Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.[CH3:24][O:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O.ClCCl>N1C=CC=CC=1>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:28]([CH2:27][CH2:26][O:25][CH3:24])(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: COCCS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COCCS(=O)(=O)Nc1cccc(C2(C)C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1.1 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at 0□ C. was added 2-methoxy-1-ethanesulfonyl chloride (J. Chem. Soc., 1968, 2895; 155 mg, 0.98 mmol), then the mixture was stirred at room temperature for 16 hours. Water (5 ml) and dichloromethane (5 ml) was added, and the mixture stirred for 10 minutes. The organic phase was washed further with water (5 ml), separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (10 g) column chromatography eluting with ethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then 60:40:1). Product-containing fractions were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (condition 4). Combination and evaporation of appropriate fractions gave the title compound as a pale brown solid (3 mg, 1%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][CH:7]([CH3:13])[CH2:8][CH2:9][C:10](=[O:12])C.[CH3:14][C:15]([O-])=O.[Na+]>CN(C=O)C>[Cl:3][C:15]([CH3:14])=[C:9]([CH2:8][CH:7]([CH3:6])[CH3:13])[CH:10]=[O:12]
Reactant: CC(=O)CCC(C)C
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cl)=C(C=O)CC(C)C
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 125.9 %

Procedure:
Phosphorusoxychloride (53.7 g, 350 mmol) is slowly added to DMF (60 mL) stirred at 5° C. Upon complete addition, the clear solution is stirred for further 30 min at 5° C. before 5-methyl-2-hexanone (20 g, 175 mmol) is added dropwise. The yellow solution is stirred for 30 min at 0° C., then for 90 min at rt. The mixture becomes warm (40° C.) and a thick suspension forms. The mixture is cooled to 25° C. and stirring is continued for 1 h before it is poured into an aq. solution of NaOAc (80 g)/ice mixture. The mixture is extracted twice with diethyl ether. The organic extracts are washed with water, combined, dried over MgSO4, filtered and evaporated to give crude 3-chloro-2-isobutyl-but-2-enal (35.4 g) as a yellow oil, LC-MS: tR=0.97 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C=O.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1.[O-]S([O-])(=O)=O.[Mg+2].[C:28]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:13]1([CH2:28][NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: O=C(NCn1nnc2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 836.3 %

Procedure:
A suspension of 4-chlorobenzamide (2.61 g, 16.8 mmol), paraformaldehyde (0.50 g, 16.8 mmol), benzotriazole (2.00 g, 16.8mmol), and MgSO4 (2.00 g, 16.6 mmol) in toluene (50 mL) was treated with p-toluenesulfonic acid (168 mg, 0.88 mmol). The mixture was heated at reflux for 4 hours, cooled to ambient temperature, filtered and concentrated to dryness. The crude material was purified by trituration with diethyl ether to provide 2.11 g of the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>ClCCl.CN(C1C=CN=CC=1)C>[C:21]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc(Br)cc1-c1c[nH]cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(Br)cc1-c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.7 %

Procedure:
To a solution of 4-bromo-2-(1H-imidazol-4-yl)phenol (2.9 g, 12.13 mmol) in dichloromethane was added DMAP (296 mg, 2.43 mmol), triethylamine (5.1 mL, 36.4 mmol) and pivaloyl chloride (3.7 mL, 30.33 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was dissolved in methanol (70 mL) and refluxed for 2 h. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 20%-70% EtOAc/hexanes as eluent) to afford the desired product as yellow solid (1.2 g, 3.72 mmol, 31%). 1H NMR: 1.35 (s, 9H), 6.90 (d, 1H, J=8.4 Hz), 7.31 (s, 1H), 7.38 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.67 (s, 1H), 8.00 (d, 1H, J=2.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]3[C:14]([CH:18]=2)=[N:15][O:16][N:17]=3)[CH:5]=[C:6](OC)[CH:7]=1.C[Sn](C)(C)[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[CH:28][N:29]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)[CH:53]=[O:54]>>[CH3:53][O:54][C:3]1[CH:2]=[CH:7][C:6]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([CH:27]=[CH:28][N:29]=3)[CH:26]=2)=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][C:13]2[C:14]([CH:18]=1)=[N:15][O:16][N:17]=2
Reactant: CN(C)C=O
Reactant: C[Sn](C)(C)c1ccc2nccn2c1
Reactant: COc1cc(Br)cc(-c2ccc3nonc3c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2ccc3nccn3c2)cc1-c1ccc2nonc2c1
Temperature: 125 °C

Procedure:
A stirred mixture of 5-(3-bromo-5-methoxyphenyl)benzofurazan (2.44 g, 8 mmol), 6-(trimethylstannyl) imidazol[1,2-a]pyridine (2.2 g, 7.9 mmol), triphenylphosphine (336 mg, 1.28 mmol), and bis(dibenzylidineacetone)palladium(0) (186 mg, 0.32 mmol) in dimethylformamide (60 mL) is heated at 125° C. under an argon atmosphere for 36 h. The solvent is evaporated off under reduced pressure to yield a crude product which is purified by chromatography (silica gel, 95% ethyl acetate/4.5% ethanol/0.5% aqueous NH3 (25%)) and recrystallised from ethyl acetate-t-butylmethyl ether to give 6-[4-methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine as a pale-yellow crystalline solid, m.p. 190-196° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[O:8][C:9]2[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=2[C:11]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:31])[CH:19]([NH:23]C(OC(C)(C)C)=O)[CH:20]([CH3:22])[CH3:21])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[O:8][C:9]2[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=2[C:11]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:31])[CH:19]([NH2:23])[CH:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(NC(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(N)C(C)C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of 49 (302 mg, 0.6 mmol) in DCM (10 mL) was added TFA (2 mL) at ambient temperature. After 2 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 235 mg (97%) of 50 as an orange oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ7.86-7.83 (m, 1H), 7.43-7.34 (m, 1H), 7.27-7.19 (m, 3H), 4.49 (m, 1H), 4.14 (q, J=6.9 Hz, 2H), 3.60-3.53 (m, 2H), 3.32 (d, J=12.9 Hz, 1H), 3.12 (app t, J=7.2 Hz, 2H), 2.81-2.74 (m, 2H), 2.42 (app t, J=12.3 Hz, 1H), 2.10-1.91 (m, 2H), 1.74-1.66 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.06-0.99 (m, 6H) ppm. Mass spectrum: m/z 401 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[CH2:15]([O:17][P:18]([CH2:23][C:24](Cl)=O)([O:20][CH2:21][CH3:22])=[O:19])[CH3:16].C([OH:29])C>>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4]([NH:3][C:2](=[O:29])[C:11]3[N:10]2[C:24]([CH2:23][P:18]([O:20][CH2:21][CH3:22])([O:17][CH2:15][CH3:16])=[O:19])=[N:13][N:12]=3)=[CH:5][CH:6]=1
Reactant: CCO
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Reactant: NNc1nc2cc(Cl)ccc2nc1Cl
Product: CCOP(=O)(Cc1nnc2c(=O)[nH]c3ccc(Cl)cc3n12)OCC

Procedure:
The title compound was prepared from 2,6-dichloro-3-hydrazinoquinoxaline (830 mg, 3.62 mmol) and (diethoxyphosphoryl)acetyl chloride (800 mg, 3.72 mmol) by the method described in example 13 (619 mg; 44%). M.p. 223°-227° C. (ethanol); 1H-NMR (DMSO-d6): δ 1.19 (t, 6H), 4.07 (quint: 4H), 4.32 (d, 2H), 7.39 (d, 1H), 7.56 (dd, 1H), 8.19 (d, 1H), 12.2 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl.Cl.[F:16][C:17]1[CH:26]=[C:25]([C:27]2[C:32]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:31][CH:30]=[CH:29][N:28]=2)[CH:24]=[CH:23][C:18]=1[C:19]([NH:21][CH3:22])=[O:20]>>[F:16][C:17]1[CH:26]=[C:25]([C:27]2[C:32]([CH:33]3[CH2:38][CH2:37][N:36]([C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=5)[N:3]=4)[CH2:35][CH2:34]3)=[N:31][CH:30]=[CH:29][N:28]=2)[CH:24]=[CH:23][C:18]=1[C:19]([NH:21][CH3:22])=[O:20]
Reactant: Fc1cccc2ccc(Cl)nc12
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CCNCC2)cc1F
Agent: Cl
Product: CNC(=O)c1ccc(-c2nccnc2C2CCN(c3ccc4cccc(F)c4n3)CC2)cc1F

Procedure:
The title compound was prepared analogously to Example 8 by using 2-chloro-8-fluoroquinoline (Combi-blocks) and 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (prepared according to Step 2 of Example 1) in Step 3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.85 (d, J=11.93 Hz, 2H) 2.04-2.19 (m, 2H) 2.91-3.03 (m, 2H) 3.09 (d, J=4.50 Hz, 3H) 3.22 (tt, J=11.61, 3.74 Hz, 1H) 4.72 (d, J=13.50 Hz, 2H) 6.80 (d, J=7.43 Hz, 1H) 7.05 (d, J=9.19 Hz, 1H) 7.08-7.15 (m, 1H) 7.20-7.25 (m, 1H) 7.32-7.39 (m, 2H) 7.44 (dd, J=8.02, 1.37 Hz, 1H) 7.88 (dd, J=9.19, 1.17 Hz, 1H) 8.27 (t, J=8.02 Hz, 1H) 8.50 (d, J=2.35 Hz, 1H) 8.55 (d, J=2.35 Hz, 1H). m/z=460 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.N1C=CC=CC=1.[S:52](Cl)(=[O:55])(=[O:54])[NH2:53].O>O1CCCC1>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][S:52]([NH2:53])(=[O:55])=[O:54])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: NS(=O)(=O)Cl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(N)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was dissolved in 0.75 ml tetrahydrofuran. Pyridine (10 μl, 0.12 mmol) and sulfamoyl chloride (11 mg, 0.10 mmol) were added and the mixture was stirred at room temperature during 2 h. The reaction was poured into water and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 38 mg (66% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH3:36].CO>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([CH3:28])([CH3:29])[C:25]([NH2:36])=[O:27])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C(N)=O)c1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
An 250-mL round bottom flask was charged with 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoic acid (0.33 g, ˜0.40 mmol) in dichloromethane (10 ml). To this mixture at 0° C. was added oxalyl chloride (0.17 mL, 2.00 mmol) followed by DMF (1 drop). After stirring for 3 h, the volatile material was removed under reduced pressure to afford crude acid chloride. The residue was dissolved in dichloromethane (20 mL), cooled to 0° C. and 7N ammonia in methanol (14.0 mL, 98 mmol) was added. After stirring for 1.25 h the volatile material was removed under reduced pressure. The residue was absorbed onto silica (5 g). Purification by chromatography on silica using hexanes/ethyl acetate as eluent afforded 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanamide (0.128 g, 79%) as a white solid. MW=404.93. 1H NMR (CDCl3, 500 MHz) δ 7.92-7.90 (m, 1H), 7.80-7.77 (m, 1H), 7.37-7.31 (m, 4H), 7.24 (s, 1H), 7.16 (d, J=8.5 Hz, 2H), 5.32 (br s, 1H), 5.16 (br s, 1H), 3.96 (s, 2H), 3.09 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.15 (quin, J=7.5 Hz, 2H), 1.57 (s, 6H). Treatment with 1.25M HCl in methanol (0.72 mL, 0.90 mmol) afforded the title compound (0.124 g, 94%) as a white solid. MW=441.39. M.p. 180-182° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.10-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.88 (br s, 1H), 7.58-7.52 (m, 2H), 7.29-7.22 (m, 4H), 6.83 (s, 2H), 5.50 (br s, 1H), 4.03 (s, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.11 (quin, J=7.5 Hz, 2H), 1.39 (s, 6H); APCI MS m/z 405 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:21]([CH3:23])[CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=2)=[CH:4][N:3]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>CN(C)C=O>[CH3:26][N:27]([CH3:29])[CH:28]=[CH:17][C:16]([C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:11]([CH:21]([CH3:23])[CH3:22])=[C:10]([CH:15]=1)[O:9][C:5]1[C:6]([N:8]=[CH:26][N:27]([CH3:29])[CH3:28])=[N:7][C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])=[N:3][CH:4]=1)=[O:18]
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(Oc2cnc(N=CN(C)C)nc2N=CN(C)C)cc1C(=O)C=CN(C)C
Temperature: 114 °C

Procedure:
To 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanone (100 mg, 0.32 mmol, from Example 16) dissolved in anhydrous N,N-dimethylformamide (0.6 mL) was added N,N-dimethylformamide dimethyl acetal (0.17 mL, 1.26 mmol) and the reaction was heated at 114° C. overnight. Concentration of the reaction mixture yielded N′-[5-[5-(3-Dimethylamino-acryloyl)-2-isopropyl-4-methoxy-phenoxy]-4-(dimethylamino-methyleneamino)-pyrimidin-2-yl]-N,N-dimethyl-formamidine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:29])[CH:14]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([S:40]([CH3:39])(=[O:42])=[O:41])[CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:29])[CH:14]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4]
Reactant: COC(=O)C1CNC2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 27 (0.9 g, 2.2 mmol) in DCM (20 mL) was cooled to 0° C. and treated with DIPEA (0.75 mL, 4.3 mmol) and DMAP (31 mg, 0.25 mmol). Methanesulfonyl chloride (0.3 mL, 3.9 mmol) was then added. After 1.5 h, the solution was diluted with DCM, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford sulfonamide 28 as an off-white foam (1.1 g) which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ5.23 (d, J=9.0 Hz, 1H), 4.74 (d, J=5.1 Hz, 1H), 4.31-4.28 (m, 2H), 4.03 (app t, J=9.3 Hz, 1H), 3.83-3.76 (m, 1H), 3.76 (s, 3H), 3.59-3.47 (m, 2H), 3.42-3.4 (m, 1H), 2.91 (s, 3H), 2.51 (dd, J=5.7, 13.8 Hz, 1H), 2.09-2.05 (m, 1H), 1.75-1.53 (m, 6H), 1.43 (s, 9H), 1.26-1.04 (m, 6H) ppm; 13C NMR (CDCl3, 75 MHz): δ172.7, 171.6, 155.9, 79.8, 66.1, 63.1, 56.9, 52.8, 50.7, 47.2, 46.2, 41.2, 35.6, 33.3, 29.8, 28.5, 28.4, 26.2, 26.1, 26.0 ppm.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)#[N:24].N12CCCN=C1CCCCC2>C(#N)C>[C:23]([CH2:25][C:26]1([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=34)[CH:3]=[N:2]2)[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)#[N:24]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 50 °C
Yield: 99.5 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (0.527 g, 1.68 mmol), tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (0.358 g, 1.84 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (135 μL, 0.903 mmol) in acetonitrile (4.0 mL) was heated at 50° C. for 1 hour. After cooling, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, neutralized with 0.5 N HCl aqueous solutions, washed brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (0.85 g, quantitative) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=509.3.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[Cl:9][C:10]1[C:11]([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]2)=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: OCC1CC=CCC1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OCC2CC=CCC2)cc1F
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
To a solution of cyclohex-3-en-1-ylmethanol (1.00 g) and 5-chloro-2,4-difluoro-benzoic acid (1.72 g) in DMSO (36 mL) at 14° C. (bath) was added potassium tert-butoxide (2.20 g) gradually. The mixture was stirred at that temp for 5 min then at rt for 30 min. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (3×) and brine, and dried (Na2SO4). After filtration and concentration, the product was obtained as white solid (2.48 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[H][H]>C(O)C.[Pd]>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:7][CH2:8]2
Reactant: [H][H]
Reactant: COc1ccc(C2=CCc3cc(OC)c(OC)cc32)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CCc3cc(OC)c(OC)cc32)cc1

Procedure:
A solution of 5,6-dimethoxy-3-(4-methoxyphenyl)indene (1.5 g, 5.32 mmol) in 60 ml of ethanol is hydrogenated in an autoclave in the presence of palladium on carbon (10%, 25 mg) under 5 bars of hydrogen for 1.5 h. After filtration of the catalyst, the evaporation of the solvent gives an oil which gradually solidifies (1.5 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[Br:11]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#Cc1cc(F)c(N)c(Br)c1
Reaction time: 15 h
Yield: 80.4 %

Procedure:
To a stirred mixture of 4-amino-3-fluorobenzonitrile (5 g, 37 mmol) in anhydrous CH2Cl2 (40 mL) under Ar at rt was added dropwise N-bromosuccinimide (6.5 g, 37 mmol). After 15 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes to afford 4-amino-3-bromo-5-fluorobenzonitrile (6.4 g, 81%) as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.62 (dd, J=1.5, 11.1 Hz, 1H), 6.44 (s, 2H); LCMS (ESI) m/z 214, 216 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:7]([F:17])=[CH:6][C:5]=2Br.[OH-].[H][H]>C(O)C.[C].[Pd]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[C:7]([F:17])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(N3CCOCC3)c(F)cc(Br)c2[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(N3CCOCC3)c(F)ccc2[nH]1
Yield: 65.7 %

Procedure:
To a solution of 24 g of 2-methyl-4-morpholino-5-fluoro-7-bromoindole in 200 ml of ethanol was added 1 g of palladium-carbon and then 15 ml of a 20% aqueous sodiium hydroxide solution. This mixture was subjected to catalytic reduction at room temperature and at atmospheric pressure. The reaction was stopped when a theoretical amount (about 1.7 l) of hydrogen was absorbed, and the catalyst was removed by filtration followed by concentration. The residue was purified through silica gel column chromatography (Wako gel C-200; eluent:chloroform:n-hexane=5:1) to give 11.8 g of 2-methyl-4-morpholino-5-fluoroindole.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1nc([C@@H](C)N)n2-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2c1nc([C@@H](C)Nc1ncnc3[nH]cnc13)n2-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (R)-1-(4-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 2 (100 mg, 0.398 mmol), 6-chloro-9H-purine (68 mg, 0.438 mmol) and DIPEA (83 μL, 0.478 mmol) in n-butanol (1 mL) was stirred in a sealed vial at 100° C. for 20 h. After cooling to RT, the mixture was partitioned between DCM and water. The organic layer was then separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then sonicated in cyclohexane affording 109 as a brown solid (62 mg, 42%) LCMS: RT 3.17 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.18-8.06 (2H, m), 7.95-7.86 (1H, m), 7.66-7.45 (5H, m), 7.11-7.00 (2H, m), 6.86 (1H, d, J=7.81 Hz), 5.49 (1H, br), 2.56 (3H, s), 1.57 (3H, d, J=6.84 Hz)