Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH:30]([CH3:32])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:40]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][CH:45]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH:30]([CH3:32])[CH3:31])=[N:9]2)=[CH:6][CH:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (200 mg, 0.41 mmol) was added a solution of triethylamine (0.23 mL, 1.64 mmol) and 4-(1-pyrrolidinyl)-piperidine (0.11 g, 0.70 mmol) in methylene chloride (8 mL) at 0° C. over 15 min. After 30 min, the reaction was worked up with water. The mixture was extracted with methylene chloride and washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. Chromatography of the residue over silica gel using 1-2% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (0.18 g, 72%) as an off-white foam. HR-MS (ES, m/z) calculated for C34H39N4O2Cl2[(M+H)+]605.2445, observed 605.2448
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:11]2[N:15]3[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]3=[N:13][C:12]=2[CH3:26])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:33][NH:34][CH3:35]>C1COCC1>[CH2:21]([CH:20]([C:19]1[C:14]2[N:15]([C:11]([C:4]3[S:3][C:2]([N:34]([CH3:35])[CH3:33])=[N:6][C:5]=3[C:7]([F:10])([F:9])[F:8])=[C:12]([CH3:26])[N:13]=2)[N:16]=[C:17]([CH3:25])[CH:18]=1)[CH2:23][CH3:24])[CH3:22]
Reactant: CNC
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C(F)(F)F)c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)C)nc3C(F)(F)F)c(C)nc12
Temperature: 120 °C
Yield: 94 %

Procedure:
100 mg of 3-(2-Bromo-4-trifluoromethyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.22 mmol) and 218 mg of cesium carbonate (0.66 mmol) are placed in 4 ml reaction vial and 3 ml of dimethylamine 2 M in THF is added. The reaction vial is capped with a Teflon cap and heated at 120° C. overnight. The reaction mixture is filtered and concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 85 mg of the title compound. Yield 94%. mass spectrum (m/e): 412 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)([O-:25])=[O:24]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:33]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)=[O:34])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-nitrophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH3:20])[C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][C:17]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:12]([O:11][CH3:10])[C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc(Br)c(OC)c1-c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccnc2)c(OC)c1-c1ccccc1C
Yield: 82.8 %

Procedure:
Pyridine-3-boronic acid (5.81 g, 47.27 mmol, Frontier Scientific, Inc.), 1,3-dimethoxy-2-(tol-2-yl)-4-bromobenzene (2) (10.7 g, 34.8mmol), glyme (200 mL), and tetrakis(triphenylphosphine) palladium (Ph3P)4Pdo (4 g, 3.46 mmol) were stirred for 15 minutes followed by the addition of potassium carbonate (16 g in 70 ml of water). After refluxing for 10 hr, the reaction mixture was poured into 800 ml of 1:1 mixture of water and ethyl acetate. The organic layer was washed with water (300 ml×2) and brine (200 ml), the solvent was removed, and the crude product was purified by silica-gel chromatography eluting with hexane and ethyl acetate (10% to 25% ethyl acetate) yielding 8.8 g (83%) of 3.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][S:8](O)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][S:8]([Cl:16])(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1ccc(CS(=O)(=O)O)cc1
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(CS(=O)(=O)Cl)cc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
5 g (22.83 mmol) of 4-cyanobenzylsulfonic acid, sodium salt, were moistened with approx. 20 ml of phosphoryl chloride after which 5.2 g (25.11 mmol) of PCl5 were added and the mixture was stirred for 15 min while being cooled with ice. The mixture was then heated at 80° C. for 4 h. After that, the mixture was poured onto ice and this fresh mixture was stirred vigorously for 30 min; the product then separated out on the ice as a white solid. After the ice had partially thawed, the mixture was filtered through a frit and the product/ice mixture which remained was washed several times with water. The crystals which remained were dried in vacuo and used directly for the next step in the synthesis.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12]>O.CS(C)=O.CCOCC>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3])[CH3:12]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCOC(COc1ccccc1Br)OCC
Temperature: 100 °C

Procedure:
A solution of KOH pellets (85%, 0.68 g, 10.3 mmol) in water (1.5 mL) was added to 2-bromophenol (1 mL, 8.6 mmol). The mixture was diluted with DMSO (20 mL) and bromoacetaldehyde diethyl acetal (1.43 mL, 9.5 mmol) was added. The mixture was heated at 100° C. for 6 h, cooled to rt, diluted with ether (175 mL), washed with water (3×40 mL) and 5% aq NaOH (40 mL), and dried over MgSO4. Removal of the solvent left 1-(2,2-diethoxyethoxy)-2-bromobenzene (2.62 g, quant) as an oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](O)(C)[CH3:22]>>[CH3:21][C:22]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:13]2[N:14]=1
Reactant: Nc1c(-c2ccccc2)ccnc1Nc1ccccc1
Reactant: CC(C)O
Product: Cc1nc2c(-c3ccccc3)ccnc2n1-c1ccccc1
Yield: 74 %

Procedure:
0.70 mol of N2,4-diphenylpyridine-2,3-diamine and 2.56 mol of ethoxy ethylene malononitrile was added in 10 ml of isopropanol, and refluxed for 6 hours. The solution was removed and was purified by using column chromatography to thereby produce a solid crystalline product at a yield of 74%.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:38])[C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35]C)=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:10])[CH2:4]1)[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:38])[C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([OH:35])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:10])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@H](N(C)C(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Solvent: C1COCCO1
Product: CCN1CC[C@H](N(C)C(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Yield: 48 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-{[N—((S)-1-ethylpyrrolidin-3-yl)-N-methylcarbamoyl]-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 126, 0.047 g) and lithium hydroxide monohydrate (0.168 g) in dioxane (3 mL) and water (1 mL) was irradiated in the microwave at 130° C. for 40 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated in vacuo. The residue was triturated with 10% methanol in DCM, filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-40%. The resultant solid was triturated with ethyl acetate and filtered off to give (1aRS,7bSR)-5-(2-{[N—((S)-1-ethylpyrrolidin-3-yl)-N-methylcarbamoyl]-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.022 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][C:25]1([CH3:31])[CH2:30][O:29][CH2:28][CH2:27][NH:26]1>>[CH3:24][C:25]1([CH3:31])[CH2:30][O:29][CH2:28][CH2:27][N:26]1[C:19]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)=[O:21]
Reactant: CC1(C)COCCN1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCOCC2(C)C)cn1
Yield: 25 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (124 mg, 0.40 mmol) was converted using 3,3-dimethyl-morpholine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 30:70, 41 mg, 25%) which was obtained as a light brown oil. MS: m/e=408.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1COCC1.O.[OH-].[Li+]>CO>[CH3:1][C:2]1[C:3]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)COc1ccc(-c2noc(-c3ccccc3)c2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccc(OCC(=O)O)cc2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
To a solution of the product of step 1 (1.4 gm, 4.15 mmoles) in a mixture of methanol (10 ml), THF (30 ml) and H2O (10 ml), lithium hydroxide (0.35 gm, 8.30 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and acidified with 1N HCl. The solid separated which was filtered, washed with water & dried over P2O5 under vacuum to give 1.25 g of title product as pale brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:25][C:26]#[CH:27])[C:13]([NH:15][CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19]C)=[O:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:25][C:26]#[CH:27])[C:13]([NH:15][CH:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:17]([OH:19])=[O:18])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
A solution of compound 3 (10.85 g; 29 mmol) in dry THF (100 mL) kept in an ice bath was treated with a solution of 1M lithium hydroxide (100 mL) and stirred for 4 h at 0° C. until the starting material disappeared (as shown by TLC). The solvent was removed and the residue was diluted with water (25 mL). The pH of the aqueous solution was adjusted to ˜2 with 5% HCl and the solution was extracted with ethyl acetate (2×250 mL) and washed with brine (100 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated, yielding a crude product which was purified by flash chromatography (silica gel; hexane/ethyl acetate 50:50) to give 4 as a white solid (8.8 g; 84% yield). 1H NMR (DMSO-d6) δ 8.1 (s, 1H), 7.5 (s, 1H), 7.3 (m, 5H), 5.0 (s, 2H), 4.4 (m, 1H), 4.2 (m, 1H), 2.8 (s, 1H), 2.5 (m, 1H), 2.4 (m, 1H), 1.6 (m, 2H), 1.4 (m, 1H), 0.8 (d, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][CH:15]=[C:16]([CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C=Cc1csc(-c2cc(OC)c(OC)c(OC)c2)n1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1csc(-c2cc(OC)c(OC)c(OC)c2)n1
Temperature: 25 °C

Procedure:
Ethyl 3-[2-(3,4,5-trimethoxyphenyl)thiazol-4-yl]propenoate (1.65 g) was suspended in methanol (20 mL), 10% palladium on carbon (800 mg) was added to the suspension under an argon atmosphere, and the mixture was stirred at room temperature under a hydrogen amosphere. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1 to 1:1) to obtain the title compound.
Reaction SMILES: CC(CC(O)=O)=O.[CH3:8][C:9]1[N:10](C(OCC(C)C)=O)[C:11]2[C:12]([N:28]=1)=[N:13][CH:14]=[C:15]([C:17]1[CH:18]=[CH:19][C:20]3[O:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]=3[CH:27]=1)[CH:16]=2.Cl[C:37]1[C:42]([CH2:43][CH3:44])=[C:41]([CH3:45])[N:40]=[C:39]([CH2:46][N:47]([CH3:49])[CH3:48])[N:38]=1>>[CH2:43]([C:42]1[C:41]([CH3:45])=[N:40][C:39]([CH2:46][N:47]([CH3:49])[CH3:48])=[N:38][C:37]=1[N:23]1[CH2:22][C:21]2[CH:27]=[C:17]([C:15]3[CH:16]=[C:11]4[N:10]=[C:9]([CH3:8])[NH:28][C:12]4=[N:13][CH:14]=3)[CH:18]=[CH:19][C:20]=2[O:26][CH2:25][CH2:24]1)[CH3:44]
Reactant: CCc1c(C)nc(CN(C)C)nc1Cl
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Agent: CC(=O)CC(=O)O
Product: CCc1c(C)nc(CN(C)C)nc1N1CCOc2ccc(-c3cnc4[nH]c(C)nc4c3)cc2C1

Procedure:
Prepared as a diacetate salt by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and 1-(4-chloro-5-ethyl-6-methylpyrimidin-2-yl)-N,N-dimethylmethanamine (reagent preparation 17) in step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (br s, 1H), 8.03 (br s, 1H), 7.67 (d, 1H), 7.52 (dd, 1H), 7.02 (d, 1H), 4.63 (s, 2H), 4.35-4.30 (m, 2H), 3.83-3.78 (m, 2H), 3.32 (s, 2H), 2.65-2.57 (m, 1H), 2.54 (s, 3H), 2.52-2.45 (m, 1H (buried)), 2.36 (s, 3H), 2.10 (s, 6H), 1.86 (s, 8H), 1.15 (t, 3H); MS (EI) for C28H31N7O: 458 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[NH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][N:11]=2)[CH2:3][CH2:2]1.[Li+].[OH-].O>C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[NH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][N:11]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1nnc(N2CCOCC2)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nnc(N2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 5-morpholino-4H-1,2,4-triazole-3-carboxylate (0.090 g, 0.398 mmols†) in THF (1 mL) was added 1 N LiOH (0.800 mL, 0.80 mmol) and H2O (1 mL). The reaction was stirred at rt for 12 h. The reaction mixture was concentrated and lypholized to get 5-morpholino-4H-1,2,4-triazole-3-carboxylic acid quantative yield and used as it is in next step.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([Br:12])[C:3]=1[NH2:4].C(OCC)(=O)C.CN(C)C=O.[H][H]>C(O)C.[Pt]>[NH2:4][C:3]1[C:2]([Br:1])=[CH:8][C:7]([NH2:9])=[CH:6][C:5]=1[Br:12]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1Br
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cc(Br)c(N)c(Br)c1

Procedure:
3.0 g of 2,6-dibromo-4-nitroaniline are dissolved in 150 ml of ethanol, 150 ml of ethyl acetate and 30 ml of dimethylformamide and, after addition of 0.5 g of platinum on carbon (5%), hydrogenated under a pressure of 1.5 bar of hydrogen in a Parr apparatus at room temperature for 1 hour. Cooling is followed by filtration, the solvent is distilled off in a rotary evaporator, and the residue is purified by column chromatography.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)[CH3:2].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:30]>C(#N)C>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:10][CH:9]=1)=[S:13]
Reactant: CCC(CC)C(c1ccc(N=C=S)cc1)n1ccnc1
Reactant: Nc1nc2ccccc2s1
Solvent: CC#N
Product: CCC(CC)C(c1ccc(NC(=S)Nc2nc3ccccc3s2)cc1)n1ccnc1
Yield: 8.2 %

Procedure:
A mixture of 1-[2-ethyl-1-(4-isothiocyanatophenyl)butyl]-1H-imidazole (0.0123 mol) and 2-benzothiazolamine (0.0148 mol) in acetonitrile (80 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was taken up in H2O and CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1). The desired fractions were collected and the solvent was evaporated. The residue was purified again by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/15/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone and DIPE. The precipitate was filtered off and dried, yielding 0.44 g (9%) (±)-N-(2-benzothiazolyl)-N′-[4-[1-(1H-imidazol-1-yl)-2-ethylbutyl]phenyl]-thiourea (compound 705).
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1)=O)C>O.C(O)C>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1
Reactant: CCOC(=O)N1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1

Procedure:
Potassium hydroxide (3.0 g) in water was added to the above-obtained 5-(4-ethoxycarbonylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.49 g) in ethanol, and the resulting mixture was heated under reflux for 8 hours. After cooling, ethanol was distilled off and water was added to the resulting residue. The resultant mixture was extracted with chloroform. The chloroform extract was dried, evaporated and chromatographed to afford 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 221°-224° C. (oxalate).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16](=[CH:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:17]([O:19]CC)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[OH-].[K+]>CO>[CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:22]\[CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)/[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
Ethyl 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylate (3.50 g) was dissolved in methanol (42 mL), and to this solution was slowly added a 8 M aqueous potassium hydroxide solution (27 mL), which had been separately prepared. After stirring at room temperature for 3 hours, methanol was evaporated under reduced pressure, followed by careful addition of concentrated hydrochloric acid for neutralization. The resulting solid was collected by filtration, washed with water, and then dried by blowing air. The crude product was washed with diethyl ether and then dried under reduced pressure to obtain (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylic acid (2.47 g).
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH3:20][C:21]([CH3:25])=[CH:22]CO>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][CH:20]=[C:21]([CH3:25])[CH3:22])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CC(C)=CCO
Product: CC(C)=CCOC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (6.0 g., 23.5 mmoles) was stirred with 30 ml. of 3-methyl-2-buten-1-ol for 3 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ice-cold ether and washed twice with ice-cold portions of 10% aqueous acetic acid, water, and 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo, and the resulting oil as distilled to give (3-methyl-2-buten-1-yl) 9-xanthenyl ether, b.p. ca. 110°C. at 0.01 mm.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:32][C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:35][CH2:34][C:33]([CH3:38])([CH3:37])[CH3:32])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CCC(C)(C)C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
Methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (800 mg, 1.93 mmol) was dissolved in DCE (15 mL), then 3,3-dimethyl-butyraldehyde (289 mg, 2.89 mmol) was added followed by sodium triacetoxyborohydride (Aldrich, 1224 mg, 5.78 mmol) and the resulting mixture stirred at 70° C. for 2 h. Reaction was allowed to cool down, dichloromethane (40 mL) was added and the organic layer was washed twice with H2O and once with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification on silicagel afforded 541 mg (56%) of the title compound as a colorless oil. HPLC, Rt: 6.42 min, purity: 98.3%); LC/MS, M+(ESI): 500.4; 1H NMR (CDCl3) δ: 7.44 (m, 4H), 7.17 (m, 5H), 6.93 (t, J=9.6 Hz, 1H), 6.73 (m, 1H), 4.46 (s, 2H), 3.88 (s, 3H), 3.40 (m, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.70-1.46 (m, 4H), 1.34 (m, 2H), 0.99-0.87 (m, 12H).