Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=1.C([O-])(=O)C.[K+]>CCO.O>[F:1][C:2]1[C:7]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=2)=[CH:6][C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][N:3]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: COCCOc1cnc(F)c(B(O)O)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COCCOc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Temperature: 100 °C
Yield: 23.9 %

Procedure:
To a 20 mL microwave reaction tube was added 2-fluoro-5-(2-methoxyethoxy)pyridin-3-ylboronic acid (1.06 g, 4.95 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 0.508 g, 3.51 mmol), Am-Phos (Aldrich, 0.125 g, 0.176 mmol) and potassium acetate (Aldrich, 1.04 g, 10.6 mmol) in EtOH (10 mL) and water (1 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 20 min. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and 10% IPA in CHCl3 (3×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was treated with DCM and the resulting solid was collected to afford 4-(2-fluoro-5-(2-methoxyethoxy)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.234 g) as an off-white solid. The filtrate was concentrated and purified by silica gel column chromatography (100 g, eluent: iPrOH in CHCl3 0% to 12.5%) to afford additional material (0.399 g) as a pale yellow solid. Total yield was 0.632 g, 64%. 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (dd, J=7.63, 3.13 Hz, 1H) 8.01 (dd, J=2.93, 1.76 Hz, 1H) 5.56 (br. s., 2H) 4.19-4.27 (m, 2H) 3.75-3.81 (m, 2H) 3.46 (s, 3H) 2.53 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1ccc(C(=O)c2ccc(C#N)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(C#N)cc1

Procedure:
A solution of 0.5 g. (0.0017 mole) of ethyl 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate in 3 ml. ethanol is brought to reflux and 1.7 ml. of 1N sodium hydroxide solution is added dropwise. The mixture is refluxed for 3 minutes and the ethanol is then evaporated in vacuo. The residue is diluted with water and acidified with dilute hydrochloric acid. A white solid precipitates, 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetic acid, which is collected by filtration and dried, m.p. 196°-198°C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH:22]#[C:23][CH3:24]>CN(C)C=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:22]#[C:23][CH3:24]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: -78 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.904 g) in dimethylformamide(2 ml) and triethylamine (10 ml) contained in a stainless steel bomb was added cuprous iodide (60 mg) and bis(triphenylphosphine)palladium(II) chloride (120 mg). The reaction vessel was cooled to -78° C. and propyne (2 g) condensed into it. The vessel was sealed and then heated at 70° C. for 18 hours and then left at room temperature for 2 days. The reaction mixture was partitioned between ether and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane:hexane (1:1) to provide the title compound as a white solid m.p. 226-8° C.
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[OH:15])[CH2:3][OH:4].[C:16](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:3][OH:4]
Reactant: COc1cccc(SC[C@@H](C)CO)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc(SC[C@@H](C)CO)c1OC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
0.43 g (0.0019 mol) of 2-(S)-methyl-3-(2-hydroxy-3-methoxyphenylthio)propan-1-ol (XXg), 10 ml of acetone and 0.26 g (0.0019 mol) of potassium carbonate are introduced into a round-bottomed flask kept under an inert atmosphere. After 15 minutes, 0.12 ml (0.0019 mol) of methyl iodide is introduced and the mixture is heated at 60° C. for 8 hours. The mixture is concentrated under reduced pressure. The residue is taken up in water and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. The residue obtained is used without additional purification in the following stage.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[C@@H:23]([CH2:24][C:25]([S:30][CH3:31])([S:28][CH3:29])[S:26][CH3:27])[CH2:22][C:21]1=[O:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[C:33](N1C=CN=C1)(=[O:35])[CH3:34]>O1CCCC1>[Si:13]([N:20]1[C@H:23]([CH2:24][C:25]([S:28][CH3:29])([S:26][CH3:27])[S:30][CH3:31])[C@@H:22]([C:33](=[O:35])[CH3:34])[C:21]1=[O:32])([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: CSC(C[C@H]1CC(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Reactant: CC(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSC(C[C@@H]1[C@@H](C(C)=O)C(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.43 ml of 2.4 m solution, 5.84 mmol) is added by syringe to a solution of diisopropylamine (591 mg, 5.84 mmol) in 25 ml of freshly distilled tetrahydrofuran at -78° C. The resulting solution is stirred at -78° C. for 15 minutes prior to the addition of a solution of (4R)-1-(t-butyldimethylsilyl)-4-[2,2,2-tri(methylthio) ethyl]azetidin-2-one (1.00 g, 2,85 mmol) in tetrahydrofuran (5 ml). This solution is stirred at -78° C. for 15 minutes, then added via a Teflon tube to a mixture of N-acetylimidazole (642 mg. 5.84 mmol) in 25 ml of THF at -78° C. The resulting yellow reaction mixture is stirred at -78° C. for 10 minutes, then quenched by addition of saturated aqueous ammonium chloride solution. The mixture is diluted with ether (200 ml) and washed with 2.5 N hydrochloric acid solution (50 ml), water (50 ml) and brine (50 ml) and dried over magnesium sulfate. Removal of solvents in vacuo gives a yellow oil which is chromatographed on silica gel (30% ether in petroleum ether) to yield (3S, 4R)-1-(t-butyldimethylsilyl)-3-(1-oxoethyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one. n.m.r. (CDCl3) δ 4.42(m,l), δ 4.32(d,l) δ 2.35(m,2), δ 2.32(s,3), δ 2.2(s,9), δ 0.98(s,9), δ 0.3(2s,6).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.[OH2:24].[OH2:25].O.O.O.O.C1(=O)OOOOC(=O)C2=CC=CC=C12.[Mg]>CN(C)C=O.CCOC(C)=O>[CH3:1][S:2]([CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1)(=[O:25])=[O:24]
Reactant: O
Reactant: CSCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Agent: O=c1ooooc(=O)c2ccccc12
Agent: [Mg]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
1-[1-(2-Methylthio-ethyl)-1H-benzimidazol-2-ylmethyl]-1H-benzotriazole (100 mg, 0.309 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Magnesium monoperoxy phthalate hexahydrate (611 mg, 1.24 mmol) was added and the reaction mixture was stirred at room temperature overnight under N2. The solvent was stripped under reduced pressure. The yellow oily residue was taken up in EtOAc (100 mL) and washed with water (2×50 mL) dried over magnesium sulfate, filtered and evaporated. Column chromatography on silica gel (EtOAc) gave 45 mg (41%) of the title compound as an oil.
Reaction SMILES: C(N(CC)CC)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[NH2:36])[CH:25]=1.[N:39]1[N:40]([C:44]2[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=2[C:46](O)=[O:47])[N:41]=[CH:42][CH:43]=1>C(Cl)Cl>[N:39]1[N:40]([C:44]2[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=2[C:46]([NH:36][CH:32]2[CH2:33][CH2:34][CH2:35][CH:31]2[CH2:30][C:26]2[CH:25]=[C:24]([C:23]([F:22])([F:37])[F:38])[CH:29]=[CH:28][N:27]=2)=[O:47])[N:41]=[CH:42][CH:43]=1
Reactant: NC1CCCC1Cc1cc(C(F)(F)F)ccn1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCC1Cc1cc(C(F)(F)F)ccn1)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Triethylamine (0.099 ml, 0.71 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.039 g, 0.29 mmol) and EDC (0.055 g, 0.29 mmol) were added to a solution 2-{[4-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-amine (Intermediate 12; 0.058 g, 0.24 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 0.054 g, 0.29 mmol) in DCM (3 ml). The reaction was stirred at room temperature for 24 hours and then diluted with DCM (40 ml) and washed with a saturated solution of sodium bicarbonate (10 ml). The organics were dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-80% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[S:11].[CH3:12]CN(C(C)C)C(C)C.Cl[CH2:22][C:23]1[N:24](C)[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[SH:11]([CH2:22][C:23]1[NH:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1)[CH3:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1c(=S)[nH]c2ccccc21
Reactant: Cn1cc(-c2ccccc2)nc1CCl
Solvent: CN(C)C=O
Product: Cn1c([SH](C)Cc2nc(-c3ccccc3)c[nH]2)nc2ccccc21
Temperature: 90 °C

Procedure:
To a solution of 1-methyl-1,3-dihydro-benzoimidazole-2-thione (28 mg, 0.18 mmol) in DMF (1.6 mL) was added DIPEA (80 μL, 0.44 mmol) and 2-chloromethyl-1-methyl-4-phenyl-1H-imidazole (40 mg, 0.19 mmol). The mixture was heated at 90° C. for 10 minutes using a microwave synthesizer. Volatiles were evaporated and the residue was purified by preparative LC-MS to yield the title compound. LC-MS: m/z=335.3 (MH+), tR=0.51 min, method C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[C@@H:15]([OH:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:23][C@@H:10]3[C:11]2=[O:22])[CH2:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[C@@H:15]([OH:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:23][C@@H:10]3[C:11]2=[O:22])[CH2:3]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)[C@H]3C[C@H]3[C@@H]12
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2[C@@H](O)C[C@]2(C)C(=O)[C@H]4C[C@H]4[C@@H]32)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 7.9 g of 3β,11β-dihydroxy-15β,16β-methyleneandrost-5-en-17-one in 39.5 ml of pyridine and 39.5 ml of acetic anhydride is left to stand at room temperature for 5 hours, diluted with 800 ml of ice-water and, after standing for 1 hour, extracted with ethyl acetate. The organic phase is washed in succession with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated sodium chloride solution, dried, and concentrated under a water-jet vacuum. Chromatography of the crude product over 30 times the amount by weight of silica gel and elution with a mixture of methylene chloride/acetone (98:2) yield 3β-acetoxy-11β-hydroxy-15β,16β-methyleneandrost-5-en-17-one which, after being dissolved and recrystallised once from methylene chloride/ether/petroleum ether, melts at 209°-211°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=O)[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].CO.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: N#Cc1c(F)cccc1C(=O)c1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1ccnc(Cl)c1)c1cccc(F)c1C#N
Yield: 47.8 %

Procedure:
Ti(OEt)4 (15 mL) was added to a solution of 2-(2-chloro-pyridine-4-carbonyl)-6-fluoro-benzonitrile (3.6 g, 13.81 mmol) and 2-methyl-propane-2-sulfinic acid amide (2.5 g, 20.72 mmol) in dry THF (100 mL) at room temperature. The resulting mixture was stirred to reflux for 40 hours and then treated with CH3OH (50 mL) and saturated sodium bicarbonate solution (10 mL). The resulting suspension was filtered through a pad of Celite® and the solids were washed with THF (50 mL) and CH3OH (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using a gradient of 25-50% EtOAc in hexane to afford the title compound (2.4 g, 48%).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)[CH:10]=1)([CH3:8])[CH3:7].[C:31](Cl)(=[O:35])[C:32](Cl)=[O:33].CC[N:39](C(C)C)C(C)C>>[C:23]([C:21]1[N:22]=[C:18]([C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]([NH:5][C:31](=[O:35])[C:32]([NH2:39])=[O:33])([CH3:8])[CH3:7])=[CH:10][C:11]=2[C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)=[O:17])[NH:19][CH:20]=1)#[N:24]
Reactant: CC(C)(N)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CC(C)(NC(=O)C(N)=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Yield: 32 %

Procedure:
The procedure of Example 4 was followed using 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide acetic acid salt (as prepared in Example 3, step (b), 28.0 mg, 0.0684 mmol), oxalyl chloride (51 μL, 0.10 mmol, 2.0 M in DCM) and DIEA (36 μL, 0.21 mmol). Flash chromatography on silica gel (1-2% MeOH/DCM) afforded 9.2 mg (34%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.14 (d, 1H, J=8.4 Hz), 7.99 (s, 1H), 7.31 (dd, 1H, J=8.4, 2.3 Hz), 7.20 (d, 1H, J=2.3 Hz), 5.81 (m, 1H), 2.22-2.31 (m, 4H), 1.74-1.89 (m, 4H), 1.71 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H24N6O3, 421.2 (M+H). found 421.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:11]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:2]2[CH:3]=[C:4]([CH:11]3[N:15]4[CH:16]=[N:17][CH:18]=[C:14]4[CH2:13][CH2:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(C2CCc3cncn32)cc1Cl
Reactant: NC1CC1
Product: O=[N+]([O-])c1ccc(C2CCc3cncn32)cc1NC1CC1
Reaction time: 30 h
Yield: 99.6 %

Procedure:
A mixture of 3.15 g of 5-(3-chloro-4-nitrophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole (prepared as described in EP-A-0,426,225) and 30 ml of cyclopropanamine was stirred for 30 hours at reflux temperature. The reaction mixture was evaporated and the residue was stirred in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was co-evaporated with methylbenzene, yielding 3.4 g (99.6%) of (±)-N-cyclopropyl-5-(6,7-dihydro-5-H-pyrrolo[1,2-c]imidazol-5-yl)-2-nitrobenzenamine (interm. 6).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[C:19]2[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[N:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[C:36]=[O:37].O>C(Cl)Cl>[NH2:25][C:20]1[C:19]([C:11]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:36]([NH:35][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[O:37])=[CH:9][CH:8]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NCc1ccc(-n2c(-c3cccnc3N)nc3cccnc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccc(NC(=O)NCc2ccc(-n3c(-c4cccnc4N)nc4cccnc43)cc2)cc1
Reaction time: 0.33 h
Yield: 15 %

Procedure:
3-(3-(4-(aminomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine HCl salt (63 mg, 0.2 mmol) was suspended in DCM (2 mL). Diisopropylethylamine (0.07 mL, 0.4 mmol) was added. After everything went into solution 1-isocyanato-4-methoxybenzene (29 mg, 0.2 mmol) were added. After 20 minutes, water (5 mL) was added and diluted with dichloromethane. The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and it was purified by silica gel chromatography (0-20% methanol in dichloromethane) to yield the desired product (14 mg, 15% yield). Mp. 224-226° C.; 400 M Hz 1H NMR (CD3OD) δ: 8.36-8.28 (m, 1H), 8.22-8.15 (m, 1H), 8.0-7.92 (m, 1H), 7.56-7.47 (m, 2H), 7.46-7.36 (m, 3H), 7.36-7.29 (m, 1H), 7.29-7.22 (m, 2H), 6.89-6.81 (m, 2H), 6.5-6.42 (m, 1H), 4.47 (s, 2H), 3.75 (s, 3H); LCMS [M+H]: 466.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Cl-].[I-:17]>C(O)(=O)C.C(OCC)(=O)C>[I:17][C:8]1[CH:7]=[CH:6][C:5]([NH2:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: [I-]
Reactant: CC(C)c1ccccc1N
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1cc(I)ccc1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-isopropyl-phenylamine (262 mg, 1.94 mmol) and sodium acetate (159 mg, 1.94 mmol) in 5 mL acetic acid, was added iodide monochloride (409 mg, 2.58 mmol) at room temperature. The mixture was stirred at room temperature for 20 minutes, then diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give 4-iodo-2-isopropyl-phenylamine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]([O:11][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16]1)([CH3:14])[CH3:13])=[O:10].[C:23]([OH:27])(=[O:26])[CH2:24][CH3:25].CCOCC>CC(C)=O>[C:23]([O:27][CH2:8][C:9]([O:11][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16]1)([CH3:14])[CH3:13])=[O:10])(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)O
Reactant: CC1(C)CCCC(C(C)(C)OC(=O)CCl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCC(=O)OCC(=O)OC(C)(C)C1CCCC(C)(C)C1
Yield: 73.8 %

Procedure:
K2CO3 (6.2 g, 45 mmol) and 1-(3,3-dimethylcyclohexyl)-1-methylethyl chloroacetate (2,5 g, 10 mmol) are added successively to a solution of propionic acid (1.8 g, 30 mmol) in acetone (20 ml). After the suspension has been heated under reflux for 36 hours, it is allowed to cool and ether (80 ml) and 10% K2CO3 solution (50 ml) are added. After phase separation has taken place, the aqueous phase is freed from residual acetone and the aqueous phase is also extracted twice with 50 ml diethyl ether. The combined organic phases are also washed once with water and once with saturated NaCl solution, then dried, filtered off and freed from solvent in a rotary evaporator. After purification by flash chromatography (cyclohexane/EtOAc=10:1, Rf=0.23) and subsequent bulb tube distillation, (BTD: 215° C., 0.9 mbar) 2.1 g (78%) 2-[1-(3,3-dimethylcyclohexyl)-1-methylethoxy]-2-oxoethyl propionate is obtained as a colorless liquid.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6]2.CN1CCOCC1.[CH3:20][C:21]1([CH3:34])[C@H:25]2[CH2:26][CH2:27][C@:22]1([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:23](=[O:28])[CH2:24]2>CO>[CH3:20][C:21]1([CH3:34])[C@H:25]2[CH2:26][CH2:27][C@:22]1([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:23](=[O:28])[CH2:24]2.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH2:12])[CH2:6]2
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: Br
Agent: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CN1CCOCC1
Solvent: CO
Product: N[C@H]1Cc2ccc(Br)cc2C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-bromo-2,3-dihydro-1H-inden-2-amine hydrobromide (107 mmol, 31.27 g) and N-methylmorpholine (112 mmol, 12.32 mL, 11.33 g) in methanol (66.6 mL) was heated to 58-62° C. and a solution of ((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (107 mmol, 24.79 g) in methanol (53.4 mL) was added over 3 min maintaining internal temp at 60-65° C. The addition funnel was rinsed with MeOH (13.3 mL) and rinsings added to reaction. The mixture was stirred at 60-65° C. for 10 min until a clear solution was obtained. The reaction was then allowed to cool to room temperature and stirred for a total of 4 h. The solids were collected by filtration and washed with a pre-cooled mixture of isopropyl acetate/methanol 2:1 (2×15 mL) followed by water (2×15 mL). The crude product was dried in a vacuum oven at 50° C. overnight to yield (18.03 g) of a fluffy white solid. This was suspended in methanol (130 mL) and heated to reflux for 4 h then allowed to cool to room temperature with stirring over 2 h and stirring continued at room temperature for a further 1 h. Solids were then isolated by filtration and washed with a pre-cooled solution of isopropylacetate/methanol (2:1, 2×18 mL). The colourless solid (13.82 g) was dried in the vacuum oven for 60 h. Refluxing in methanol followed by washing the solid with isopropyl acetate/methanol was repeated until the desired enantiomeric ratio was obtained. (S)-5-bromo-2,3-dihydro-1H-inden-2-amine((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate was obtained as a colourless solid (12.28 g, e.e. 100:0, 25.9%).