2:20][CH:21]1[C:29]2[C:24](=[C:25]([F:31])[CH:26]=[CH:27][C:28]=2[F:30])[CH2:23][CH2:22]1.[C:32]([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:20][CH:21]3[C:29]4[C:24](=[C:25]([F:31])[CH:26]=[CH:27][C:28]=4[F:30])[CH:23]([CH3:32])[CH2:22]3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C=O)c2)cnc1N
Reactant: NC1CCc2c(F)ccc(F)c21
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=O)c1nc(-c2cccc(CNC3CC(C)c4c(F)ccc(F)c43)c2)cnc1N
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a stirred solution of 3-amino-6-(3-formylphenyl)-N-methylpyrazine-2-carboxamide (50 mg, 0.19 mmol) and 1-amino-4,7-difluoroindane (67.6 mg, 0.4 mmol) in THF (5 mL) was added sodium cyanoborohydride (62.8 mg, 1 mmol) and 1 drop of acetic acid. The solution was stirred overnight and solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and saturated aqueous solution of Na2CO3 (10 mL). The phases were separated. The organic layer was washed with HCl (5 mL 0.5 M) then saturated aqueous sodium chloride and dried (Na2SO4). Filtration and concentration follow by hplc purification gave (42.2 mg, 50% yield) of 3-amino-6-(3-{[(4,7-difluoro-3-methyl-2,3-dihydro-1H-inden-1-yl)amino]methyl}phenyl)-N-methylpyrazine-2-carboxamide. An excess of HCl in dioxane (0.2 mL, 4.0 M) was added to the solution and the solvent was removed to give hydrochloride: 1H NMR (400 MHz; DMSO-d6): 10.1 (br s, 1H); 9.7 (br s, 1H); 9.0 (m, 1H); 8.85 (s, 1H); 8.2 (m, 1H); 7.5 (m, 2H); 7.3-7.2 (m, 2H); 5.0 (m, 1H); 4.6-4.15 (m, 3H); 3.4 (m, 1H); 2.95 (m, 1H); 2.85 (d, 3H); 2.6 (m, 1H); 2.46 (m, 1H); MS (EI) for C22H21N50F2 HCl: 410 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([N+:13]([O-])=O)=[C:6](/[CH:8]=[CH:9]/N(C)C)[CH:7]=1>[Ni].CCO>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[NH2:16])[NH:13][CH:9]=[CH:8]2
Reactant: CN(C)/C=C/c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2[nH]ccc2cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.2 %

Procedure:
A suspension of (E)-2-(5-chloro-2,4-dinitrophenyl)-N,N-dimethylethenamine (9.8 g, 36 mmol) and Raney Nickel (9.8 g) in EtOH (140 mL) was stirred under H2 (1 atm) at room temperature for 4 h. After filtration, the filtrate was concentrated and the residue was purified by column chromatograph (petroleum ether/ethyl acetate=10:1) to give 5-chloro-1H-indol-6-amine (0.97 g, 16%) as a gray powder. 1HNMR (CDCl3) δ 7.85 (br s, 1H), 7.52 (s, 1H), 7.03 (s, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.91 (br s, 1H); MS (ESI) m/e (M+H+) 166.0.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)=O)cs3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[N:6]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:5]2[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:31])[CH2:29]Br)[CH3:26]>CN(C)C=O>[C:28]([CH2:29][N:8]1[C:7](=[O:9])[N:6]2[N:10]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[C:5]2[N:4]=[C:3]1[S:2][CH3:1])([O:27][CH2:25][CH3:26])=[O:31]
Reactant: CSc1nc2cc(-c3ccccc3)nn2c(=O)[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(SC)nc2cc(-c3ccccc3)nn2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 260 mg of 2-methylthio-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one and 140 mg of anhydrous potassium carbonate in 5 ml dry dimethylformamide is stirred at room temperature for 15 min while 0.14 ml ethylbromacetate is added dropwise. The mixture is stirred at room temperature overnight, filtered, and the filter cake washed with dimethylformamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[CH3:31][O:32][C:33](=[O:47])[C@@H:34]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)[NH2:35]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:47])[C@H:34]([NH:35][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:11]=1)[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Reactant: COC(=O)[C@H](N)Cc1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
3-(tert-Butoxycarbonylaminomethyl)benzoic acid (5.32 g; 21.2 mmol) was dissolved in N,N-dimethylformamide (20 ml). 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (4.06 g, 21.2 mmol) was added and the mixture was stirred for 20 min. A solution of (R)-3-(2-naphthyl)alanine methyl ester (4.85 g, 21.2 mmol) in N,N-dimethylformamide (20 ml) and triethylamine (4.4 ml) was added and stirring was continued for 18 h. The mixture was diluted with ethyl acetate (400 ml) and the organic phase was washed with water (200 ml), 10% aqueous sodium hydrogensulfate (50 ml), 5% aqueous sodium hydrogencarbonate (100 ml) and water (100 ml). The phases were separated and the organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to afford 8.9 g of (R)-2-(3-(tert-butoxycarbonylaminomethyl)benzoylamino)-3-(2-naphthyl)propionic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[C:39]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[C:39]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OCc2ccccc2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(OC)cc3)c2OCc2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.4 %

Procedure:
p-Methoxyaniline (0.035 g, 0.28 mmol), triethylamine (0.029 g, 0.28 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.048 g, 0.28 mmol) were added to a methylene chloride solution (5 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.060 g, 0.14 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.038 g, 0.072 mmol, 51%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1.C(=O)([O-])[O-:24].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:6](=[O:7])([OH:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[N:18][C:19]([NH:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([OH:5])=[O:7])=[N:20][CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: Clc1ncc(Br)cn1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)O
Product: O=C(O)N1CCC[C@H]1CNc1ncc(Br)cn1
Temperature: 25 °C
Yield: 85 %

Procedure:
(S)-2-Aminomethyl-pyrrolidine-1-carboxylic acid tert butyl ester (2 g), 5-bromo-2-chloropyrimidine (1.93 g) were combined in xylene (40 ml) containing potassium carbonate (2.76 g) and diisopropylethylamine (5.23 ml) and warmed to reflux for 20 h. The mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, pentane-25% ethyl acetate/pentane). The appropriate fractions were collected, solvent removed at reduced pressure to give the title compound (1.78 g) as a colourless gum