Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([OH:26])[C:22]([F:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([C:22]([F:25])=[CH:23][CH:24]=2)[O:26][C@H:29]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6 difluoro-phenol (0.700, 1.59 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.572g, 3.17mmol) and triphenylphosphine (0.831g, 3.17 mmol) in dry benzene (10 mL) was added diethylazodicarboxylate (0.50 mL, 3.17 mmol) dropwise at room temperature under a dry nitrogen atmosphere. The reaction mixture was sealed in a pressure bottle and immersed in a pre-heated oil bath at 105° C. and heated for 2.5 hours. After stirring at ambient temperature for 14 hours the reaction mixture was diluted with methylene chloride and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (90/10 petroleum ether/ethyl acetate) to give (R)-2-[3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-difluoro-phenoxy ]-3-phenyl-propionic acid, methyl ester as an off white solid (0.73g., 76%). To a solution of this methyl ester (0.66g, 1.09 mmol) in tetrahydrofuran (2 mL) and methanol (7 mL) was added a 1 N aqueous solution of potassium hydroxide (1.64mL, 1.64mmol). After stirring for two hours the solvents were removed and the residue was combined with water (50 mL) and acidified with 10% HCl. The solid was extracted into ether and the layers were shaken well together for several minutes before they were separated. The organic layer was washed with water and concentrated to give the title compound as a white solid (0.613 g, 95%): [a]D25 =-13.81 (9.413 mg/mL chloroform); NMR (400 MHz, DMSO-d6): δ13.21 (s, 1H), 8.30 (d, J=8 Hz, 1 H), 8.08 (d, J=8 Hz, 1 H), 7.82 - 7.78 (m, 1 H), 7.62 - 7.41 (m, 4 H), 7.35 - 7.14 (m, 7 H), 6.74 (dd, J=8, 9 Hz, 1 H), 5.17 - 5.11 (m, 1 H), 3.32 - 3.24 (m, 1 H), 3.19 -3.12(m, 1H), NMR indicates that 0.22 mole eq. of benzene is present; MS (+FAB): (M:+): one bromine pattern observed, 588/590 (78%, 75%); Anal. Calc. for C31H19BrF2O3S.0.22 C6 H6: C, 63.99, H, 3.38, N, 0.00. Found: C, 64.52, H, 3.48. N, 0.06.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C@@H:20]([NH:22][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4C3CCCCO3)[CH3:21])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:38])=[O:4]>CO.Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11]([CH:20]([NH:22][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH3:21])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:38])=[O:4]
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1c(F)ccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c12
Yield: 50.2 %

Procedure:
A solution of 5-fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid methyl ester (50 mg, 0.097 mmol) in MeOH (2 mL) and 4N HCl in dioxane (0.5 ml) was stirred at RT for 30 min then the volatiles were removed under reduced pressure. The resulting residue was dissolved in a minimum amount of MeOH and EtOAc. A solid precipitated on standing and was collected by filtration to afford 197 (21 mg, 46%). LCMS (Method K): RT 3.28 min [M+H]+ 432.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.65 (1H, s), 9.92 (1H, br s), 8.61 (1H, s), 8.50 (1H, s), 7.89 (1H, dd, J=8.90, 4.75 Hz), 7.59-7.48 (2H, m), 7.45-7.30 (3H, m), 7.25 (1H, dd, J=10.49, 8.90 Hz), 5.51-5.40 (1H, m), 3.09 (3H, s), 1.65 (3H, d, J=6.84 Hz)
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21]2=[O:24])=[CH:17][CH:16]=1)#[N:14].CI.Cl>CCCCCC.C1COCC1>[C:13]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH3:1])[C:21]2=[O:24])=[CH:17][CH:16]=1)#[N:14]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCCCC1Cc2ccc(C#N)cc2C1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCCCCC1(C)Cc2ccc(C#N)cc2C1=O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 339.2 %

Procedure:
In a 2 liter-reaction vessel, 1.6 g (1.15×10-1M) of diisopropylamine and 450 ml of dry THF were placed and cooled to -10 ° C. Under stirring, 72.8 ml (1.5 M) of a solution of n-butyllithium in hexane was added dropwise to the above mixture in 10 minutes and cooled to -70° C. A solution of 28.0g (1.04×10-1M) of 6-cyano-2-octyl-indanone in 150 ml of dry THF was then added dropwise in 30 minutes, followed by stirring for 2 hours while the reaction temperature was gradually restored to room temperature. After the reaction, the reaction mixture was cooled to -20° C., and 28.0 g (1.97×10-1M) of methyl iodide was added dropwise thereto in 10 minutes. After the addition, the resultant mixture was stirred for 18 hours while the reaction temperature was gradually restored to room temperature. After the reaction, 1N-HCl was added dropwise to the reaction mixture under cooling to decompose the reaction mixture. The organic layer was successively washed with water, sodium hydrogencarbonate and water, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: chloroform/n-hexane=1/1; 300 mesh silica gel: 50 times in weight) to obtain 15.2 g of 6-cyano-2-octyl-2-methyl-1-indanone (Yield: 52%).
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]1[Cl:17])#[N:2].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)C[N:26]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=3)=[N:29][N:28]=[N:27]2)C=CC=CC=1>>[C:1]([C:3]1[N:7]([CH2:43][C:40]2[CH:41]=[CH:42][C:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30]3[NH:26][N:27]=[N:28][N:29]=3)=[CH:38][CH:39]=2)[C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]1[Cl:17])#[N:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2CC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(-n2c(Cl)ccc2Cl)c(C#N)[nH]1
Product: CCCc1nc(-n2c(Cl)ccc2Cl)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the procedure from Example 13, 5-cyano-4-(2,5-dichloro-1H-pyrrol-1-yl)-2-propylimidazole (Example 30) and N-triphenylethyl-5-[4'-(bromomethyl)bipheyl-2-yl]tetrazole (Example 12) are reacted and deprotected to give the title compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=2)[C:6]=1[C:23]([OH:25])=[O:24])([OH:3])=[O:2].OS(O)(=O)=O.[CH2:31](O)[CH3:32]>O>[C:20]([C:16]1[CH:15]=[C:14]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([CH2:4][C:1]([O:3][CH2:31][CH3:32])=[O:2])=[C:6]2[C:23]([OH:25])=[O:24])[CH:19]=[CH:18][CH:17]=1)([OH:22])=[O:21]
Reactant: O=C(O)Cc1c(C(=O)O)n(-c2cccc(C(=O)O)c2)c2ccccc12
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1c(C(=O)O)n(-c2cccc(C(=O)O)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a solution of solution of 3-carboxymethyl-1-(3-carboxy-phenyl)-1H-indole-2-carboxylic acid (0.743 g, 2.2 mmol) in ethanol (5 mL) was added a drop of conc. H2SO4 and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL). The extract was washed with brine, dried over MgSO4 and concentrated to give 0.94 g of 1-(3-carboxy-phenyl)-3-ethoxycarbonylmethyl-1H-indole-2-carboxylic acid as a yellow oil (94% yield): 1H NMR (CDCl3, 300 MHz) δ 1.17 (t, J=7.25 Hz, 3H), 4.09 (q, J=7.05 Hz, 2H), 4.18 (s, 2H), 7.04 (d, J=8.39 Hz, 1H), 7.20 (t, J=7.25 Hz, 1H), 7.30 (t, J=7.25 Hz, 1H), 7.71–7.60 (m, 2H), 7.76–7.80 (m, 2H), 8.02 (d, J=7.06 Hz, 1H).
Reaction SMILES: [O-]CC.[Na+].[Na].[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.Br[CH2:15][C:16]1[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][CH:21]=1>C(O)C>[C:22]([C:17]1[C:16]([CH2:15][O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=2)=[CH:21][CH:20]=[CH:19][N:18]=1)#[N:23]
Reactant: Oc1cccc(F)c1
Reactant: N#Cc1ncccc1CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: N#Cc1ncccc1COc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled solution of sodium ethoxide, prepared from 13.8 g of sodium metal and 240 ml of absolute ethanol, 56.9 ml of 3-fluorophenol was added and the mixture was stirred at room temperature for 30 minutes. Crude 3-bromomethyl-2-cyanopyridine (103 g) was added to the mixture at 5° C., and the mixture was reflexed for 2 hours. After being concentrated, the reaction mixture was diluted with ether, and the resultant insoluble materials were removed by filtration. The filtrate was washed with 10% aqueous sodium hydroxide solution and with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was crystallized by trituration with a mixture of ether and n-hexane to yield 58.0 g of pale brown crystals, which were recrystallized from isopropyl ether to give pale yellow needles, mp 52°-53° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:4]=[C:5]([CH3:7])[CH:6]=1.[C:17]([CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])(=O)[CH3:18]>C(O)C>[CH3:7][C:5]1[CH:6]=[C:2]([NH:1]/[C:17](=[C:20]2/[C:21](=[O:22])[O:23][CH2:24][CH2:25]/2)/[CH3:18])[N:3]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:4]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: Cc1cc(N)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Solvent: CCO
Product: C/C(Nc1cc(C)nn1-c1c(Cl)cc(Cl)cc1Cl)=C1/CCOC1=O
Yield: 49.7 %

Procedure:
3-Amino-2-(2,4,6-trichlorophenyl)-5-methylpyrazole (1 g, 3.62 mmol) was dissolved in ethanol (10 mL). α-Acetyl-γ-butyrolactone (0.409 mL, 3.80 mmol) was added, followed by heating under reflux for two days. After ethanol was evaporated, the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (700 mg, 1.80 mmol) as a pale yellow oil.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:5]([CH3:21])=[C:6]([C:19]#[N:20])[N:7](S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=1.[H-].[Na+].I[CH3:25]>CO.O1CCCC1>[Br:3][C:4]1[C:5]([CH3:21])=[C:6]([C:19]#[N:20])[N:7]([CH3:25])[CH:8]=1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c(C)c2C#N)cc1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Br)cn(C)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium hydroxide (3.65 g, 65.1 mmol) is added all at once to a suspension of 4-bromo-3-methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole-2-carbonitrile (4.66 g, 13.7 mmol) in methanol (95 mL) cooled using an ice bath. After 15 minutes, the suspension is stirred at ambient temperature for 17 hours. The methanol is evaporated to dryness. The evaporation residue is taken up in MTBE (25 mL) and washed with water (25 mL). The aqueous phase is extracted with MTBE (2×25 mL). The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained is dissolved in tetrahydrofuran (50 mL) and the solution is cooled using an ice bath. NaH (60% in oil) (1.02 g, 25.5 mmol) is added. After 10 minutes, iodomethane (2.4 mL, 38.6 mmol) is also added. The mixture is stirred at ambient temperature for 1.5 hours. The tetrahydrofuran is evaporated to dryness. The residue is taken up in dichloromethane and washed with water. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo to obtain the expected compound in the form of a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1)#[CH:12].C(N(CC)CC)C>ClCCl.O>[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[O:20])[CH2:15][CH2:14]1)#[CH:12]
Reactant: C#CC1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: C#CC1CCC(C=O)CC1

Procedure:
Oxalyl chloride (354 μl.) was dissolved in dry dichloromethane (3 ml.) at -70° under nitrogen. Dimethyl sulphoxide (650 μl) in dichloromethane (3 ml.) was then added. After stirring for 5 minutes a solution of 4-ethynylcyclohexylmethanol (0.5 g.) in dichloromethane (5 ml.) was added dropwise over 5 minutes. The reaction mixture was stirred for 30 minutes at -70° before triethylamine (2.5 ml.) was added. After warming to 25° over 3 hours, water was added and the organic phase separated, washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine, and dried. Evaporation gave 4-ethynylcyclohexanecarboxaldehyde as a colourless oil.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20](Cl)=[O:21])=[CH:15][N:14]=1>C1COCC1>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20](=[O:21])[NH:4][CH:1]([CH3:3])[CH3:2])=[CH:15][N:14]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A solution of isopropylamine (1.28 ml, 15.0 mmol) and triethylamine (2.10 ml, 15.1 mmol) in dry THF (5 ml) was added dropwise over 30 minutes to a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (obtained as described in J. Med. Chem., 1972, 15, 200; 3.18 g, 15.0 mmol) in dry THF (8 ml) at −10° C. The solution was stirred 0° C. for 2 hours, filtered and evaporated to dryness to yield the product (0.93 g), which was used without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:21][CH:20]([O:30][CH:31]([CH3:33])[CH3:32])[CH2:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[CH3:34])([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][C@H:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH2:21][C@H:20]([O:30][CH:31]([CH3:33])[CH3:32])[CH2:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[CH3:34])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(OC(C)C)C=C(c2cccnc2)O3)ccc1OC(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(=O)N2CCC3(CC2)C[C@@H](OC(C)C)C[C@@H](c2cccnc2)O3)ccc1OC(C)C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To a solution of (4-isopropoxy-3-methyl-phenyl)[8-isopropoxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]methanone (163 mg, 0.35 mmol) in ethanol (10 mL) under nitrogen was added palladium (37 mg, 0.035 mmol) (10 wt % on carbon, wet). The reaction was purged with hydrogen gas and allowed to stir under a balloon of hydrogen overnight. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The reaction mixture was purified by column chromatography (50-100% ethyl acetate/hexane) to provide (4-isopropoxy-3-methyl-phenyl)-[cis-8-isopropoxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-3-yl]methanone (28.7 mg) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.54 (d, J=3.9 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.37-7.24 (m, 1H), 7.22-7.13 (m, 2H), 6.80 (d, J=8.1 Hz, 1H), 4.65-4.50 (m. 1H), 4.55 (dp, J=12.2, 6.1 Hz, 1H), 4.36 (br s, 1H), 3.85 (s, 1H), 3.76 (dt, J=12.1, 6.1 Hz, 1H), 3.70-3.01 (m, 3H), 2.25 (m, 2H), 2.19 (s, 3H), 1.95 (dd, J=12.8, 2.9 Hz, 1H), 1.84-1.37 (m, 5H), 1.34 (d, J=6.0 Hz, 6H), 1.16 (dd, J=6.0, 3.6 Hz, 6H). ESI-MS m/z calc. 466.28, found 467.6 (M+1)+; Retention time: 1.41 minutes (3 min run).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[C:6]([C:8](=[CH:13]N(C)C)[CH:9]=[N+](C)C)#[N:7].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].N1C2C(=CC=CC=2)C=CC=1.[O-]CC.[Na+]>Cl>[C:6]([C:8]1[CH:13]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]2[S:17][CH:21]=[CH:20][C:19]=2[CH:9]=1)#[N:7]
Reactant: CN(C)C=C(C#N)C=[N+](C)C
Reactant: CCOC(=O)Cc1cccs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)c1cc(C#N)cc2ccsc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
N-[2-cyano-3-(dimethylamino)prop-2-en-1-ylidene]-N-methylmethanaminium perchlorate (see Collect. Czech. Chem. Commun.; 32; 5; 1967; 1704; 5.84 g, 23.2 mmol) and ethyl 2-thienylacetate (3.95 g, 23.2 mmol) were mixed with quinoline (117 mL) at 0° C. Sodium ethoxide (1.97 g, 27.9 mmol) was added and the mixture was stirred at 0° C. for 30 min and then at room temperature for 15 min. The reaction mixture was heated to 75° C. under nitrogen for 5 h and then cooled to 0° C. Hydrochloric acid (200 mL of 2 M aqueous solution) was added and the mixture extracted thrice with chloroform. The organic solution was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (hexane-ethyl acetate, 8:1). There was obtained 2.3 g (43%) of ethyl 5-cyano-1-benzothiophene-7-carboxylate as a pale yellow solid. 1H NMR (300 MHz, CDCl3): 1.5 (t, 3H), 4.5 (qt, 2H), 7.5 (d, 1H), 7.7 (d, 1H), 8.3 (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=1)[CH2:7][N+:8]([O-])=O)C>CCOC(C)=O.CCO.[Ni]>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([CH:6]2[CH2:7][NH:8][C:4](=[O:3])[CH2:5]2)[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1cccc(OCc2ccccc2)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CC(c2cccc(OCc3ccccc3)c2)CN1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.9 %

Procedure:
A mixture of 3-(3-benzyloxyphenyl)-4-nitrobutyric acid ethyl ester (3.2 g) in 10 mL EtOAc and 20 mL EtOH was created in a dry round bottom flask. Raney Ni was added and the resulting mixture was stirred under H2 for 10 h at r.t. and filtered through celite. The solution was heated under reflux for 40 h, cooled to r.t., and concentrated. Chromatography of the residue on silica gel (EtOAc:Hexane=1:1 to 3:1) gave 1.89 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)O)=[CH:9][N:10]=2)[N:7]=1.II.O[PH2]=O>CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc21
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)ccc21

Procedure:
A solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanol (156.8 mg, 0.50 mmol), I2 (381 mg, 1.50 mmol) and H3PO2 (0.273 mL, 2.50 mmol) in 4 mL AcOH was heated at 110° C. for 7 hours. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound which contains some iodine and used in the next step without further purification (180.0 mg, 44%, 36% pure). LCMS (method A): [MH]+=298, tR=5.37 min
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=O)[CH:6]=1.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1>C(O)(=O)CC>[CH3:1][O:2][C:3]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:18]3[NH:14][C:15]([C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:13])[CH:6]=4)=[C:15]4[N:14]=[C:18]([C:11]([C:7]5[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:13])[CH:6]=5)=[C:15]5[NH:14][C:18](=[C:11]([C:7]6[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:13])[CH:6]=6)[C:15]6[CH:16]=[CH:17][C:18]=2[N:14]=6)[CH:17]=[CH:16]5)[CH:17]=[CH:16]4)=[CH:16][CH:17]=3)[CH:8]=[CH:9][CH:10]=1)=[O:13]
Reactant: c1cc[nH]c1
Reactant: COC(=O)Cc1cccc(C=O)c1
Solvent: CCC(=O)O
Product: COC(=O)Cc1cccc(-c2c3nc(c(-c4cccc(CC(=O)OC)c4)c4ccc([nH]4)c(-c4cccc(CC(=O)OC)c4)c4nc(c(-c5cccc(CC(=O)OC)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
17.82 g (0.10 mol) of (3-formylphenyl)-acetic acid methyl ester (B RN 3231441) is dissolved in 300 ml of propionic acid and the solution is heated to 60° C. 6.71 g (0.10 mol) of pyrrole is instilled slowly and the dark solution is stirred for 1 hour at 110° C. After cooling, it is completely concentrated by evaporation in a vacuum, the residue is taken up in dichloromethane and shaken out with saturated aqueous sodium bicarbonate solution. After the drying of the organic phase on sodium sulfate, it is filtered and concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/methanol. The residue of the product fractions that are concentrated by evaporation is recrystallized from isopropanol.
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=1)[CH2:4][CH2:5][CH3:6].Cl>C1COCC1.O>[CH2:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(C(=O)OCC)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C(=O)O)cs1
Reaction time: 16 h

Procedure:
Lithium hydroxide (5.00 g) was added to a stirred mixture of ethyl 2-butylthiazole-4-carboxylate (example 78, step f) (6.50 g) in THF (80 mL) and water (20 mL). After 16 h, concentrated hydrochloric acid (10 mL) was added and the solution concentrated to ˜40 mL. The reaction mixture was partitioned between ethyl acetate and brine. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and evaporated in vacuo to give the subtitled compound as an off white solid. Yield 4.6 g.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]1[CH2:19][CH2:20][CH2:21][C:22](=[O:23])[C:14]1=[C:13]2[CH3:24].BrBr>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]1[CH2:19][CH2:20][CH:21]([Br:1])[C:22](=[O:23])[C:14]1=[C:13]2[CH3:24]
Reactant: Cc1c2n(c3ccc(Br)cc13)CCCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Solvent: ClCCl
Product: Cc1c2n(c3ccc(Br)cc13)CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aged N-bromosuccinimide (4.89 g, 27.5 mmol) was added in small portions (over 15 min) to a solution of 2-bromo-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one (described in Example 8, 5.0 g) in methylene chloride (100 mL) and stirring at room temperature was continued for 30 min. This crude mixture was then protected against light, and a solution of bromine (2 ML) in methylene chloride (200 mL) was added very slowly from a dropping funnel. The reaction mixture was washed successively with cold water, 5% sodium bicarbonate, and water again. After drying (MgSO4) and filtration, the solvent was evaporated, and the title compound was crystallized from chloroform, mp 156° C.; yield 6.6 g; Anal. Calcd for C13H11Br2NO: C, 43.72% H, 3.10% N, 3.92% and Found: C, 43.35% H, 3.00% N, 3.99%.