Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].CCN(CC)CC.Br[C:16]1[C:17]([CH:34]([CH3:36])[CH3:35])=[N:18][N:19]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[N:19]([C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:18]=[C:17]([CH:34]([CH3:36])[CH3:35])[C:16]=2/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:23]=1
Reactant: C=CC(=O)OCC
Reactant: CC(C)c1nn(-c2cnccn2)c(-c2ccc(F)cc2)c1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1c(C(C)C)nn(-c2cnccn2)c1-c1ccc(F)cc1
Yield: 58.6 %

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (2.55 g, 3.6 mmol) and ethyl acrylate (49.2 mL, 454 mmol) were dissolved in DMF (200 mL) and Et3N (200 mL) at reflux under an inert atmosphere. The bromopyrazole (32.82 g, 91 mmol, Step B) was then added and the reaction was refluxed overnight. An additional 0.005 eq of catalyst and 10 mL of ethyl acrylate were added to push the reaction to completion. The reaction was cooled and partitioned between H2O and EtOAc. The organic layer was dried (MgSO4) and evaporated to give a brown oil. Elution from a 6-inch silica column gave 20.3 g (59%) of a tan solid. Recrystallization from hexanes produced a brilliant white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:17]([Si:21](Cl)([CH2:24]C)[CH2:22]C)([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:11][CH2:12][CH:13]([O:16][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:22])[CH2:14][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC[Si](Cl)(CC)C(C)(C)C
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc(N)cc2C#N)CC1
Yield: 75.5 %

Procedure:
5-Amino-2-(4-hydroxypiperidino)benzonitrile (4.0 g), tert-butyldiethylsilyl chloride (3.0 g) and imidazole (1.6 g) were stirred in dimethylformamide (20 ml) at room temperature for 1 h. The reaction mixture was treated with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from n-hexane to give the title compound (4.2 g), melting point: 88–90° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[S:18][C:17]2[C:16]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=1>>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:16]3[C:17]4[S:18][C:10]([C:3]5[CH:4]=[CH:5][S:1][CH:2]=5)=[CH:11][C:12]=4[N:13]=[CH:14][N:15]=3)=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: OB(O)c1ccsc1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccsc3)cc2n1

Procedure:
The title compound was prepared from thiophene-3-boronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 11.2 (s, 1H), 8.86 (s, 1H), 8.10 (s, 1H), 7.70 (m, 3H), 7.46 (m, 3H), 7.21 (d, 1H), 6.49 (s, 1H), M.P. 178-189° C.; LC-MS: 349 (MH+); HPLC RT 4.05 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:6]=[C:5]2[CH:19]=[O:20].[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:6]=[C:5]4[CH:19]=[O:20])[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(CO)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Yield: 64.8 %

Procedure:
6-Bromo-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 26d 16.8 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (20.61 g), Pd-118 (1.619 g) and potassium carbonate (17.16 g) in DMF (140 mL) was heated to 70° C. for 4 h under nitrogen. The mixture was cooled, diluted with water (250 mL), and extracted with ethyl acetate (300 mL). The separated organic layer was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with 50 to 100% ethyl acetate in DCM) to give a solid, which was triturated with isohexane 1:1 diethyl ether (200 mL) for 1 h. The suspension was filtered and dried to give the subtitle compound (14.5 g) as a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:2]=1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[BH4-].[Na+]>CC#N>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:8]1[CH2:9][C:10]2[N:1]=[CH:2][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:5]=2[CH2:6][CH2:7]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cnc2cnccc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(c1)CCN(CC(=O)OC(C)(C)C)C2

Procedure:
A mixture of ethyl 1,7-naphthyridine-3-carboxylate (905 mg, 4.476 mmol) and tert-butyl bromoacetate (1.0 g, 5.15 mmol) in CH3CN (15 mL) is refluxed overnight. Solvent is removed in vacuo and the residue is dissolve in MeOH (20 mL). To the solution is added NaBH4 (677 mg, 17.9 mmol) and the mixture is refluxed for 4 hr. The solvent is removed in vacuo and the residue is partitioned between water (30 mL) and EtOAc (30 mL). The layers are separated and the aqueous layer is extracted with EtOAc (20 ml). The combined extracts are washed with brine (20 mL), dried and evaporated. The residue is purified by flash column to give the title compound as a light yellow oil. MS (M+1): 321.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)NC1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-piperidinylamine (5 g, 26.1 mmol), 2-(4-fluorophenyl)acetic acid (4 g, 26 mmol), 1-hydroxybenzotriazole monohydrate (3.89 g, 28.6 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (6 g, 31.2 mmol) and triethylamine (4.4 ml, 31.2 mmol) were stirred together for 18 hours in dichloromethane (250 ml). The mixture was evaporated under reduced pressure and the residue dissolved in ethyl acetate before washing with water (x3). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a white solid, 9 g.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(OCC)C.CN(C=O)C>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[N:9]=[N:10][N:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:12]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(C(c2ccccc2)c2nnn[nH]2)cc1
Reactant: COC(=O)CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(=O)CCCCCCCCn1nnc(C(c2ccccc2)c2ccccc2)n1
Yield: 76.1 %

Procedure:
A mixture of 5-(diphenylmethyl)-1H-tetrazole (5 g, 21 mmol) obtained according to J. W. Cusic, U.S. Pat. No. 3,155,666, methyl 9-bromononanoate (5.84 g, 23 mmol), potassium carbonate (3.50 g, 25 mmol), potassium iodide (catalytic quantity) and DMF (75 mL) was stirred at 110° C. for 15 minutes. The mixture was cooled, diluted with water and extracted three times with diethyl ether. The combined extracts were washed three times with water, dried over sodium sulfate and concentrated in vacuo to give an oil. Chromatography on a column of silica gel using a mixture of hexanes and diethyl ether (1:1) as eluent gave methyl 5-(diphenylmethyl)-2H-tetrazole-2-nonanoate (6.50 g, 75%).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-].[K+].C([OH:24])C.Cl>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:24])([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1C#N
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(F)c1

Procedure:
A 5.5 g. portion of ethyl 5-cyano-1-(3-fluorophenyl)-4-pyrazolecarboxylate and 4.7 g. of potassium hydroxide were dissolved in 100 ml. of ethanol at the reflux temperature and the mixture was stirred at that temperature for 2 hours. The mixture was then diluted to 350 ml. with cold water, and was heated slightly to obtain a solution which was made acid with concentrated hydrochloric acid. The product was precipitated by adding small amounts of ice, and the precipitated product was then collected by filtration and crystallized from ethanol-water to obtain 3.6 g. of the desired product, m.p. 215°-216°, having the following elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=1.[OH-:22].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[NH:7][C:6](=[O:22])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=1
Reactant: [OH-]
Reactant: Fc1ccc(N2CCN(c3nc(Cl)nc(Cl)n3)CC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc(Cl)[nH]1
Yield: 77.9 %

Procedure:
To a tetrahydrofuran solution (200 mL) of 2,4-dichloro-6-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazine (21.0 g, 63 mmol) synthesized in Reference Synthesis Example 1, 1 M sodium hydroxide aqueous solution (128 mL, 128 mmol) was added at room temperature and the resultant solution was stirred for 1 day. To the reaction solution, 1 M sodium hydroxide aqueous solution (32 mL, 32 mmol) was added and the resultant mixture was stirred for 6 hours. To the reaction solution, 1 M sodium hydroxide aqueous solution (19 mL, 19 mmol) was further added and the resultant solution was stirred for 2 hours. After completion of the reaction, pH of the reaction solution was adjusted to 4 by adding 1 M hydrochloric acid. After removing impurities, the resultant mixture was concentrated under reduced pressure to obtain a solid. The solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (15.2 g, yield 79%).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C1COCC1>[CH:10]([C:5]1[N:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:18])=[O:2])=[CH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccnc1C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1C=Cc1ccccc1
Yield: 96.9 %

Procedure:
A solution of the ester 19 (55.0 g, 0.23 mol) in THF (100 mL) was treated with a 3 N NaOH solution (110 mL, 0.25 mol) for 21 h at ambient temperature. After removal of solvents, the residue was taken up in water and ethyl ether. The phases were separated, and the aqueous phase was washed with ether (2×). The resulting aqueous phase was neutralized with a 2 N HCl solution, and the precipitate was then collected by filtration to afford the acid 20 (50.2 g, 97%) as a cream solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.C([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:26])[NH:11][N:10]=1
Reactant: Cc1cc(CC(=O)O)cc(Cl)c1Oc1cc(C(C)C)c(Cl)nn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(CC(=O)O)cc(Cl)c1Oc1cc(C(C)C)c(=O)[nH]n1
Temperature: 105 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
A solution of [3-chloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-5-methyl-phenyl]-acetic acid (9b) (1.0 g, 2.81 mmol) in glacial acetic acid (30 mL) was treated with sodium acetate (808 mg, 9.83 mmol) at room temperature. The reaction mixture was heated to 105° C. for 24 h. At this time, the reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was diluted with water, brought to pH=10 by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ethyl acetate. The ethyl acetate layer was discarded. The water layer was acidified by the addition of a 3N aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was dissolved in methylene chloride and methanol and then was absorbed onto silica. The preabsorbed solid was purified by column chromatography using silica gel eluted with 20% ethyl acetate in hexanes containing 2% glacial acetic acid. The desired fractions were concentrated as several separate batches and placed under high vacuum for 15 min. The solid was diluted with a 1:1 methylene chloride:hexanes solution. This process was performed three times. The solid was dried under high vacuum overnight. The solid was then slurried in acetonitrile, filtered, and dried in the vacuum oven at 80° C. overnight to afford [3-chloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-5-methyl-phenyl]-acetic acid (10b) (300 mg, 32%) as a white solid; EI(+)-HRMS m/z calcd for C16H17ClN2O4 (M+H)+ 337.0950, found 337.0949. Molecular Weight=336.7779; Exact Mass=336.0877
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl>C(O)CCC>[CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([O:27][CH2:16][CH2:1][CH2:2][CH3:3])=[O:26])=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCc1cc2cc(C(=O)OCCCC)ccc2[nH]1
Yield: 121.8 %

Procedure:
A solution of 2-(n-pentadecyl)indole-5-carboxylic acid (17.4 g) in n-butanol (100 ml) containing aqueous hydrochloric acid (10 ml of strength 36.5% w/v) was heated in a steam bath for 18 hours. The solution was concentrated in vacuo to about one half of its volume and the residue was dissolved in diethyl ether. The ethereal solution was washed with water (2×50 ml) and was dried over magnesium sulphate. Evaporation of the solvent in vacuo gave a solid, which was recrystallised from light petroleum ether (b.p. 40°-60° C.) and then from methanol to give n-butyl 2-(n-pentadecyl)indole-5-carboxylate (12.2 g), in the form of a white powder, m.p. 79°-80° C.
Reaction SMILES: CO[CH:3]([O:10]C)[C:4]1[S:5][CH:6]=[C:7](Br)[CH:8]=1.[Cu](C#N)[C:13]#[N:14].C(OCC)(=O)C>CN(C=O)C.C(O)(=O)C>[C:13]([C:7]1[CH:8]=[C:4]([CH:3]=[O:10])[S:5][CH:6]=1)#[N:14]
Reactant: N#C[Cu]C#N
Reactant: COC(OC)c1cc(Br)cs1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1csc(C=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
4-Bromo-2-thiophenecarboaldehyde dimethylacetal (6.82 g) was dissolved in DMF (50 ml), and copper cyanide (4.29 g) was added thereto. After heating under reflux for 3 hours, the mixture was cooled as it was to room temperature and ethyl acetate was added thereto. The mixture was washed with an aqueous ammonia, water, 0.1N aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate and then evaporated, to give an oil. The residue was dissolved in an 80% aqueous acetic acid (100 ml), and the mixture was stirred at 0° C. for one hour. The mixture was washed with brine. After cooling as it was to room temperature, ethyl acetate was added thereto. The mixture was washed with an aqueous saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), and then recrystallized from ethyl acetate-hexane, to give the title compound as pale yellowish white crystals (2.44 g, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[I:10]Cl.O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: ClI
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(O)ccc1I
Yield: 6.5 %

Procedure:
3-Hydroxy-benzonitrile (15 g, 0.126 mol) and iodine monochloride (28 g, 0.172 mol) is heated in acetic acid for 15 hours at 45° C. H2O is added to precipitate the product out. After the precipitate is collected and washed with Na2SO3, the residue is chromatographed with chloroform to get the product (2 g, 7%). MS (ESI): 244.0 (M−1)−1.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([C:21]#[CH:22])[CH:17]=[CH:18][C:19]=1[F:20].C(NCC)C.[Li+].[OH-].Cl>CN(C=O)C.O.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.[Cu]I>[F:13][C:14]1[CH:15]=[C:16]([C:21]#[C:22][C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(F)c(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C#Cc2ccc(F)c(F)c2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 4-iodobenzoate (5.0 g, 18.1 mmol) in DMF (15 mL) was added 3,4-difluorophenylacetylene (2.99 g, 21.7 mmol), Pd(Ph3P)4 (520 mg, 0.45 mmol), CuI (173 mg, 0.90 mmol) and diethylamine (3 mL). The reaction vessel was sealed and heated at 60° C. for 1 h in a microwave reactor. The reaction was cooled to room temperature, diluted with EtOAc:hexanes (2:1, 150 mL) and washed with water (2×100 mL) and brine (100 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was dissolved in THF (60 mL) added MeOH (14 mL) and a solution of LiOH (1.52 g, 36.2 mmol) in water (14 mL). The reaction was stirred at room temperature and for 4 h. The reaction was acidified with 1 N HCl (60 mL) and 4-((3,4-difluorophenyl)ethynyl)benzoic acid was isolated (2.45 g, 57%) as a white solid; 1H-nmr (400 MHz, d6-DMSO) δ 7.96 (d, J=8.5 Hz, 2H), 7.73 (td, J=8.5, 2.0 Hz, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.55-7.43 (m, 2H); LC (290 nM) 5.08 min (>98%); MS (ESI) m/z=258.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)=[C:6]([NH:8][C:9]([N:11]([CH3:13])[CH3:12])=O)[CH:7]=1>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]3[CH2:15][CH2:16][C:17]4[C:22]3=[C:21]([CH:20]=[CH:19][CH:18]=4)[C:9]([N:11]([CH3:13])[CH3:12])=[N:8][C:6]=2[CH:7]=1
Reactant: CN(C)C(=O)Nc1cc(Br)ccc1N1CCc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C1=Nc2cc(Br)ccc2N2CCc3cccc1c32
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A mixture of 10.8 g (0.030 mole) of N-[5-bromo-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-N',N'-dimethylurea and 110 ml of phosphorus oxychloride, under nitrogen, was heated under reflux for 6 hours, with stirring, and then cooled to room temperature. The excess phosphorus oxychloride was removed under vacuum with gentle warming. The residue was chilled in an ice-bath (with exclusion of moisture) and treated first with 250 ml of ice-cold 2N sodium hydroxide solution, and then with 500 ml of dichloromethane. The mixture was stirred and triturated until all the material passed into solution. The organic phase was separated, washed with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to an oil. The oil was dissolved in 50 ml of ethyl acetate and the solution was concentrated under a stream of nitrogen. At a volume of about 30 ml, the mixture was filtered. Concentration of the filtrate was continued to a volume of about 20 ml, during which crystallization resulted. The solid was dissolved by heating, the hot solution was filtered and allowed to crystallize to afford 4.9 g (48%) of product, mp 124°-127° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.[Na+].[I-:15]>O1CCOCC1.[Cu]I>[I:15][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(=O)NC(C)c1ccc(Br)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC(C)c1ccc(I)cc1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To 8.70 g (35.9 mmol) N-(1-(4-bromophenyl)ethyl)acetamide (III.2) in 100 mL 1,4-dioxane are added 0.69 g (3.62 mmol) CuI, 0.97 mL (9.11 mmol) N,N″-dimethyl-ethylendiamine and 10.8 g (71.9 mmol) NaI. The reaction mixture is stirred at 120° C. for 3 d. The mixture is allowed to cool to r.t. and half of the solvent is removed in vacuo. EtOAc and diluted aq. ammonia solution are added and the layers are separated. The aq. layer is once more extracted with EtOAc. The organic layers are combined, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is triturated with diethylether and dried in vacuo.
Reaction SMILES: Cl.Cl.[C:3]1([CH:13]([NH:16][CH3:17])[CH2:14][NH2:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.O.C(=O)(O)[O-].[Na+].[CH3:24][O:25][C:26]([NH:28][C:29](=NC(OC)=O)SC)=[O:27]>C(Cl)(Cl)Cl.C(O)(C)C>[CH3:17][N:16]1[CH:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[CH2:14][N:15]=[C:29]1[NH:28][C:26]([O:25][CH3:24])=[O:27]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CNC(CN)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)NC1=NCC(c2cccc3ccccc23)N1C
Yield: 92.7 %

Procedure:
Six grams of 1-(1-naphthyl)-1-methylamino-2-aminoethane, dihydrochloride, prepared in Part A, are stirred into 25 ml of water. Thereafter 35 ml of saturated sodium bicarbonate are added and stirred for several minutes. Then 160 ml of isopropanol followed by 4.16 g of 1,3-bis(methoxycarbonyl)-S-methylisothiourea dissolved in 120 ml of chloroform are added to the mixture. The resulting mixture is stirred under nitrogen for 7 days. The organic solvents are removed in a rotary evaporator and 10% aqueous HCl is added until the pH of the mixture is just acidic. The resulting mixture is extracted with ether and the aqueous mixture is neutralized with saturated sodium bicarbonate, filtered, and pumped dry to give 5.3 g of crude 1-methyl-4,5-dihydro-2-(methoxycarbonylamino)-5-(1-naphthyl)-imidazole, m.p. 187°-190° C. One gram of the crude material is recrystallized from ethanol to give 0.77 g of more pure material, m.p. 194°-197° C.