Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].[CH:11](O)=O>>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[N:10]=[CH:11][NH:1][C:2]=2[CH:7]=1
Reactant: O=CO
Reactant: Nc1cc(Cl)c(Cl)cc1N
Product: Clc1cc2nc[nH]c2cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 200 mg of 1,2-diamino-4,5-dichlorobenzene dissolved in 5 mL of 97% formic acid was heated to 100° C. in a sealed tube for 15 hours. After cooling to room temperature, the reaction was quenched by the addition of 3.3 mL of concentrated aqueous NH4OH and stirred for 30 minutes. Following dilution with 20 mL of H2O, and extraction with 2×20 mL EtOAc, the organic phases were dried over MgSO4 and concentrated under reduced pressure to yield 210 mg of the title compound as a brown oil. No further purification was performed. RF: 0.38 (5% MeOH in CH2Cl2). 1H NMR (500 MHz, CD3OD): δ 8.22 (s, 1H), 7.74 (s, 2H). Mass Spectrum (ESI) 188 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:8]([NH2:10])=S.[CH2:18](N)[CH2:19][NH2:20]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:8]1[NH:20][CH2:19][CH2:18][N:10]=1)([CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C(N)=S)(c1ccccc1)c1ccccn1
Reactant: NCCN
Product: CC(C1=NCCN1)(c1ccccc1)c1ccccn1
Temperature: 140 °C

Procedure:
Under a nitrogen atmosphere, heat (bath at 140° C) under reflux conditions 2 g. of α-(2-pyridyl)-α-phenylthiopropionamide and 20 ml. of ethylene diamine. Evaporate off the excess diamine, dissolve the residue in benzene, filter, wash, dry and evaporate the benzene solution. Crystallize the residual pale green oil from isopropyl ether to yield 2-[α-(2-pyridyl)-α-methylbenzyl]-imidazoline, m.p. 102°-103° C. The maleate salt, crystallized from acetonitrile, melts at 156.5°-158° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.[I:14]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[I:14]
Reactant: II
Reactant: Fc1cccc(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
(Roe, A. M.; Burton, R A.: Willey, G. L., Baines, M. W., Rasmussen, A. C. J. Med. Chem. 1968, 11, 814-819. Tamborski, C., Soloski, E. J. Org. Chem. 1966, 31, 746-749. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J.; Sall, D. J. J. Med. Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78° C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N2. By controlling the addition rate the internal temperature was maintained below −70° C. The total addition time was ˜½ hour. The resulting slurry was stirred an additional ½ hour, then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate that maintained an internal temperature below −70° C. After complete addition the mixture was allowed to warm to room temperature, and was treated with H2O (100 mL) and 10% aqueous Na2S2O3 solution (100 mL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2×250 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at ˜1-5 mm at ˜80° C. provided a light yellow oil (89.5 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.87 (m, 2H) GCMS m/e 240 (M+).
Reaction SMILES: [O:1]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([OH:18])=O.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[O:1]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([Cl:21])=[O:18]
Reactant: O=C(O)CCC1CCCCCCCCCCC1=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CCC1CCCCCCCCCCC1=O
Reaction time: 8 h

Procedure:
Ten parts of β-(2-oxocyclododecyl)propionic acid, 6 parts of thionyl chloride, and 35 parts of anhydrous benzene were placed into a reactor and allowed to stand at 0° C for 3 hours and further at room temperature overnight. Then, the excess amount of thionyl chloride and the benzene were distilled off under reduced pressure to give β-(2-oxocyclododecyl)propionic acid chloride. The acid chloride was dissolved in 25 parts of benzene. Into the resulting solution was added dropwise 35 parts of benzene solution containing 30 wt.% pyridine and the mixture was stirred for 6 hours. The produced crystals were filtered off. The filtrate was washed with dilute hydrochloric acid to remove excess pyridine, the organic layer was washed to remove the hydrochloric acid, and then dried with Glauber's salt. Thereafter the resulting solution was treated by the same method as in Example 1 to give 6.3 parts of 13-oxabicyclo(10.4.0)-hexadec-1(12)-en-14-one in 68.4% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:18]=1[O:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:21]1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:18]=3[O:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:21]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(Cl)cc1O[C@H]1CCCN(C(=O)C(F)(F)F)C1
Product: COC(=O)c1sc2ncnc(Nc3ccc(Cl)cc3O[C@H]3CCCN(C(=O)C(F)(F)F)C3)c2c1C
Reaction time: 2 h

Procedure:
Prepared analogously to example 65.1. from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (S)-1-(3-(2-amino-5-chlorophenoxy)piperidin-1-yl)-2,2,2-trifluoroethanone. The temperature was 110° C. for 2 h and no purification with chromatography was necessarily.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:35]1CCOC[CH2:36]1>>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=[C:11]([N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:20][C:36]3=[O:35])[N:12]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccccc1Nc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Reactant: C1COCCO1
Product: O=c1[nH]c2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Temperature: 110 °C
Yield: 32 %

Procedure:
A mixture of N-[4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)-thieno[3,2-d]pyrimidin-2-yl]benzene-1,2-diamine (50 mg, 0.10 mmol) and N,N′-carbonyldiimidazole (50 mg, 0.31 mmol) in 1,4-dioxane (0 5 mL) was heated at 110° C. for 4 h. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 96:4) to afford 173 as a tan solid (17 mg, 32%). LCMS (method E): RT=6.42 min, [M+H]+=508.1. 1H NMR (CDCl3, 400 MHz) δ 8.50 (bs, 1 H), 7.76-7.72 (m, 1 H), 7.32 (s, 1 H), 7.13-7.04 (m, 3 H), 4.05 (t, J=4.7 Hz, 4 H), 3.97 (s, 2 H), 3.86 (t, J=4.7 Hz, 4 H), 3.73 (m, 4 H), 3.62 (m, 2 H), 3.06 (s, 3 H), 2.33 (m, 4 H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:26]=[CH:25][C:10]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=2)=[O:12])=[CH:9][CH:8]=1.[H-].[Na+].[C:29]1([CH2:35][CH2:36][CH2:37][CH:38]([C:49]([O-:51])=[O:50])[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([CH2:35][CH2:36][CH2:37][C:38]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([CH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:10]3[CH:25]=[CH:26][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:8][CH:9]=3)=[CH:18][CH:19]=2)([C:49]([O:51][CH2:2][C:7]2[CH:26]=[CH:25][CH:10]=[CH:9][CH:8]=2)=[O:50])[C:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(NCCCc1ccc(CCl)cc1)c1ccc(-c2ccccn2)cc1
Reactant: O=C([O-])C(CCCc1ccccc1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(NCCCc1ccc(CC(CCCc2ccccc2)(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1)c1ccc(-c2ccccn2)cc1
Yield: 133 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using 4-[3-(4-pyridine-2-ylbenzoylamino)propyl]benzylchloride (488 mg), which is the product of Reference example 50(c), sodium hydride (55% suspension in oil, 64 mg) and benzyl (3-phenylpropyl)malonate (540 mg) and the reaction mixture was treated to afford the title compound (0.65 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].O.[C:39]([O:42][CH2:43][CH3:44])(=O)C>>[C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH2:44][C@H:43]1[CH2:39][O:42]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[C:2]([Cl:1])[CH:7]=1)#[N:20]
Reactant: CCOC(C)=O
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl
Temperature: 50 °C

Procedure:
N-[2-Chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-methylurea (600 mg) was added to dimethylformamide (4 ml), and then p-toluenesulfonic acid (2R)-glycidyl ester (484 mg) and potassium carbonate (450 mg) were added thereto and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized with ethyl acetate to obtain the title compound (650 mg) as light yellow crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30]([CH2:32][C:33](Cl)=[O:34])#[N:31]>>[C:30]([CH2:32][C:33]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)=[O:34])#[N:31]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: N#CCC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)CC#N)C3)cc1

Procedure:
Compound ex was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-cyanoacetyl chloride. LC-MS: m/z=+464 (M+H)+.
Reaction SMILES: C(OC(N[C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.[C:15]([O:19][C:20]([NH:22][C@H]1CCNC1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH:14]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: CC(C)(C)OC(=O)NC1CCNCC1

Procedure:
3-(S)-tert-butoxycarbonylaminopiperidine (B=formula (2)) and 3-(S)-tert-butoxycarbonylaminopyrrolidine (B=formula (3)) (Synth. Comm. 1998, 28, 3919) in the last two cases Y=COOC(CH3)3; tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-exo-carbamate (B=formula (4), tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-endo-carbamate (B=formula (5)) (J. Med. Chem. 1991, 34, 656), tert-butyl 9-azabicyclo[3.3.1]-non-3-yl exo-carbamate (B=formula (6)) and tert-butyl 9-azabicyclo-[3.3.1]-non-3-yl-endo-carbamate (B=formula (7)), (J. Med. Chem. 1993, 36, 3720)) (Y=COOC(CH3)3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.C1COCC1.[Pd]>[N:10]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: O=[N+]([O-])c1cccc(-n2ccnn2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(-n2ccnn2)c1
Yield: 101.6 %

Procedure:
1-(3-Nitro-phenyl)-1H-[1,2,3]triazole (9.66 g, 51 mmol) were dissolved in 300 ml methanol and 70 ml THF. Palladium on charcoal (10%, 500 mg) were added and the reaction mixture was stirred with a hydrogen balloon for 36 h. Palladium on charcoal was filtered off and washed with methanol. The solvent was evaporated off to yield the title compound (8.3 g, 100%) as an off-white solid, mp 71-73° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][CH2:6][NH:7][C:8](=O)[O:9]CC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:8](=[O:9])[NH:7][CH2:6][CH2:5]2
Reactant: CCOC(=O)NCCc1cccc(C)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)CCNC2=O
Yield: 19 %

Procedure:
Ethyl 3-methylphenethylcarbamate (I-69c: 13.5 g, 65.217 mmol) was reacted with P2O5 (18.51 g, 130.434 mmol) and POCl3 (135 mL) at 110° C. for 1 hour. The reaction mass was concentrated under reduced pressure, quenched with ice, basified using saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 2 g of the product (19% yield). LCMS: 75.24%, m/z=162.3 (M+1)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[N:3]=[N:2]1.Cl.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[O:20])[CH2:17][CH2:18]2)=[O:10])[N:3]=[N:2]1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)CCc1c[nH]nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(1H-1,2,3-Triazol-4-yl)propanoic acid (step 2) (42 mg, 0.294 mmol) and 3,5-dichlorobenzyl 4-aminopiperidine-1-carboxylate hydrochloride (Example 17, step 2) (100 mg, 0.294 mmol) were dissolved in DMF (1 ml) and treated with DIPEA (257 μl, 1.472 mmol) followed by 50% T3P® solution in DMF (344 μl, 0.589 mmol). The reaction mixture was stirred at RT for 2 days and then concentrated under reduced pressure. The crude product was dissolved in DCM and washed with 10% citric acid. The organic portion was separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure. Purification by chromatography on silica eluting with 0-10% MeOH in EtOAc afforded the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[C:13]3[CH3:18])=[CH:7][CH:8]=1
Reactant: CCCCCI
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc2c(C)cccc2c1-c1ccc(OC)cc1
Yield: 4.5 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.23 g, 1.0 mmol), sodium hydride (60% in oil, 0.048 g, 1.2 mmol) and 1-iodopentane (0.26 mL, 2.0 mmol) to give the title compound (0.014 g). Used as is in the next step.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:37])([F:36])[O:15][C:16]1[CH:17]=[C:18]([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)[C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[C:39]1([CH2:38][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:36])([F:37])[F:13])[CH:17]=2)[C:23]#[N:24])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
To a solution of diisopropyl amine (2.48 mL, 17.5 mmol) in THF (60 mL) at −78° C. was added dropwise n-BuLi (1.6 M in hexane, 11.5 mL, 18.3 mmol) and the reaction mixture was stirred for 5 min. A solution of (2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile (5.51 g, 15.3 mmol), prepared as described in Procedure 14, in THF (5 mL) was added dropwise to the reaction mixture and stirred for 1h. Benzyl bromide (2.17 mL, 18.3 mmol) was added dropwise, then the cooling bath was removed and the reaction mixture was stirred at rt for 45 min. The reaction mixture was poured into H2O (75 mL) and extracted with diethyl ether (2×75 mL). The combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified on a silica gel ISCO cartridge with elution at 5 to 15% Et2O/hexane to give 3-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)propanenitrile (6.75 g, 98% yield) as a clear yellow oil. LCMS: RT=2.18 min [M-CN] 425.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H(CDCl3) ppm 3.63 (s, 2 H), 6.87 (d, J=7.03 Hz, 2 H), 7.15-7.26 (m, 9 H), 7.40 (t, J=8.13 Hz, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:43]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:14]=[C:6]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([O-:45])=[O:44]
Reactant: CC(C)(C)OC(=O)c1cc(O)cc(C(=O)OC(C)(C)C)c1
Reactant: O=C(CCCCCCCCCCBr)OCc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCCC(=O)OCc2ccccc2[N+](=O)[O-])cc(C(=O)OC(C)(C)C)c1

Procedure:
Previously prepared di-tert-butyl 5-hydroxyisophthalate (0.597 g, 2.03 mmol) and previously prepared 2-nitrobenzyl 11-bromoundecanoate (1.62 g, 4.06 mmol) were combined and dissolved in acetone (50 mL), producing a light yellow solution. Potassium carbonate (0.505 g, 3.65 mmol) was added and the mixture was heated to reflux for 40 hours. The mixture was filtered using vacuum filtration, and the solvent was removed from the filtrate by rotovap. The crude product was purified with silica gel column chromatography with CH2Cl2: hexanes (v/v 5:1) as eluent to afford the product as a yellow oil, which was dried by vacuum. Yield: 0.152 g (12.2%). 1H-NMR (CDCl3) δ (ppm): 8.2 (s, 1H, Ar) 8.1 (d, 1H, Ar), 7.7 (s, 2H, Ar) 7.6 (t, 1H, Ar), 7.5 (d, 1H, Ar), 7.4 (t, 1H, Ar), 5.5 (s, 2H, O—CH2), 4.0 (t, 2H, CH2—O), 2.4 (t, 2H, CH2—C═O), 1.8 (m, 2H, CH2), 1.6 (m, 2H, CH2), 1.6 (s, 18H, CH3), 1.4 (m, 2H, CH2), 1.3 (m, 10H, CH2). 13C-NMR (CDCl3) δ (ppm): 173.5, 165.4, 159.3, 147.9, 134.1, 133.7, 132.7, 129.4, 129.1, 125.4, 122.9, 119.5, 81.9, 68.8, 63.1, 34.5, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 28.5, 26.3, 25.3.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH3:24])[C:9]3[N:13]=[C:12]([C:14]4[C:15]([O:21]C)=[N:16][CH:17]=[CH:18][C:19]=4[I:20])[NH:11][C:10]=3[CH:23]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>Cl.C(OCC)(=O)C>[N:1]1([C:6]2[CH:7]=[C:8]([CH3:24])[C:9]3[N:13]=[C:12]([C:14]4[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=4[I:20])[NH:11][C:10]=3[CH:23]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1nccc(I)c1-c1nc2c(C)cc(-n3ccnc3)cc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(I)cc[nH]c3=O)nc12
Temperature: 70 °C
Yield: 81 %

Procedure:
The suspension of 6-imidazol-1-yl-2-(4-iodo-2-methoxy-pyridin-3-yl)-4-methyl-1H-benzimidazole in 1 N HCl (6 mL) was heated to 70° C. for 3 days, cooled to room temperature, and diluted with ethyl acetate. After extraction, the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (1% NH4OH/10% MeOH/CH2Cl2) to yield the title compound (78 mg, 81%) as a solid. 1H NMR (300 MHz, CD3OD) δ 8.12 (1H, s), 7.58 (2H, s), 7.29–7.31 (2H, m), 7.16 (1H, s), 7.01 (1H, J=6.8 Hz), 2.66 (3H, s). LCMS (M+H)+ m/z 418 (t=0.75 min.)
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4]1.[CH2:11]([NH:13][C:14]1[C:19]([CH:20]=O)=[CH:18][N:17]=[C:16]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:15]=1)[CH3:12].O>C(OCCO)C>[CH2:11]([N:13]1[C:14]2[N:15]=[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:17]=[CH:18][C:19]=2[CH:20]=[C:8]([C:5]2[CH:6]=[CH:7][S:3][CH:4]=2)[C:9]1=[NH:10])[CH3:12]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Reactant: N#CCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Product: CCn1c(=N)c(-c2ccsc2)cc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of 2-ethoxyethanol was added 3-thiopheneacetonitrile (168 mg, 1.36 mmol). After stirring for 5 minutes at room temperature, 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.24 mmol) was added, and the reaction heated at 120° C. for 2 hours, resulting in a dark brown solution. Upon cooling, the solution was poured into water which caused precipitation. The resulting precipitate was removed by filtration and washed with water. The crude product was purified by flash chromatography, eluting with 5% methanol/methylene chloride, followed by 10% methanol/methylene chloride. Concentration of product fractions yielded 340 mg (78%) of (8-ethyl-7-imino-6-thiophen-3-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine; mp 220°-222° C.