Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Clc1ccccc1CBr
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccccc1OCc1ccccc1Cl
Yield: 79.6 %

Procedure:
A solution of 2.42 g (19.47 mmol) of 2-hydroxybenzyl alcohol in 100 ml of dry acetonitrile is mixed with 4.12 g (19.47 mmol) of 2-chlorobenzyl bromide and 2.96 g (21.42 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 3.856 g (15.5 mmol, 79% yield) of a solid are obtained.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[C:7]1([C:13]2([CH2:19][C:20]#[N:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:7]1([C:13]2([CH2:19][C:20]([NH2:1])=[NH:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC1(c2ccccc2)CCCCC1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)CC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a suspension of NH4Cl (2.34 g, 43.65 mmol) in toluene (20.0 mL) was added drop-wise a solution of trimethyl aluminium (3.15 g, 43.65 mmol, 2M in toluene) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h prior to the addition of a solution of (1-phenyl-cyclohexyl)-acetonitrile (253) (2.9 g, 14.55 mmol) in toluene (10.0 mL). The resulting solution was heated to 80° C. for 16 h. The cooled reaction mixture was poured into a slurry of silica-gel (10.0 g) in CHCl3 (20.0 mL) followed by vigorous stirring for 30 min. The silica gel was filtered off and the cake was rinsed in turn with methanol. The solvent was evaporated and the crude product was taken up in 10% methanol in dichloromethane (200.0 mL) and stirred for 30 min. The solid suspension was removed by filtration and the filtrate was evaporated. The crude product was triturated in diethyl ether and the solid was collected by filtration and dried under vacuum to afford HCl-salt of 2-(1-phenyl-cyclohexyl)-acetamidine (254) (2.5 g, 68.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:26]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: COC1=CCCCCCCCC1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC1=CCCCCCCCC1
Yield: 65.7 %

Procedure:
The compound 8 (375 mg, 1 mmol) was converted to the enol ether with 1-methoxy-1-cyclodecene (505 mg, 3 mmol) in the same manner as the example 10 to give the compound 12 (336 mg, 66%) as oil. Rf 0.55 (Al2O3 60, Type E, 10:1 toluene - EtOAc).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11].[CH2:12]([O:14][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH:16]=[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:13]
Reactant: CCOC(=O)C=Cc1cccnc1
Reactant: Clc1n[nH]c2ccc(Br)cc12
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
3-(3-Chloro-1H-indazol-5-yl)-3-pyridin-3-yl-acrylic acid ethyl ester CCXXIII was prepared from 5-bromo-3-chloro-1H-indazole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][CH2:11][CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH2:15]([N:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20](=[O:22])[CH3:21])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([NH:19][C:20](=[O:22])/[CH:21]=[CH:12]/[CH2:11][O:10][CH2:9][C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: O=CCOCC#Cc1ccccc1
Reactant: CC(=O)N(CC(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: CC(C)CNC(=O)/C=C/COCC#Cc1ccccc1

Procedure:
N-isobutyl-4-(3-phenyl-2-propynoxy)-(2E)-butenamide was prepared from 2-(3-phenyl-2-propynoxy) ethanal and N-isobutyl acetamidotriphenylphosphonium chloride as in Example 9.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1(O)[C@:24]2([CH3:25])[CH:11]([CH:12]3[C:21](=[CH:22][CH2:23]2)[C@:20]2([CH3:26])[C:15](=[CH:16][C:17](=[O:27])[CH:18]=[CH:19]2)[C@@H:14]([CH3:28])[CH2:13]3)[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[C:30]([O-])([O-])([O:32]CC)[CH3:31].Cl.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:30]([C@@:1]1([CH3:2])[O:3][C@:8]2([C@:24]3([CH3:25])[CH:11]([CH:12]4[C:21](=[CH:22][CH2:23]3)[C@:20]3([CH3:26])[C:15](=[CH:16][C:17](=[O:27])[CH:18]=[CH:19]3)[C@@H:14]([CH3:28])[CH2:13]4)[CH2:10][CH2:9]2)[C:6](=[O:7])[CH2:5][O:4]1)(=[O:32])[CH3:31]
Reactant: CCOC(C)([O-])[O-]
Reactant: CC(=O)OCC(=O)C1(O)CCC2C3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC(=O)[C@]1(C)OCC(=O)[C@]2(CCC3C4C[C@H](C)C5=CC(=O)C=C[C@]5(C)C4=CC[C@@]32C)O1

Procedure:
2-((6S,10R,13S)-17-hydroxy-6,10,13-trimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate is dissolved in toluene and heated with 1.5 equivalents of ethyl orthoacetate and a trace of pyridinium hydrochloride. Ethanol is distilled off the reaction mixture to drive it to completion.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:15]2)[CH:6]=[C:7]([N+:11]([O-])=O)[C:8]=1[O:9][CH3:10].[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:15]2)[CH:6]=[C:7]([NH2:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c([N+](=O)[O-])c3)S2)cc(OC)c1OC
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(N)c1OC

Procedure:
trans-2-(3,4-Dimethoxy-5-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene (0.3 g, 0.69 mmole) was suspended in 10 ml of ethanol. To this was added CaCl2 (72.63 mg, 0.65 mmole) in 2 mL water, followed by zinc metal (1.01 g). The suspension was refluxed for 5 hours, filtered, and the residue was washed with ethanol. The combined filtrate was washed with 10% NaHCO3, water and saturated aqueous sodium chloride, dried over MgSO4 and evaporated in vacuo to an oil that was purified by flash column chromatography using 1:1 hexane/ethyl acetate as solvent (30 mg, 10.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([NH:21][C:22](=[O:24])[CH3:23])[N:10]([CH2:25][CH2:26]O)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([NH:21][C:22](=[O:24])[CH3:23])[N:10]([CH2:25][CH2:26][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCO
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
To a suspension of N-(3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (269 mg, 0.74 mmol) in CH2Cl2 (9 mL) and triethylamine (155 μl, 1.11 mmol) was added methanesulphonyl chloride (65 μl, 0.81 mmol and the reaction stirred at room temperature for 16 h. The reaction mixture was poured onto ice/water and the organic layer was dried over MgSO4, filtered and evaporated. The crude product was dissolved in THF (10 ml) and morpholine (320 μl, 3.7 mmol) was added. The reaction was heated to 55° C. for 24 h before evaporating the solvent in vacuo. The crude was partitioned between CH2Cl2 and dilute aqueous NaHCO3 and the organic layer was dried over MgSO4, filtered and evaporated. Purification using chromatography (silica gel, gradient 0 to 10% methanol/CH2Cl2) gave N-(3-(4-fluorophenyl)-1-(2-morpholinoethyl)-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide as a white solid (141 mg) which was used as such in the subsequent step.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:34][CH:35]2[CH2:38][O:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[O:37]1[CH2:38][CH:35]([CH2:34][N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[N:9]2)[CH2:36]1
Reactant: NS(=O)(=O)c1ccc(-c2n[nH]c3cc[nH]c(=O)c23)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(-c2nn(CC3COC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (52.0 mg) obtained in Step B of Example 100 in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 8.60 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added oxetan-3-ylmethyl 4-methylbenzenesulfonate (52.1 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (10.0 mg).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][S:36][CH2:37][CH2:38][C:39](O)=[O:40]>>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][CH2:37][S:36][CH3:35])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CSCCC(=O)O
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Product: CSCCC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2n1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and 3-methylsulfanyl-propionic acid (45 μL, 0.436 mmol) by a similar method to that employed in Example 16 (130 mg).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].CN(C=O)C>O>[O:8]1[CH2:9][CH2:10][CH:6]([CH2:5][N:22]2[C:18](=[O:28])[C:19]3=[CH:27][CH:26]=[CH:25][CH:24]=[C:20]3[C:21]2=[O:23])[CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC1CCOC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture comprising 30.0 g of (tetrahydro-3-furanyl)methyl tosylate, 23.0 g of potassium phthalimide and 150 ml of DMF was stirred at 80° C. for 8 hours. Water was poured into the reaction mixture, and crystals precipitated out was separated by filtration to obtain 27.0 g of N-{(tetrahydro-3-furanyl)methyl}phthalimide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:16]CC)=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([O:19][CH3:20])[N:4]=1.Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([O:19][CH3:20])[N:4]=1
Reactant: CCOC(=O)C=C(OCC)c1ccc(OC)nc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1ccc(OC)nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-ethoxyacrylate (600 mg, 2.13 mmol) in CH2Cl2 (18 mL) was gradually added 3N aqueous HCl (3.5 mL). The reaction mixture was stirred at room temperature for 2 hours, then carefully added to a saturated sodium bicarbonate solution (30 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were passed though a plug of cotton to dry and concentrated in vacuo. The resulting oil was purified by flash chromatography (0-60% EtOAc/heptanes) to provide the title compound (515 mg, 95% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:30]([O:18][C:15]1[CH:14]=[N:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6]([CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=[C:2]3[F:1])=[CH:7][CH:8]=2)=[N:17][CH:16]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCOc1cc2ccc(-c3ncc(O)cn3)cc2c(F)n1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1cnc(-c2ccc3cc(OCCCCCCCC)nc(F)c3c2)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxyisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1-fluoro-3-octyloxyisoquinoline. 1-Fluoro-7-(5-hydroxypyrimidin-2-yl)-3-alkyloxyisoquinolines can for example be reacted analogously to Example 3 with 2-fluoroalkyl sulfonates, 2,3-difluoroalkyl sulfonates, 3-alkyloxirane-2-methyl sulfonates, (ω-bromoalkyl)cyclopropanes or 1-bromodimethylsilanylalkanes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[NH:24][C:25](=[O:41])[CH2:26][NH:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:14]>C(N(CC)CC)C>[CH3:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25](=[O:41])[CH2:26][N:27]([CH:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH3:12]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)N(CC(=O)Nc1c(C(C)C)cccc1C(C)C)C(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
2-Methoxy benzoyl chloride (0.65 g) was added to a mixture of 1.50 g the product of Example 4 and excess triethylamine in 100 mL EtoAc. The reaction mixture was allowed to sit 2 days at room temperature and was then concentrated to dryness, the residue dissolved in 250 mL CH2Cl2, the organic solution washed with dilute sulfuric acid, brine, potassium carbonate solution, and brine. The solution was dried over MgSO4, filtered, and concentrated to an oil which crystallized upon addition of 1/1, hexane/EtoAc to give the title compound. Total yield, 1.53 g (76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.S(Cl)(Cl)=O.[CH3:21]O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:21])=[O:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: CO
Reactant: COc1ccc(/C=C/C(=O)O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)/C=C/c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88 %

Procedure:
To a mixture of (2E)-3-(4-methoxy-2-nitrophenyl)acrylic acid (16 g, 0.067 mol) in dry MeOH (150 mL) under nitrogen is added dropwise thionyl chloride (12.3 mL, 0.169 mol) at 0° C. The reaction mixture is refluxed for 3 h then cooled to room temperature. The solvent is removed under reduced pressure and the residue is taken up in EtOAc. The organic layer is washed with 10% aqueous NaHCO3, water and brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 14 g (88%) of the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.03-8.07 (m, 1H), 7.58-7.60 (m, 1H) 7.51 (s, 1H), 7.16-7.18 (m, 1H), 6.29-6.33 (m, 1H), 3.91 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][CH:13]=2)[CH2:2]1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][CH:13]=2)[CH2:2]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1cc(NC2CCCNC2)c2cc[nH]c2n1
Reactant: O=Cc1ccccc1
Product: c1ccc(CN2CCCC(Nc3ccnc4[nH]ccc34)C2)cc1

Procedure:
Reaction of N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine with benzaldehyde using the method of Example 8 affords the title compound.
Reaction SMILES: C=O.C(N[CH2:6][CH3:7])C.[CH2:8]1[CH2:12]O[CH2:10][CH2:9]1>>[CH:10]#[C:9][CH2:8][C:12]#[C:12][CH2:8][CH2:9][CH2:10][CH2:6][CH3:7]
Reactant: CCNCC
Reactant: C1CCOC1
Agent: C=O
Product: C#CCC#CCCCCC

Procedure:
19.5 G (0.65 mole) of paraformaldehyde, 54.8 g (0.75 mole) of diethylamine, 2.6 g of hydrated copper (II) acetate and 65 ml of THF were charged into a 1 l reactor. The mixture was maintained at reflux for 30 min and, still at reflux, the solution of deca-1,4-diyne obtained as described above was added thereto. The reaction mixture was kept at reflux for 11/2 h until the deca-1,4-diyne had completely disappeared. The mixture was then extracted at 0° with a 15% solution of HCl (3×70 ml) and the acidic layers were extracted with two fractions of 50 ml each of petroleum ether 80:100°, then 150 ml of a 30% NaOH solution were added thereto at 0°. The basic phase thus obtained was extracted with three fractions of 150 ml each of ethyl acetate and the organic extracts treated with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered and evaporated to give 105 g of N,N-diethyl-undeca-2,5-diynyl-amine.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30]([OH:32])=O)=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([NH2:46])[CH2:43][CH2:44][CH3:45]>C1COCC1>[CH2:42]([NH:46][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:32])[CH2:43][CH2:44][CH3:45]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: CCCCN
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of butylamine was added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP) 498.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH:15]([CH2:19][CH3:20])[C:16]([CH3:18])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[C:15]([CH2:19][CH3:20])=[C:16]([CH3:18])[N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: N=C(N)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1c(C)nc(-c2ccc(N)cn2)nc1O
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl-2-ethylacetoacetate (0.379 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature and the reaction mixture was stirred for 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][C:29]#[N:30])=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: N#CCc1ccc(B(O)O)cc1
Product: CC(c1ccc(-c2ccc(CC#N)cc2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 4-cyanomethylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=515.4 [M+H+].