Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.C(O)(=O)C.[NH2:32][CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:37][N:36]([CH3:38])[C:34]([CH2:33][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])=[O:35]
Reactant: CN(C)C(=O)CN
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 80.2 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (38 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (39 mg), 2-amino-N,N-dimethyl-acetamide acetic acid salt (48 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 478. 1H NMR (DMSO-d6, 400 MHz): δ 12.49 (br, 1H), 8.46 (t, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.82 (m, 2H), 7.68 (m, 1H), 7.53 (d, 1H), 4.13 (d, 2H), 3.66 (s, 3H), 3.04 (s, 3H), and 2.87 (s, 3H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[S:17]([O:8][CH2:7][CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:19])(=[O:18])[CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OCCOS(C)(=O)=O
Reaction time: 72 h

Procedure:
Combine 2-t-butoxyethanol (3.37 g, 28.5 mmol), triethylamine (6 mL, 43 mmol), and dichloromethane (150 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (2.9 mL, 37.5 mmol). After 3 days, dilute the reaction mixture with dichloromethane and extract with a saturated solution of sodium bicarbonate and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 2-(t-butoxy)ethyl mesylate: Rf =0.75 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][CH2:12][CH2:13][OH:14])([O-:3])=[O:2].[OH:15]S(O)(=O)=O>O1CCCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][OH:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1C#CCCO
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCO)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of HgO (0.21 g, 1.0 mmol) in 50 ml of 0.12N H2SO4 is heated to 60° C., treated dropwise with a solution of 4-(o-nitrophenyl)-3-butyne-1-ol (3.70 g, 19.4 mmol) in 25 ml of tetrahydrofuran over a 10 minute period, held at 60° C. for 3 hours, treated with additional HgO (0.84 g, 3.9 mmol) suspended in 25 ml of 0.12N H2SO4, held at 60° C. for 4 hours, cooled to room temperature and diluted with water. The resultant aqueous mixture is extracted with ether. The extracts are combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give a residue. The residue is purified by flash column chromatography (silica gel; gradient 1:1→2:1 ethyl acetate: hexanes as eluent) to give the title product as a brown oil, 1.48 g, 37% yield, identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([Cl:18])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)c1cccs1
Product: CC(C)(C)OC(=O)NCC(Cl)c1cccs1

Procedure:
Following the procedure described in Example 42(b), 15 g of 2-t-butoxycarbonylamino-1-(2-thienyl)ethanol were chlorinated using phosphorus pentachloride to afford 13.6 g of the title product as crystals melting at 40°-43° C. This substance was used for next step without purification because it was decomposed by silica gel column chromatography.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[S:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[Cl-:1].[C:22]1([C:16]2[CH:15]=[C:20]3[C:19]([CH2:14][CH2:13][C:12]([C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N+:30]5[CH:31]=[CH:32][S:28][CH:29]=5)=[CH:4][CH:5]=4)=[O:11])=[CH:21]3)=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1cscn1
Reactant: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C[n+]2ccsc2)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 48 h

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg), and to the mixture was added thiazole (91 μl). The mixture was stirred at 100° C. for 48 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 3-[4—(7-phenyl-3,4-dihydronaphthalene-2-carboxamido)benzyl]thiazolium chloride (Compound 29) (133 mg) as pale brown crystals.
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH3:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.O>O1CCOCC1>[C:1]([NH:16][NH:15][C:13](=[O:14])[C:12]1[CH:17]=[C:18]([CH3:20])[CH:19]=[C:10]([CH3:9])[CH:11]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: Cc1cc(C)cc(C(=O)NN)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=O)NNC(=O)c1cc(C)cc(C)c1
Yield: 70.2 %

Procedure:
265 g of ethoxalyl chloride are added, in the course of one hour, to 316 g of 3,5-dimethylbenzhydrazide and 195 g of triethylamine in 1.58 liters of anhydrous dioxane, whilst keeping the temperature of the reaction medium at about 10°-12° C. The stirring is continued (sic) for about two hours. whilst allowing the temperature to return to the ambient value. The reaction mixture is then poured into seven liters of water, whilst stirring. The precipitate which has formed is filtered off, washed three times with one liter of water and then dried at 20° C. under a pressure of one millimeter of mercury. 357 g of 1-ethoxalyl-2-(3,5-dimethylbenzoyl)-hydrazine, which melts at 159° C., are obtained.
Reaction SMILES: C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[CH3:10][C:11]1[N:15]([CH2:16][CH2:17][OH:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][N:12]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:10][C:11]1[N:15]([CH2:16][CH:17]=[O:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][N:12]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc([N+](=O)[O-])n1CC=O
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
To 160 ml of CH2Cl2 was added dropwise 2 ml (22 mmol) of oxalyl chloride under nitrogen gas. The solution was cooled to -50° C. and 17 ml (240 mmol) of Me2SO was added dropwise to the stirred solution. About 20 min later, 3.42 g (20 mmol) of metronidazole [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole] dissolved in 15 ml of Me2SO was added. After 20 min of additional stirring, 33 ml (240 mmol) of triethylamine was added. The reaction mixture was stirred for another 10 min and then allowed to warm to room temperature. The mixture was diluted with 400 ml of ethyl acetate and washed 4 times with water, first with 100 ml and then 3 times with 50 ml. The 250 ml water volume was extracted 3 times with 250 ml of ethyl acetate and the ethyl acetate was added to the CH2Cl2. The mixture was washed with 100 ml of saturated NaCl solution, dried over anhydrous MgSO4, filtered, and concentrated to dryness in a rotary evaporator. The resulting crude residue was purified by flash silica gel chromatography to give the pure desired aldehyde (2-methyl-5-nitroimidazol-1-yl-acetaldehyde).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:30]>C1(C)C=CC=CC=1>[Cl:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Yield: 90.2 %

Procedure:
To a suspension of 4-hydroxy-6-(4-fluorophenyl)-quinazoline (720 mg, 3 mmol) in toluene (20 ml) was added diisopropylethylamine (1.5 ml, 9 mmol) and POCl3 (0.84 ml, 9 mmol). The mixture was refluxed for 1 hour. The solvents were evaporated in vacuo. The residue was redissolved in dichloromethane and the organic layer was washed with ice water till pH 6-7. The combined organic layers were dried over MgSO4 and concentrated to yield the title compound as a yellow solid (700 mg, yield: 90%) was characterized by its mass spectrum as follows: MS (m/z): 259 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1.O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[C:9]([CH2:11][O:12][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ccc(Cl)nc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Cl)nc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.20 g of 5-chloro-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 44), 2.83 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.51 ml of tributylphosphine, 1.53 g of 1,1'-(azodicarbonyl)dipiperidine and 25 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 2:1 to 1:1 by volume as the eluent, to give 1.29 g of the title compound, melting at 97°-99° C. (softening).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][CH3:18])=[C:8]2[CH2:19][C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][CH3:18])=[C:8]2[CH2:19][C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: CCOC(=O)Cc1c(SC)c2cc(F)ccc2n1Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CSc1c(CC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the procedure of Preparation 6, but using ethyl 1-(p-chlorobenzyl)-5-fluoro-3-methylthioindole-2-acetate from Example 3 as the starting material and tetrahydrofuran as the solvent, the title compound was prepared, mp 154 155° C. (dec.).
Reaction SMILES: C(OCC)(=O)C.Cl.C(OC([NH:15][C:16]1[C:17]([NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])[C:32]([NH:34][C:35]3[CH:44]=[CH:43][C:38]4[O:39][CH2:40][CH2:41][O:42][C:37]=4[CH:36]=3)=[O:33])=[CH:26][N:25]=2)=[O:23])=[CH:18][S:19][CH:20]=1)=O)(C)(C)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[NH2:15][C:16]1[C:17]([NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])[C:32]([NH:34][C:35]3[CH:44]=[CH:43][C:38]4[O:39][CH2:40][CH2:41][O:42][C:37]=4[CH:36]=3)=[O:33])=[CH:26][N:25]=2)=[O:23])=[CH:18][S:19][CH:20]=1
Reactant: CN(C)CCN(Cc1ccc(C(=O)Nc2cscc2NC(=O)OC(C)(C)C)nc1)C(=O)Nc1ccc2c(c1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CCN(Cc1ccc(C(=O)Nc2cscc2N)nc1)C(=O)Nc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
4.0M Hydrogen chloride-ethyl acetate solution (5.0 mL) was added to a solution of N-(4-t-butoxycarbonylaminothiophen-3-yl)-5-[3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(2-dimethylaminoethyl)ureidomethyl]pyridine-2-carboxylic acid amide (Reference Compound No. 6-4, 60 mg, 0.10 mmol) in a mixed solvent of ethyl acetate (2.0 ml)—methanol (3.0 mL), and then the reaction mixture was stirred at room temperature for 2 hours. Chloroform (0.10 L) and saturated aqueous sodium hydrogen carbonate solution (0.15 L) were added to a reaction solution, and then the whole was partitioned. The organic layer was washed with brine (0.10 L). The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give 38 mg of the title compound as an orange amorphous product. (Yield 77%)
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[N:2]1.[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][CH2:6][C:4]1[N:3]=[N:2][S:1][CH:5]=1
Reactant: O=Cc1csnn1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CNCc2csnn2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3-thiadiazole-4-carboxaldehyde (750 mg, 6.57 mmol) and 2,4-dimethoxybenzylamine (1086 μl, 7.23 mmol) in 1,2-dichloroethane (13.1 mL) at 0° C. was added molecular sieves (powdered, 4 A) (2.50 g, 6.57 mmol) followed by sodium triacetoxyborohydride (1950 mg, 9.20 mmol). The reaction was allowed to warm to room temperature with stirring overnight. Then, the resulting suspension was poured into dichloromethane (75 mL) and aqueous sodium hydrogen carbonate (saturated, 75 mL). The layers were mixed and then filtered through celite. The aqueous layer was then extracted with dichloromethane (3×50 mL) and the combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes+1% triethylamine gradient) to afford the title compound as a pale yellow liquid. LRMS (APCI) calculated for C12H16N3O2S [M+H]+, 266.1. found 266.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[C:33]=1Cl)[CH:29]=[O:30]>CS(C)=O>[CH:12]1([CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:33]4[C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][C:26]=4[C:25]([F:24])([F:39])[F:40])[CH:3]=3)[NH:7][CH:6]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=Cc1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Reactant: Oc1ccc2[nH]cc(CC3CCCCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(CC4CCCCC4)c3c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Analogously to the procedure of Example V, 2.0 g (8.72 mmol) of 5-hydroxy-3-cyclohexylmethyl-indole are dissolved in 50 ml of DMSO, 1.33 g (9.59 mmol) of potassium carbonate are added, the mixture is stirred for 10 min at room temperature and afterwards 2.41 g (8.72 mmol) of 3,5-bis-trifluoromethyl-4-chlorobenzaldehyde are introduced in portions. After stirring overnight at 50° C., the batch is worked up analogously to Example V and the crude product is chromatographed on silica gel 60 by means of toluene.
Reaction SMILES: [NH2:1][C:2](N)=[O:3].[CH2:5]([OH:9])[CH2:6][CH2:7][CH3:8]>>[C:2](=[O:3])([O:9][CH2:5][CH2:6][CH2:7][CH3:8])[O:9][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:5]([O:9][C:2](=[O:3])[NH2:1])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCO
Reactant: NC(N)=O
Product: CCCCOC(=O)OCCCC
Product: CCCCOC(N)=O

Procedure:
The same procedure as used in Example 1 was followed, however, 2-methylpentamethylene 1,5-dibutylurethane was used in the mixing vessel cascade instead of hexamethylene dibutylurethane. In doing this, 660 parts 2-methylpentamethylene-1,5-diamine, 680 parts urea, and 76 parts n-butanol were added during the course of one hour. In this case, about 2400 parts/hour n-butanol was obtained at the top of the first distillation column and was cycled back into the cascade. At the top of the stripping column, 1430 parts of a mixture comprising dibutyl carbonate, carbamic acid butyl ester, and residual butanol was obtained. This mixture was returned to the second vessel in the mixing vessel cascade together with the evaporator discharge. The evaporator was run in such a way that the ratio of evaporated 2-methylpentamethylene-1,5-dibutylurethane to discharging melt was approximately 46:54. A mixture of ca. 74 weight percent 2-methylpentamethylene 1,5-diisocyanate and 26 weight percent methylpentamethylene monourethane monoisocyanates condensed in the first condenser. From this condensate, 887 parts/hour 2-methylpentamethylene 1,5-diisocyanate was obtained in a subsequent distillation process at a purity ≥98 percent (selectivity based on charged 2-methylpentamethylene 1,5-diamine: 93.6 percent).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:18]([C:21]1[S:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>C(N(CC)CC)C>[CH3:17][O:16][C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[S:25][C:21]([C:18](=[O:20])[CH3:19])=[CH:22][CH:23]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: COC(=O)CCNc1ccc2ncc(Br)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: COC(=O)CCNc1ccc2ncc(-c3ccc(C(C)=O)s3)n2n1
Yield: 79 %

Procedure:
The methyl 3-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)propanoate was then subjected to Suzuki coupling reaction with (5-acetyl-thiophen-2-yl)boronic acid as described in example 5.6.19. However for this reaction, triethylamine was used as the base in place of the regular base (K2CO3). The desired product was obtained in 79% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.62-2.65 (m, 3H) 2.88 (t, J=5.94 Hz, 2H) 3.77 (s, 3H) 3.88 (t, J=5.68 Hz, 2H) 7.06 (d, J=9.85 Hz, 1H) 7.70 (d, J=4.04 Hz, 1H) 7.77 (d, J=4.04 Hz, 1H) 8.15 (s, 1H) 8.33 (d, J=9.85 Hz, 1H); LRMS (ESI) m/e 345.0 [(M+H)+, calcd for C16H16N4O3S 344.0].
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].S[CH:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[CH2:20](N(CC)CC)[CH3:21]>COCCOCCOC>[CH2:20]([C:12]([CH2:13][S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])([CH:17]=[CH:16][CH2:15][CH3:14])[CH:11]=[O:18])[CH3:21]
Reactant: CCN(CC)CC
Reactant: OCc1ccccc1S
Reactant: OC(S)c1ccccc1
Agent: Cl
Solvent: COCCOCCOC
Product: CCC=CC(C=O)(CC)CSc1ccccc1CO
Yield: 484.6 %

Procedure:
A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HCl and extracted with methylene chloride. The methylene chloride extract was wasted twice with 10% NaOH, dried over MgSO4 and concentrated in vacto to give 9.6 g of residue. Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%) of 16 as an oil.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20](O)=O.C=O.[OH-].[Na+]>O>[CH3:20][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:18][CH:19]=2)[CH2:6][CH2:5]1
Reactant: O=CO
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCOC(=O)c1ccc(N2CCN(C)CC2)cc1

Procedure:
19.6 g. (75 mmole) n-Butyl 4-(piperazin-1-yl)-benzoate are heated to reflux temperature for 12 hours in a mixture of 112 ml. 80% formic acid and 37.5 ml. 40% formaldehyde solution. After cooling, the reaction mixture is poured into 2.5 liters of water, rendered alkaline with 10N aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extracts are dried and evaporated to give 17.8 g. (86% of theory) of the desired product; m.p. 118°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].C(=O)=O.CC(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][N:13]([C:31](=[O:32])[C:30]3[CH:29]=[C:28]([O:27][CH3:26])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CN1CCOCC1
Product: COc1ccc(C2(CCO)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Temperature: 25 °C

Procedure:
2-[3-(3,4-Dimethoxy-phenyl)-pyrrolidin-3-yl]-ethanol (2.27 g, 9.03 mmol) and dichloromethane (100 mL) were combined. 4-Methylmorpholine (2.28 mL, 22.6 mmol, 2.5 eq.) was added. The mixture was cooled in a ice/NaCl bath and a solution of 3,4,5-trimethoxy-benzoyl chloride (2.19 g, 9.48 mmol) in dichloromethane (30 mL) was added dropwise. After the addition was complete, the dry-ice/acetone bath was changed to an ice bath and the mixture was allowed to warm to ambient temperature and maintained overnight. The solution was extracted with 1N HCl (3×100 mL), saturated K2CO3 (3×100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel eluting with ethyl acetate/methanol (20:1) to obtain a residue. The residue was dissolved in dichloromethane (50 mL), extracted with water (2×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue. Heated at 110° C./0.3 Torr for 16 h to obtain the title compound: Rf =0.14 (silica gel, 20:1 ethyl acetate/methanol), mp=60°-62° C.