Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[OH-].[K+].[ClH:21].[Cl:22][CH2:23][C:24]1[C:25]([NH:35][CH3:36])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=2.Cl.CO>C1(C)C=CC=CC=1>[ClH:22].[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:23][C:24]1[C:25]([NH:35][CH3:36])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=2
Reactant: CNc1nc2ccc(C)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCc1nc(O)c(Cc2cc3cc(C)ccc3nc2NC)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1 mmol) in toluene (15 mL) in a 20 mL microwave vial was added a 2 N KOH solution (1 mL, 2 mmol) following by 3-(chloromethyl)-N,6-dimethylquinolin-2-amine hydrochloride MDE 32062 (352 mg, 1.2 mmol). The reaction mixture was stirred at 160° C. for 1.5 h under microwave irradiation then cooled to RT. The volatiles were removed under vacuum and the residue was taken back in a mixture of CH2Cl2:MeOH=9:1 (50 mL). The organic layer was washed with water (3×20 mL), brine (20 mL), dried over Na2SO4, filtered and evaporated to give yellow solid that was purified by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 90:10) to give, after evaporation and drying, 6,7-dimethoxy-4-(6-methyl-2-methylamino-quinolin-3-ylmethyl)-1-propyl-isoquinolin-3-ol (26 mg). This free base was dissolved in MeOH (5 mL) and a 0.19 N HCl solution in MeOH (600 μL, 0.11 mmol) was slowly added. The reaction mixture was stirred at 4° C. for 15 min. After evaporation of the solvent and drying under vacuum pump over P2O5, 6,7-dimethoxy-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol hydrochloride 34 was obtained as a yellow solid (28.7 mg, 5% yield).
Reaction SMILES: N1(C2C=CC(C[C:11]3[C:12]([O:24][CH3:25])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4C)=CC=2)C=CC=N1.[S:28]1[C:32]([CH2:33]C2C(Cl)=NC3C(C=2Cl)=CC(Br)=CC=3)=[CH:31][C:30]2[CH:47]=[CH:48][CH:49]=[CH:50][C:29]1=2.N1(C2C=CC(CC3C(OC)=NC4C(C=3Cl)=CC(Br)=CC=4)=CC=2)C=CC=N1>>[S:28]1[C:32]([CH2:33][C:11]2[C:12]([O:24][CH3:25])=[N:13][C:14]3[C:19]([C:20]=2[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=3)=[CH:31][C:30]2[CH:47]=[CH:48][CH:49]=[CH:50][C:29]1=2
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1cc2ccccc2s1
Agent: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1cc2ccccc2s1

Procedure:
The title compound was prepared by substituting 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (Intermediate 6: step c) with 3-(benzo[b]thiophen-2-ylmethyl)-6-bromo-2,4-dichloroquinoline (Intermediate 10: step c) then following the procedure described for the preparation of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (Intermediate 16).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:13]([CH3:12])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:6]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(F)c(Cl)c1
Reaction time: 8 h
Yield: 29 %

Procedure:
3-Chloro-4-fluorobenzoyl chloride (60 mg, 0.31 mmol, CAS RN 65055-17-6) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μL, 0.45 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the product as a waxy solid (23 mg, 29%). MS (ESI): m/z=355.0 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:14][C:15]([OH:17])=O)=[CH2:2].Cl.[N:19]1([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]3[C:31](=[O:34])[O:32][CH2:33][C:29]=3[CH:28]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:14][C:15]([N:22]1[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]3[C:31](=[O:34])[O:32][CH2:33][C:29]=3[CH:28]=2)[CH2:20][CH2:21]1)=[O:17])=[CH2:2]
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: C=Cc1cc(-n2cnnn2)ccc1CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C=Cc1cc(-n2cnnn2)ccc1CC(=O)N1CCN(CCc2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [2-ethenyl-4-(1H-tetrazol-1-yl)phenyl]acetic acid (43 mg, 0.19 mmol) in 10 mL of anhydrous DCM was added 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (53 mg, 0.19 mmol), EDC (56 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), TEA (115 mg, 1.14 mmol) and then stirred at ambient temperature overnight. Then DCM was added and then mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to afford 5-[2-(4-{[2-ethenyl-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 9.0 (s, 1H), 7.75˜7.78 (m, 2H), 7.48˜7.51 (m, 1H), 7.26˜7.31 (m, 3H), 6.76˜6.84 (rn, 1H), 5.7 (d, J=17.2 Hz, 1H), 5.44 (d, J=10.9 Hz, 1H), 5.22 (s, 2H), 3.75 (s, 2H), 3.6˜3.65 (m, 2H), 3.45˜3.48 (m, 2H), 2.86˜2.9 (m, 2H), 2.59˜2.64 (m, 2H), 2.41˜2.5 (m, 4H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)=O.O.C[N:39](C)[CH:40]=[O:41]>N>[CH:40]([NH:39][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:41]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(COS(C)(=O)=O)C4)C(=O)NC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CNC=O)C4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 120 mg of the pyrroledione product of Example 6 in 6 ml of dimethylformamide and 6 ml of 33% aqueous ammonia was heated to 140° C. for 6 hours. The cooled mixture was poured into water and the precipitate was filtered off. The product was purified by chromatography on silica gel with dichloromethane/acetic acid/methanol/water (60:18:2:3). Trituration with ethyl acetate gave 50 mg of 3-[8-(formamidomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 332°-334° C.
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([OH:23])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[CH2:25](O)[CH3:26]>>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH2:25][CH3:26])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCO
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: Cl
Product: CCCCCCCCCCCc1cc2ccc(C(=O)OCC)cc2[nH]1

Procedure:
A solution of 2-(n-undecyl)indole-6-carboxylic acid (11.9 g) in ethanol (50 ml) containing a solution of hydrogen chloride gas in ethanol (75 ml, of strength 39% w/v) was refluxed for 4.5 hours. The solution was cooled and a solid was collected which was dissolved in diethyl ether, and the ethereal solution was washed with water (2×100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to give a residue which was recrystallised from methanol to give ethyl 2-(n-undecyl)indole-6-carboxylate (6.2 g), in the form of very pale yellow needles, m.p. 84°-86° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: c1ccc2c(c1)CNC2
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2Cc3ccccc3C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A mixture of 2-(1, 2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), Isoindoline (23 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 16.3 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(isoindolin-2-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.C[Al](C)C.[Si:21]([O:38][C@H:39]1[CH2:43][CH2:42][O:41][C:40]1=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Si:21]([O:38][C@@H:39]([CH2:43][CH2:42][OH:41])[C:40]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:5]=1)=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](O[C@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@@H](CCO)C(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)(c1ccccc1)c1ccccc1
Yield: 99.8 %

Procedure:
Synthesized according to General Procedure 5. The reaction was set up with sulfathiazole (11.2 g, 44 mmol), CH2Cl2 (150 mL), trimethylaluminum (2.0 M in hexanes, 22 mL, 44 mmol), and (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (12.6 g, 37 mmol) in CH2Cl2 (10 mL). Purification by silica gel chromatography (10% MeOH in DCM) afforded the desired amide as a white solid (22 g, 84% yield). 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76 (dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m, 8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1, 6.7 Hz, 1H), 3.64-3.59 (m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91 (m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=596.5; tR=1.93 min.
Reaction SMILES: C(O)C#C.[H-].[Na+].[C:7]([O-:11])(=O)[C:8]#[CH:9].[Na+].Cl[C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH3:29])[N:22]=2)[N:15]=1>O1CCCC1.C(Cl)(Cl)Cl>[CH3:20][C:18]1[CH:19]=[C:14]([O:11][CH2:7][C:8]#[CH:9])[N:15]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH3:29])[N:22]=2)[N:17]=1
Reactant: C#CC(=O)[O-]
Reactant: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Agent: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C#CCOc1cc(C)nc(-c2cccc(CCC)n2)n1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of propargyl alcohol (0.82 g) in anhydrous tetrahydrofuran (80 ml) was added 60 % oily sodium hydride (0.58 g) to prepare sodium propargylate. To this solution was added at room temperature 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (3 g). The mixture was stirred for one hour and then concentrated under reduced pressure. To the redidue obtained was added chloroform (100 ml). The mixture was washed twice with water (30 ml each) and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The crystalline residue obtained was washed with hexane to obtain 4-methyl-6-propargyloxy-2-(6-n-propyl-2-pyridinyl)pyrimidine (2.7 g, yield: 83 %).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10](CCO)[CH2:9]1)=[O:7])([CH3:4])(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.CCN(C(C)C)C(C)C>[CH2:10]1[CH:9]2[N:8]([C:6](=[O:7])[O:5][CH2:1][CH2:4]2)[CH2:13][CH2:12][NH:11]1
Reactant: CC(C)(C)OC(=O)N1CCNC(CCO)C1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCCC2CNCCN12
Reaction time: 0.5 h

Procedure:
3-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.25 mmol) was dissolved in 4 mL of dichloromethane and 1 mL of DIPEA, and then triphosgene (27 mg, 0.09 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes, and the solvent was removed in vacuo. The residue was dissolved in 3 mL of dichloromethane and 1 mL of TFA. After the reaction mixture was stirred for 1 hour, the solvent was removed in vacuo to give hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one trifluoro acetitic acid salt (Compound D) as a crude product which was used directly without further purification. LC/MS: calc'd 157 (MH+), exp 157 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1>O>[CH3:13][C:14]1[C:18]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9][C:10]([OH:12])=[O:11])=[C:17]([CH3:19])[O:16][N:15]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: Cc1cc(C)on1
Solvent: O
Product: Cc1noc(C)c1C(CC(=O)O)c1ccc(O)cc1
Temperature: 130 °C
Yield: 20.96 %

Procedure:
To a 50 mL sealed was charged with (2E)-3-(4-hydroxyphenyl)prop-2-enoic acid (3.0 g, 0.018 mmol) and 3,5-dimethyl-1,2-oxazole (3.54 g, 0.054 mmol) and heated at 130° C. for 16 h. The reaction mixture diluted with water (10 mL) was added and extracted with DCM (20 mL). The combined extract was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was taken for next step with out purification (1.0 g, yield: 20.96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:25][N:26]([CH3:33])[CH2:27][CH:28]=[CH:29][C:30](Cl)=[O:31]>>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH:3]=[CH:4][C:5]=3[CH3:24])[CH:14]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Reactant: CN(C)CC=CC(=O)Cl
Product: Cc1ccc(NC(=O)/C=C/CN(C)C)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1

Procedure:
N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine (Int-F) and 4-dimethylamino-2-butenoyl chloride were combined in a manner similar to that described in Scheme 4a to give (E)-N-[3-(6-{3-chloro-4-fluorophenyl}amino-pyrimidin-4-ylamino)-4-methylphenyl]-4-(dimethylamino)but-2-enamide (I-54). MS (m/z): 455/457 (M+1, 100/39%). 1H NMR (DMSO-d6) δ 11.02 (bs, 1H), 10.66 (bs, 1H), 9.92 (bs, 1H), 9.39 (bs, 1H), 7.92-7.94 (m, 1H), 7.75 (bs, 1H), 7.27-7.56 (m, 4H), 6.80 (m, 1H), 6.54 (d, 1H), 5.89 (bs, 1H), 3.92 (bs, 2H), 2.75 (bs, 6H), 2.17 (bs, 3H).
Reaction SMILES: C[N:2](C)/[C:3](=[N:5]/[C:6]([C:8]1[N:17]=[C:16]2[N:10]([CH2:11][CH2:12][O:13][C:14]3[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:15]=32)[CH:9]=1)=O)/[CH3:4].C(O)(=O)C.Cl.[CH:29]([NH:32]N)([CH3:31])[CH3:30]>>[Br:22][C:20]1[CH:19]=[CH:18][C:15]2[C:16]3[N:10]([CH2:11][CH2:12][O:13][C:14]=2[CH:21]=1)[CH:9]=[C:8]([C:6]1[N:32]([CH:29]([CH3:31])[CH3:30])[N:2]=[C:3]([CH3:4])[N:5]=1)[N:17]=3
Reactant: CC(C)NN
Reactant: C/C(=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)N(C)C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Temperature: 95 °C
Yield: 83.8 %

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid [1-dimethylamino-eth-(E)-ylidene]-amide (0.340 g, 0.000901 mol) in acetic acid (3.0 mL, 0.053 mol) was added isopropylhydrazine hydrochloride (0.1196 g, 0.001082 mol). The reaction was heated to 95° C. for 3 h. The acetic acid was removed in vacuo and the product was loaded as a solid onto silica and purified by flash chromatography (0-10% MeOH in DCM) to give 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (293 mg) as an orange solid. MS (ESI+) 388.1/390.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10]1[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]2=1.CC(C)([O-])C.[K+].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>C1COCC1.O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:11]2[C:10]3[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]=3[C:4]3[C:12]2=[C:13]([F:15])[CH:14]=[C:2]([F:1])[CH:3]=3)=[CH:29][CH:28]=1
Reactant: O=C(O)CC1CCCc2c1[nH]c1c(F)cc(F)cc21
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 639.6 %

Procedure:
A solution of 11:1 g of acid from Step II in 100 cc of THF was added portionwise 10.3 g of potassium tert-butoxide. The resulting mixture was stirred for 45 min. at room temperature and 10.3 g p-chlorobenzyl bromide was added portionwise. the reaction mixture was stirred 18 hours at room temperature. The resulting mixture was diluted with 100 cc of water and washed with hexane. The aqueous layer was acidified with HCl (1N) and the resulting precipitate filtered washed with water and air-dried to afford 9.4 g of the title compound. m.p. 168.5°-170° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]1([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(O)Cc1cccc(Br)n1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CCCC(O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 50 °C
Yield: 77.8 %

Procedure:
1-(6-Bromopyridin-2-yl)pentan-2-ol (3.23 g, 13.2 mmol) was dissolved in 30 mL of 1,2-dimethoxyethane. Tetrakis(triphenylphosphine)palladium(0) (0.76 g, 0.66 mmol) was added and the solution was heated to 50° C. for 15 min. After cooling the solution, 2,4,6-trimethylbenzeneboronic acid (2.60 g, 15.9 mmol) in 15 mL 1,2-dimethoxyethane was added to parent solution. Potassium t-butoxide (2.96 g, 26.5 mmol) in 15 mL t-butanol was added last. The reaction was heated at 90° C. for 0.5 h. After cooling, the solution was filtered and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave the title compound (2.91 g, 77% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15]Br)[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[C-:17]#[N:18].[Na+]>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][C:17]#[N:18])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)Nc1ccc2cc(CBr)ccc2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2cc(CC#N)ccc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.9 %

Procedure:
Compound 46 (0.254 g, 0.91 mmol) was diluted with anhydrous DMF (10 mL), and NaCN (0.230 g, 4.55 mmol) was added. The orange mixture was stirred at room temperature for 17 h. The mixture was concentrated and partitioned between EtOAc and H2O (50 mL each) and the layers were separated. The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with H2O (2×80 mL) and sat aq. NaCl (50 mL), and dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography (SiO2), eluting with a gradient of 15% EtOAc in CH2Cl2 to 25% EtOAc in CH2Cl2 to yield the title compound as a white solid (0.170 g, 83%): mp 154-155° C.; 1H-NMR (500 MHz; CDCl3): δ 8.48 (d, J=8.6 Hz, 1 H), 8.22 (br s, 1 H), 8.20 (d, J=9.0 Hz, 1 H), 7.85 (d, J=8.7 Hz, 1 H), 7.81 (d, J=1.0 Hz, 1 H), 7.61 (dd, J=8.7, 2.1 Hz, 1 H), 3.96 (s, 2 H), 2.30 (s, 3 H); 13C-NMR (126 MHz; CDCl3): δ 169.1 (1 C), 151.3 (1 C), 145.8 (1 C), 138.6 (1 C), 129.8 (1 C), 128.3 (1 C), 126.74 (1 C), 126.64 (1 C), 126.2 (1 C), 117.6 (1 C), 114.9 (1 C), 25.0 (1 C), 23.7 (1 C); ESIMS m/z (rel. intensity) 472 (2M+Na+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12]
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CC(C)(C)O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)/C=C/[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 1.51 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in benzene and 0.754 ml of tert.-butanol were reacted to obtain 0.235 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclo-propane-1-carboxylate with a specific rotation of [α]D20 =-23°±1.5°(c=0.9% in chloroform).
Reaction SMILES: [CH:1]1([CH:5]([OH:7])[CH3:6])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[C:16]2[N:17]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]3)[CH:18]=[N:19][C:15]=2[CH:14]=[C:13]([Cl:28])[N:12]=1>CN(C=O)C>[Cl:28][C:13]1[N:12]=[C:11]([O:7][CH:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH3:6])[C:16]2[N:17]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]3)[CH:18]=[N:19][C:15]=2[CH:14]=1
Reactant: CC(O)C1CCC1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1nc(Cl)cc2ncn(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-cyclobutylethan-1-ol (1.76 g, 17.60 mmol) in DMF (10 mL) was added 60% NaH (1.4 g, 35.19 mmol) in several portions at 0° C. After stirring for 20 minutes, 4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (Preparative Example 2.3, 3.5 g, 11.73 mmol) in DMF (30 mL) was added slowly over a time period of 10 minutes. The reaction was then warmed to room temperature and stirred for 16 h. After this time, the reaction was quenched with ice, diluted with water (80 mL), and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with (12-15% EtOAc/petroleum ether) to yield 6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine. MS ES/APCl calc'd. for C20H28ClN3O [M+H]+ 362. found 362.