Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([CH2:21][OH:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:24]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CC(O)C>[OH:22][CH2:21][C:14]1[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:16][C:10]2[N:6]3[CH2:7][CH2:8][N:9]([C:24]4[N:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:26][N:25]=4)[C@H:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[N:12][C:11]=2[CH:13]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CC(C)[C@H]1NCCn2c1nc1cc(CO)c(S(C)(=O)=O)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of (R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol (30 mg, 0.093 mmol) in CH2Cl2 (0.5 mL) and iPrOH (0.5 mL) was added ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (36 mg, 0.14 mmol) and DIEA (36 mg, 0.28 mmol). The mixture was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure. Water (5 mL) was added to the mixture and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-ethyl 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (42.0 mg, 83.7% yield) as a white solid. Analytical chiral HPLC: tR=9.927 min in 15 min chromatography, 96.74% ee (Method: OD-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 542.1 [M+H]+. 1H NMR (CD3OD 300 MHz): δ 8.96 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 6.12-6.00 (m, 1H), 5.45-5.29 (m, 1H), 5.01 (s, 2H), 4.51-4.47 (m, 1H), 4.33-4.18 (m, 3H), 3.91 (t, J=10.8 Hz, 1H), 3.18 (s, 3H), 2.63-2.47 (m, 1H), 1.35-1.26 (m, 6H), 1.05 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([CH2:11][C:12](=[O:14])[CH3:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]>[Ru].CO>[CH3:4][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH2:1][CH2:11][CH:12]([OH:14])[CH3:13]
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Agent: [Ru]
Solvent: CO
Product: CC(C)CCCC(C)CCCC(C)O
Temperature: 40 °C
Reaction time: 0.21 h
Yield: 96.6 %

Procedure:
To a glass autoclave liner is added 299 g of geranylacetone, 3.8 g or 5% ruthenium on carbon and 150 ml of methanol. The glass liner is sealed inside a 3 L, stainless steel, rocking autoclave and the autoclave purged once with 250 psig N2, once with 250 psig H2 and then charged with 1000 psig H2. With mixing, the reaction mixture is heated. At about 75° C., the reaction initiates and begins consuming H2 and exotherms to 170-180° C. In 10-15 minutes, the temperature has dropped to 100-110° C. and the pressure dropped to 500 psig. The autoclave is boosted to 1000 psig with H2 and mixed at 100-110° C. for an additional 1 hour and 40 minutes with the reaction consuming an additional 160 psig H2 but at which time no more H2 consumption is observed. Upon cooling the autoclave to 40° C., the reaction mixture removed, filtered to remove catalyst and concentrated by evaporation of methanol under vacuum to yield 297.75 g of 6,10-dimethyl-2-undecanol.
Reaction SMILES: CN(OC)[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C.O>O1CCCC1>[CH2:13]([C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at 0° C. under nitrogen was added a solution of benzyl magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, dried, filtered, and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05 g) in 70% yield as oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1Oc1ccccc1N
Yield: 61.8 %

Procedure:
To a solution of 1-tert-butyl-2-(2-nitrophenoxy)benzene (˜20 g, crude) in MeOH/THF (1:1, 200 mL) was added 10% Pd/C (2 g). The mixture was hydrogenated under 75 psi overnight. The mixture was filtered through Celite® cake and the filtrate was evaporated to give the crude product as a black oil. Purification by flash chromatography (0-30% EtOAc/hexane) provided 135a (11 g) as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH2:20][C:21]1[CH:22]=[C:23]2[CH2:38][C:28]3([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27][C:24]2=[N:25][CH:26]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([NH:20][C:21]1[CH:22]=[C:23]2[CH2:38][C:28]3([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27][C:24]2=[N:25][CH:26]=1)=[O:18]
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C([O-])Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1c(=O)n2c3c(cccc31)NC(=O)C2)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of sodium (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate (62 mg, 0.23 mmol, described in Intermediate 9), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7].CS(O[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)=O>O1CCCC1>[CH2:16]([O:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][O:10][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH3:3])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN(CCO)CCO
Reactant: CCCCCCCCCCCCCCOS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOCCN(C)CCOCCCCCCCCCCCCCC

Procedure:
A dry vessel under an argon atmosphere was charged with 1.15 g (29 mmol, 2.2 eq) 60% sodium hydroxide in mineral oil. A positive argon pressure was maintained throughout the experiment. The mineral oil was removed by trituration with 3×12 mL dry hexane, then 80 mL anhydrous tetrahydrofuran were added and stirring was initiated. A solution of N-methyldiethanolamine (1.55 g, 13 mmol) in 15 mL anhydrous tetrahydrofuran was added dropwise to the magnetically stirred suspension at room temperature, followed by reflux overnight. A solution of tetradecyl methane sulfonate (9.37 g, 32 mmol, 2.5 eq) in 23 mL anhydrous tetrahydrofuran was added and the reaction was maintained at reflux for three days. The reaction mixture was then cooled, and the slurry vacuum filtered through a 0.75 cm pad of Celite. The reaction vessel and filtration apparatus were rinsed with 100 mL tetrahydrofuran. The combined filtrates were evaporated to yield the crude product which was purified using silica gel (4.5×35 cm bed) in conjunction with a step gradient of ethyl ether:hexane (10:90 to 100:0). Pure fractions were determined by aliquot thin layer chromatography (2:1 ether:hexane). These fractions were pooled, evaporated and resuspended in neat ether and dried with a small amount of magnesium sulfate. Filtration through a 0.2 μm PTFE filter, then rotary evaporation followed by high vacuum treatment yielded pure [bis-(2-tetradecyloxyethyl)-methyl amine] (DEMOA) (2.30 g, 35%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([N:24]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]3)[CH:21]=[CH:20][C:19]=2[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=1.BrC1C=C[C:38]([C:41](C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=[O:42])=C(C)C=1.NC1C=C(C(=O)C)C=CC=1>>[OH:31][CH2:30][CH2:29][C:27]1[N:26]=[N:25][N:24]([C:22]2[CH:21]=[CH:20][C:19]([CH3:32])=[C:18]([CH:23]=2)[C:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:3]3[CH:4]=[C:5]([C:41](=[O:42])[CH3:38])[CH:6]=[CH:7][CH:2]=3)=[CH:11][C:12]=2[CH3:33])=[O:17])[CH:28]=1
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: CC(=O)c1cccc(N)c1
Product: CC(=O)c1cccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(C)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 1-(3-amino-phenyl)-ethanone (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (CDCl3) δ 197.8, 197.1, 147.1, 146.3, 143.3, 142.3, 141.2, 138.5, 137.1, 135.3, 134.7, 132.3, 129.8, 128.5, 124.8, 123.2, 121.5, 120.0, 119.9, 119.6, 118.7, 111.8, 61.6, 28.7, 26.7, 22.2, 19.6
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:27][C:22]1[N:21]=[C:20]([N:16]2[CH2:15][CH2:14][CH:13]([N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)[CH:25]=[C:24]([CH3:26])[N:23]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: Cc1cc(Cl)nc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)nc(C)n1
Yield: 62 %

Procedure:
A mixture of benzyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-52) (17.24 mmol, 1.0 eq.), 4-chloro-2,6-dimethylpyrimidine (2.94 g, 2068 mmol, 1.2 eq.) and K2CO3 (4.76 g, 34.48 mmol, 2.0 eq.) in acetone (80 ml) was refluxed for 14 hours. The mixture was concentrated, and the residue was taken up in water (150 ml) and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with water (150 ml) and sat. NaCl solution (150 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 70% ethyl acetate/hexane). Yield: 62% (3.8 g, 10.73 mmol)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:2]>ClC1C=CC=CC=1.C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:5]1[C:13]2[CH:12]=[CH:11][C:10]([O:14][CH3:15])=[CH:9][C:8]=2[S:7][CH:6]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)CSc1cccc(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1csc2cc(OC)ccc12
Temperature: 112 °C

Procedure:
306 g Polyphosphoric acid (Riedel-de-Haen 04101) are heated up to 70° C. Then 250 ml chlorobenzene are added, followed by a solution of 50.5 g (0.2 Mol) of crude 3-(3-methoxy-phenylsulfanyl)-2-oxo-propionic acid ethyl ester in 280 ml chlorobenzene. The mixture is heated up to 112° C. for 4 h. From the resulting 2-phasic hot mixture, the yellow-brownish upper layer is sucked off. The black lower phase is extracted by 3 portions of 250 ml boiling toluene. The upper layer and the 3 toluene extracts are combined and concentrated in vacuo (→crude 1). The residue from the black lower phase is hydrolysed in 7 l water. Extraction with 2 portions of CH2Cl2 gives more material (→crude 2). Both batches (crude 1 & 2) are combined and diluted with CH2Cl2, water and sat. NaHCO3. The aq. phase is separed off and extracted twice with CH2Cl2. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/CH2Cl2 9:1→7:3→1:1) and crystallization from hexane at −20° C. gives the title compound: m.p.: 68-69° C.; TLC(hexane/acetone 4:1): Rf=0.47.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:15])[N:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][CH2:10][CH:11]=1.CO.[NH2:19][O:20][K].C(O)(=O)C>C(OCC)(=O)C>[CH2:12]([N:8]1[CH2:9][CH2:10][CH:11]=[C:6]([CH2:5][CH2:4][C:3]([NH:19][OH:20])=[O:2])[C:7]1=[O:15])[CH:13]=[CH2:14]
Reactant: NO[K]
Reactant: C=CCN1CCC=C(CCC(=O)OC)C1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCN1CCC=C(CCC(=O)NO)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
24 mg of 3-(1-allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (i1) prepared from the above Step 2 was dissolved in methanol solution (0.11 mmol) and then 0.122 ml of 1.7M NH2OK suspension solution (0.207 mmol) was added thereto at 0° C. and stirred for 3 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10 ml of ethyl acetate solution, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:10) solvent mixture as an eluant to give 11 mg (yield: 48%) of the title compound (j1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2([CH3:25])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]2)[CH2:11][CH2:10]1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27]>C(#N)C>[CH3:25][C:15]1([N:12]2[CH2:13][CH2:14][CH:9]([N:8]3[C@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH:1][C:26]3=[O:27])[CH2:10][CH2:11]2)[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)C1
Solvent: CC#N
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7 %

Procedure:
A solution of ethyl 3-[4-[[(1S,2S)-2-aminocyclohexyl]amino]-1-piperidyl]-3-methyl-pyrrolidine-1-carboxylate (600 mg, 1.70 mmol) in anhydrous acetonitrile (30 mL) was added with 1,1′-carbonyldiimidazole (551.92 mg, 3.40 mmol) and stirred at room temperature for 12 h. The solvent was removed in vacuo; the residue was dissolved in dichloromethane (60 mL), washed with water and brine and dried over anhydrous MgSO4. Concentrated in vacuo and the residue was purified by flash chromatography (dichloromethane/methanol) to afford the title compound as a white solid (45 mg). 1H NMR (CD3OD, 400 MHz): δ 4.15 (q, 2H), 3.62-3.51 (m, 2H), 2.41 (m, 2H), 3.22 (m, 1H), 3.19 (brd, 1H), 2.99 (m, 3H), 2.76 (brs, 1H), 2.45 (m, 3H), 2.01-1.82 (m, 6H), 1.74 (brd, 1H), 1.65 (brd, 1H), 1.45 (m, 4H), 1.25 (t, 3H), 1.12 (s, 3H). MS (M+1): 379.18.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].I[CH3:14].O>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH3:14])[C:7]=12
Reactant: Clc1nccc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2ccnc(Cl)c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
To a solution of 7-chloro-1H-pyrrolo[2,3-c]pyridine (3.00 g, 19.7 mmol) in THF (30 mL) cooled to 0° C. was added 60% NaH in mineral oil (0.940 g, 23.6 mmol NaH). The reaction mixture was stirred at 0° C. for 20 minutes. Iodomethane (6.20 g, 43.7 mmol) was added and the reaction mixture was stirred at 0° C. for 1 h and at 20° C. for 2 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with a gradient of 17-33% EtOAc/petroleum ether to give the title compound as a yellow solid (2.8 g, 85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1>CO.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2ccncc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C2CCNCC2)cc1
Yield: 99.3 %

Procedure:
Methyl 4-(pyridin-4-yl)benzoate (285 g, 1336.57 mmol) and palladium (5% on carbon, 50% wet, JM Type 87L) (57 g, 13.39 mmol) in methanol (2850 mL) were stirred under an atmosphere of hydrogen at 5 bar and 70° C. for 15 hours. The catalyst was removed by filtration and washed with methanol (2850 mL). The solvent was evaporated to dryness to afford methyl 4-(piperidin-4-yl)benzoate (291 g, 99%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([CH2:10][C:11]#[N:12])[N:3]=1.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([CH2:10][C:11]#[N:12])[CH:5]=1
Reactant: Cc1nn(CC#N)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1nn(CC#N)cc1N
Temperature: 80 °C
Reaction time: 48 h
Yield: 20.6 %

Procedure:
A mixture of (3-methyl-4-nitro-1H-pyrazol-1-yl)acetonitrile (2.6 g, 15.7 mmol), NH4Cl (3.4 g, 62.7 mmol) and Fe powder (3.5 g, 62.7 mmol) in MeOH (60 mL) and water (12 mL) was stirred at 80° C. for 2 days. The mixture was filtered, concentrated and the residue was purified by flash chromatography (MeOH: CH2Cl2 20:1) to give the title compound (440 mg, 15% yield) as brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]2=O)=[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]=1[O:26][CH3:27])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C1COCC1.Cl>O>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=1[O:26][CH3:27])[CH2:9][C:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(CC(C)(C)C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(CC(C)(C)C)=C2
Temperature: 5 °C
Yield: 91.8 %

Procedure:
To a mixture of 19.7 g of 6-tert-butyl-2-(2,2-dimethylpropyl)-5-methoxy-4-phenyl-1-indanone of 93% purity (50.3 mmol), 15.0 g of NaBH4, and 200 ml of THF 100 ml of water was slowly (for ca. 10 h) added by vigorous stirring at 5° C. The resulting mixture was stirred overnight at room temperature. Further on, 500 ml of cold water was added, the resulting mixture was acidified by 12 N HCl to pH 1, and then the crude product was extracted with 3×150 ml of dichloromethane. To a solution of the residue in 300 ml of toluene 0.5 g of TsOH was added, the resulting mixture was refluxed for 15 min with Dean-Stark head, then quickly cooled to room temperature, and treated with 50 ml of 10% aqueous K2CO3 to remove acidic impurities. The organic layer was separated, the aqueous layer was extracted with 2×75 ml of dichloromethane. The combined organic extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-64 um, 450 m3 of silica gel, eluent: hexanes-dichloromethane=4:1, vol.). Yield 17.3 g (99%) of the title product as yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]([CH3:19])[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:20](=[O:22])[NH2:21])[CH:7]=[N:6][N:5]2[CH:23]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([C:8]1[CH:7]=[N:6][N:5]2[CH:23]=[C:2]([C:29]3[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]([CH3:19])[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])(=[O:22])[NH2:21]
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)C(C)(C)[C@@H](C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)[C@@H](C)Nc1c(C(N)=O)cnn2cc(-c3ccc(OC)nc3)cc12
Temperature: 135 °C
Yield: 66 %

Procedure:
A mixture of (R)-methyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-2,2-dimethylbutanoate (170 mg, 0.444 mmol) and (6-methoxypyridin-3-yl) boronic acid (102 mg, 0.665 mmol) were taken in 1,4-dioxane (5 mL) in a sealed tube. To this mixture were added 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (21.15 mg, 0.044 mmol) and palladium (II) acetate (4.98 mg, 0.022 mmol) followed by K3PO4 (2M solution) (0.554 mL, 1.109 mmol). The reaction mixture was degassed and heated to 135° C. for 1 h. After completion of the reaction, the reaction mixture was cooled, quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (60 mL), dried over anhyd. sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product as a brown liquid. The crude product was purified by flash chromatography over silica gel and eluted using 40% ethyl acetate in petroleum ether to give the title compound (125 mg, 0.293 mmol, 66.2% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.24-1.25 (d, J=1.6 Hz, 6H), 1.28-1.3 (d, J=6.8 Hz, 3H), 3.57 (s, 3H), 3.89 (s, 3H), 4.65-4.69 (m, 1H), 6.87-6.89 (d, J=8.4 Hz, 1H), 7.28-7.29 (d, J=1.6 Hz, 1H), 8.12-8.15 (dd, J=2.4 Hz, J=2.8 Hz, 1H), 8.205-8.209 (d, J=1.6 Hz, 2H), 8.65-8.66 (d, J=2.4 Hz, 1H), 10.91-10.94 (d, J=10 Hz, 1H). [α]24.8=8.0 (c=0.1, MeOH).