Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[Li]CCCC.[C:31]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:43]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][C:49]=2[CH3:55])[CH2:44][CH:45]([CH3:47])[CH3:46])(=[O:42])=[O:41])=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>O1CCCC1>[CH3:55][C:49]1[CH:50]=[C:51]([CH3:54])[CH:52]=[CH:53][C:48]=1[N:43]([CH2:44][CH:45]([CH3:47])[CH3:46])[S:40]([C:37]1[CH:38]=[CH:39][C:34]([C:31]([OH:33])([CH3:32])[CH2:1][C:2]2[N:3]=[N:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(C)(O)Cc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 15.3 %

Procedure:
To a solution of 5-methyl-2-trityl-2H-tetrazole (68.5 mg, 0.21 mmol) in tetrahydrofuran (THF) (1 mL) stirred under nitrogen at −70° C., was added a solution of n-BuLi (1.6 M in hexanes, 0.144 mL, 0.231 mmol) and tetrahydrofuran (THF) (1 mL) dropwise over 1 minute. The reaction mixture was stirred at −78° C. for 45 minutes, then 4-acetyl-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (106 mg, 0.294 mmol) in tetrahydrofuran (THF) (1 mL) was added dropwise at −78° C. over 1 minute. The reaction mixture was stirred at −78° C. for 1 hour, then allowed to warm to room temperature. The reaction was carefully quenched using a few drops of water under nitrogen. Ethyl acetate (3 mL) and water (2 mL) were then added and the reaction stirred vigorously for 5 minutes. The organic phase was separated using a hydrophilic frit and concentrated in vacuo to give a residue. LCMS analysis showed incomplete reaction, so the above reaction procedure repeated using fresh n-butyl lithium solution and reintroducing the crude residue instead of new starting material, this resulted in improved conversion. The residue was then purified by flash silica (Si) chromatography (using a 0-25% ethyl acetate-cyclohexane gradient) to give the required product (22 mg) as a colourless gum. LCMS (M+1) 686, RT 1.57 mins.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH2:12])[NH:8][C:5]2=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[C:54]([N:56]1[CH2:60][CH:59]=[CH:58][CH2:57]1)=[O:55])[C:48](O)=[O:49]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][C:48](=[O:49])[C:47]3[CH:51]=[CH:52][C:53]([C:54]([N:56]4[CH2:57][CH:58]=[CH:59][CH2:60]4)=[O:55])=[C:45]([CH3:44])[CH:46]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NCc1nc2cc(Br)cnc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NCc2nc3cc(Br)cnc3[nH]2)ccc1C(=O)N1CC=CC1

Procedure:
Prepared analogously to Example 1g from C-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)methylamine, TBTU, diisopropylethylamine, and 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid in tetrahydrofuran. Purification is effected by chromatography on silica gel (gradient: dichloromethane/ethanol=100:0□80:20). Yield: 240 mg (96%); Rf value: 0.68 (silica gel; dichloromethane/ethanol=8:2+2% ammonia solution); C20H18BrN5O2 (440.30); mass spectrum: (M+H)+=440/442 (bromine isotope).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br.Br>C(O)(=O)C>[Br:14][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-tert-butylacetophenone (5 g, 28.4 mmol) in acetic acid (2 mL) was carefully (the reaction was exothermic) treated with Br2 (1.46 mL, 28.5 mmol), followed by 48% aq. HBr (0.015 mL, 0.132 mmol). The reaction was stirred at room temperature for 4 hours, then was poured onto ice and was extracted with diethyl ether. The organic phase was concentrated and was then chromatographed on silica gel, eluting with 5% ethyl acetate-hexane, followed by 10% ethyl acetate-hexane, to afford the title compound as a pale brown oil, 1.305 g (18%). 1H NMR (DMSO-d6) δ 7.94 (d, 2H, J=8.5 Hz), 7.58 (d, 2H, J=8.5 Hz), 4.90 (s, 2H), 1.31 (s, 9H); MS (ESI+) m/z 255 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:13][NH:14][O:15][CH3:16].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([N:14]([O:15][CH3:16])[CH3:13])=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc(Br)ccc1F
Yield: 90.5 %

Procedure:
A solution of compound 13 (98.0 g, 447 mmol), N,O-dimethylhydroxylamine hydrochloride (52.4 g, 537 mmol), and BOP-Cl (171 g, 671 mmol) in pyridine (490 mL) was stirred at room temperature for 3 h. After this time, the reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (2×1 L). The combined extracts were washed with 1 N hydrochloric acid (3×500 mL), saturated aqueous NaHCO3 (500 mL), brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 14 (106 g, 91%) as a pale yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.70-7.40 (m, 2H), 7.00 (d, J=8.8 Hz, 1H), 3.56 (br s, 3H), 3.35 (br s, 3H); ESI MS m/z 262 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[OH-].[Li+].Cl>CO>[OH:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:14])=[O:2])[CH2:12][CH2:11]1
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.200 g of 2-(cis-4-hydroxy-cyclohexyl)-2-methyl-propionic acid methyl ester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueous lithium hydroxide solution are added and the mixture is stirred for 16 hours at room temperature. The reaction mixture is then neutralised with 1M HCl and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60 F) based on its Rf value.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:29]=[C:28]3[C:24]([N:25]=[CH:26][N:27]3[C@@H:30]3[CH2:34][C@H:33]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:32]([OH:40])[C@H:31]3[OH:41])=[C:23]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:22]=2)[CH2:17][CH2:16]1)(C)(C)C.[ClH:58]>CO>[ClH:58].[ClH:58].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:29]=[C:28]3[C:24]([N:25]=[CH:26][N:27]3[C@@H:30]3[CH2:34][C@H:33]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:32]([OH:40])[C@H:31]3[OH:41])=[C:23]([NH:42][CH2:43][CH:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:22]=2)[CH2:17][CH2:16]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CCC(NC(=O)OC(C)(C)C)CC4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CCC(N)CC4)nc32)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
{1-[9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethyl-amino)-9H-purin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester trifluoroacetate (0.02 g, 0.03 mmol) is dissolved in HCl (1 ml of a 1.25 M solution in methanol) and allowed to stand at room temperature overnight. The solvent is removed in vacuo to yield the titled compound.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9].[I:15][Cl:16].Cl>CO>[ClH:16].[I:15][C:12]1[CH:11]=[C:10]([CH3:14])[C:8]([NH2:9])=[C:7]([CH3:6])[CH:13]=1
Reactant: Cc1cccc(C)c1N
Reactant: ClI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(I)cc(C)c1N
Reaction time: 3 h

Procedure:
To a suspension of sodium bicarbonate (126 g, 1.5 moles) and 2,6-dimethylaniline (61.5 mL, 500 mmoles) in methanol (700 mL) was added iodine monochloride (1.0 M in dichloromethane, 550 mL, 550 mmoles) at room temperature over 1 h. After addition was complete, stirring was continued for 3 h. The reaction was filtered to remove excess sodium bicarbonate and the solvent removed in vacuo. The residue was re-dissolved in diethyl ether (1.5 L) and treated with hydrochloric acid (2M in ether, 375 mL, 750 mmoles). The resulting suspension was stored in the freezer (−15° C.) overnight. The solid was filtered and washed with diethyl ether until it became colorless, to give 126.5 g (89%) as a grey-green powder. 1H-NMR (DMSO-d6) δ 2.33 (s, 6H), 7.48 (s, 2H), 9.05 (bs, 3H); 13C-NMR (DMSO-d6) δ 17.4, 91.5, 133.1, 131.2, 136.9.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](Cl)(=[O:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:3]1([CH2:2][CH2:1][NH:9][C:10](=[O:13])[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCCc1ccccc1

Procedure:
The title compound was prepared in a reaction between phenethylamine (12.1 g, 100 mmol), propionyl chloride (9.25 g, 100 mmol) and triethylamine (20 ml) in methylene chloride (200 ml). The product (10.1 g) was used without purification; MS [M+H]+ 178.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].I[CH:19]([CH3:21])[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[N:9]([CH:19]([CH3:21])[CH3:20])[C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc2c(c1)OCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OCC(=O)N2C(C)C
Temperature: 25 °C
Yield: 24.9 %

Procedure:
To a solution of 7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.00 g) in dimethylformamide (10 ml) were added 60% sodium hydride (in oil) (0.25 g) and 2-iodopropane (1.00 g) and the mixture was stirred at room temperature for a day. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.30 g).
Reaction SMILES: [C-:1]#[N:2].C([Al+]CC)C.[CH3:8][O:9][C:10]1[CH:27]=[CH:26][C:25]2[C:24]3[C:23](=[O:28])[CH2:22][C@@:20]4([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]4[O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[C:15]=3[CH2:14][CH2:13][C:12]=2[CH:11]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C@@:15]12[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([O:9][CH3:8])[CH:27]=[CH:26][C:25]=3[C@H:24]1[C:23](=[O:28])[CH2:22][C@@:20]1([CH3:21])[C@H:16]2[CH2:17][CH2:18][C@@H:19]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)CCC1=C2C(=O)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Agent: CC[Al+]CC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CC[C@]1(C#N)[C@@H]2C(=O)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@H]21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
195 ml of diethylaluminum cyanide (1.0 M, in toluene) was added in drops at a temperature of −5° C. under argon to a solution of 24.5 g of 11-ketosteroid 2 in 330 ml of toluene, and it was stirred for 1.5 hours while cooling was continued. Then, the mixture was poured onto 470 ml of ice-cooled 1N sodium hydroxide solution, stirred for 1 hour, extracted several times with ethyl acetate, and the collected organic phases were washed with water and brine and dried with magnesium sulfate. The chromatography of the evaporation residue on silica gel (solvent mixture: cyclohexane/ethyl acetate=4/1) yielded 3 as a foam in a yield of a total of 12.0 g (37%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([CH:15]([C:19]([OH:21])=[O:20])[C:16]([OH:18])=O)(C)(C)C>>[C:3]([O:21][C:19]([C:15]1[C:16](=[O:18])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)=[O:20])([CH3:6])([CH3:4])[CH3:2]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CC(C)(C)C(C(=O)O)C(=O)O
Product: CC(C)(C)OC(=O)c1cc2ccc(O)cc2oc1=O

Procedure:
2,4-dihydroxyl benzaldehyde and tert-butyl malonic acid are reacted to obtain 7-hydroxyl-3-coumarin formic acid tert-butyl ester, which in turn is Mitsunobu condensed with 2-(5-methyl-2-phenyl-4-oxazole)ethanol to obtain the compound 17. The solvents used in Mitsunobu reaction are the anhydrous inert solvents, such as anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous benzene, anhydrous ether, chloroform, dichloromethane or the like, and the anhydrous tetrahydrofuran is preferable. The reaction temperature is between −10-100° C., and the room temperature is preferable. The reaction time is between 0.1-72 hours, and 24 hours are preferable.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13](=[O:35])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][C:15]=3[O:33][CH3:34])[C:5]=2[N:4]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCOCC>N1C=CC=CC=1>[CH3:34][O:33][C:15]1[CH:16]=[C:17]([C:20]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C:11]1[C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[NH:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(CN)nc12
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(CNS(C)(=O)=O)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To an ice-bath-cooled solution of N-(2-aminomethyl-1H-benzimidazol-4-yl)-2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (100 mg) in pyridine (5 ml) was added methanesulfonyl chloride (24.4 mg) and the solution was stirred at room temperature for 4 hours. After removing the solvent by evaporation, the product was purified by silica gel column chromatography (chloroform) to give a syrup and the syrup was solidified with ether to give 2-methoxy-N-(2-methanesulfonylaminomethyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (98 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Cu][C:13]#[N:14]>CC(N(C)C)=O>[C:13]([C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)#[N:14]
Reactant: COC(=O)c1ncc(Br)cn1
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ncc(C#N)cn1
Temperature: 110 °C
Yield: 47.9 %

Procedure:
To a mixture of methyl 5-bromopyrimidine-2-carboxylate (2.30 g, 10.6 mmol) and copper (I) cyanide (1.92 g, 21.4 mmol) in a 100 mL round bottom flask was added DMA (21 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 min. The reaction mixture was heated to 110° C. for 2 d and cooled to room temperature. The reaction mixture was diluted with EtOAc and water and filtered through a glass frit (medium). The filtrate was transferred to a separatory funnel. The aqueous phase was extracted with EtOAc (4×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, concentrated to give a yellow oil. Purification by flash column chromatography on silica gel (80 g, 5% to 50% EtOAc in heptane) gave methyl 5-cyanopyrimidine-2-carboxylate (0.83 g, 5.08 mmol, 48% yield) as a white solid. LC/MS (ESI+) m/z=164.0 (M+H). Calculated for C7H5N3O2 163.0.
Reaction SMILES: Br[C:2]1[C:3]2[NH:10][CH:9]=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[C:11]([Si](C)(C)C)#[CH:12]>>[C:11]([C:2]1[C:3]2[NH:10][CH:9]=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1)#[CH:12]
Reactant: Brc1cncc2nc[nH]c12
Reactant: C#C[Si](C)(C)C
Product: C#Cc1cncc2nc[nH]c12

Procedure:
The title compound can be synthesized from 7-ethynyl-1H-imidazo[4,5-c]pyridine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl) benzamide in a manner similar to that described for Example 1. 7-ethynyl-1H-imidazo[4,5-c]pyridine is prepared from 7-bromo-1H-Imidazo[4,5-c]pyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:15]1[C:25]2=[C:26]3[C:21](=[CH:22][CH:23]=[CH:24]2)[CH2:20][CH2:19][C:18](=[O:27])[N:17]3[CH2:16]1.N.C1(C)C(CC#N)=CC=CC=1>O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]([C:23]2[CH:22]=[C:21]3[C:26]4=[C:25]([CH2:15][CH2:16][N:17]4[C:18](=[O:27])[CH2:19][CH2:20]3)[CH:24]=2)=[O:14])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C1CCc2cccc3c2N1CC3
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Agent: Cc1ccccc1CC#N
Agent: N
Solvent: O
Product: CC(=O)N1CCC(CCC(=O)c2cc3c4c(c2)CCN4C(=O)CC3)CC1
Temperature: 105 °C
Reaction time: 7 h
Yield: 98 %

Procedure:
A mixture of 1-acetyl-4-piperidinepropionic acid (1.99 g, 9.99 mmol), 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one (1.73 g, 9.99 mmol) and polyphosphoric acid (24 g) was stirred at about 105° C. for 7 hours under nitrogen. Cold water (16 mL) at about 5° C. was slowly added dropwise thereto at −40 to 70° C. and 25% aqueous ammonia was added dropwise thereto at 40 to 50° C. to adjust pH to 8.5. A mixture of toluene-acetonitrile (1:1) (20 mL) was added. The layers were separated, a mixture of toluene-acetonitrile (1:1) (10 mL) was added to the aqueous layer, and the layers were separated. The organic layers were combined, and concentrated to a volume of the solution of ⅕. Diisoporpyl ether (7 mL) was added to the residue to precipitate crystals. The mixture was stirred at about 25° C. for about 1 hour and then at 0 to 5° C. for about 1 hour. Precipitated crystals were separated, washed with diisopropyl ether (3 mL) and dried to obtain 3.47 g (yield 98.6%) of the desired compound as crystals.
Reaction SMILES: Cl[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[Cl:8].[NH2:11][CH2:12][CH2:13][CH2:14][OH:15]>O>[Cl:8][C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: NCCCO
Solvent: O
Product: Cn1ncc(Cl)c(NCCCO)c1=O
Reaction time: 4 h
Yield: 19.3 %

Procedure:
3.58 g (20 mmoles) of 4,5-dichloro-2-methyl-3(2H)-pyridazinone and 3.76 g (50 mmoles) of 3-aminopropanol are dissolved in 35 ml of water. The mixture is boiled for 4 hours under stirring and reflux cooling, then it is cooled and extracted with 200 ml of dichloromethane. The organic phase is dried, evaporated and the crude product is subjected to chromatography on a silica gel column. Thus 0.84 g (19%) of the desired compound is obtained. M.p.: 65°-66° C., Rf =0.7.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:12](\[C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[N:19][CH:20]=2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>CO>[OH:28][C:25]1[CH:26]=[CH:27][C:22](/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:6][CH:7]=2)=[C:12](/[C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[N:19][CH:20]=2)\[CH2:13][CH3:14])=[CH:23][CH:24]=1
Reactant: CN
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)nc1
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc(O)nc1

Procedure:
Following the same procedure as described in example 11, step D, (Z)-5-(1-(4-(2-chloroethoxy)phenyl)-1-(4-hydroxyphenyl)but-1-en-2-yl)pyridin-2-ol (0.02 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (brs, 1H), 7.13 (dd, J=9.2 Hz, 2.8 Hz, 1H), 6.96 (s, 1H), 6.91 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 6.71 (d, J=8.4 Hz, 4H), 6.12 (d, J=9.2 Hz, 1H), 3.97 (t, J=5.6 Hz, 2H), 2.93 (t, J=5.6 Hz, 2H), 2.40 (s, 3H), 2.29 (q, J=7.2 Hz, 2H), 0.90 (t, J=7.2 Hz, 3H); m/z=391[M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:5]=1[CH2:6]O)([O-:3])=[O:2].S(Cl)([Cl:18])=O>>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:5]=1[CH2:6][Cl:18])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1OC
Product: COc1cc(CCl)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 86.4 %

Procedure:
570 g of 2-nitro-4,5-dimethoxybenzyl alcohol was added over 1 hour to 733 ml of thionyl chloride at 0° C. The solution was heated to 25° C. over 2 hours and to 50°-56° C. for 2 hours. The solution was cooled to 5° C. and the mixture was poured onto 12 l of ice water with stirring. The supernatant was poured off and the solid washed with water. The oily solid was blended with ice and water, filtered, and dried in a 40° C. vacuum oven to yield 535 g, 86.4% yield.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH:33]([OH:38])[C:34]([O:36]C)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:31][CH2:32][CH:33]([OH:38])[C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: COC(=O)C(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)NCC(O)C(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a mixture of 4-{[cyclohexyl(2-methyl-5-phenylthiophen-3-yl)methyl]amino}benzoic acid (300 mg) synthesized in Example 278-(7), methyl 3-amino-2-hydroxypropanoate hydrochloride (138 mg), 1-hydroxybenzotriazole monohydrate (136 mg) and triethylamine (124 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (170 mg), and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (80% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (169 mg, 46%) as a white solid.