Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:25]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: Oc1ccccc1
Product: CCCCCCCCCCCCCCCCCCc1ccccc1O
Temperature: 70 °C

Procedure:
This example is directed to the preparation of a typical alkylated phenol component using the process disclosed in U.S. Pat. No. 4,976,882 and alkyl phenol-sulfur condensates produced thereby. Octadecyl phenol was prepared by charging into a four-neck, 5-liter round bottom flask equipped with a mechanical stirrer, 933 grams of phenol (9.93 moles) and 286 grams of Amberlyst 15 catalyst. A reflux condenser, a thermometer, an addition funnel, and a nitrogen inlet tube were attached to the flask and the mixture was heated to 70° C. With stirring under a blanket of nitrogen, 834 grams (3.31 moles) of 1-octadecene was added dropwise over a period of about one hour. The temperature was raised to 90° C and maintained at this temperature for four hours. The reaction mixture was then cooled to 50° C. and filtered to remove the catalyst. The excess phenol was removed by vacuum distillation. The yield was 1,008 grams or 88%. The product has a refractive index of 1.4859 at 25° C., a viscosity of 38.0 cP at 40° C., and a hydroxyl number of 144 mg KOH/g. The infrared spectrum of the product showed absorption bands at 830 and 750 cm-1 m which are characteristic of alkyl phenols. The aromatic substitution pattern was determined by 13C-NMR spectroscopy and showed that the ortho to para ratio was 2.0:1.0. The alkyl substitution pattern was determined by 1H-NMR spectroscopy and showed that the product consisted of 50 mole % 2-substituted alkylate and 50 mole %≥3-substituted alkylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (30 mg, 0.14 mmol) in dichloromethane (1 mL) was added pyrrolidine (11 mg, 0.16 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C15H16N2O2: 256.1212, found 256.1214.
Reaction SMILES: [CH3:1][SH:2].Br[C:4]1[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:17][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:2][CH3:1])[C:14]=1[O:15][CH3:16]
Reactant: CCOC(=O)c1ccc(Br)c(OC)c1Br
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Br)c(OC)c1SC

Procedure:
A solution of methanethiol (47 ml) in dimethyl formamide was added to a mixture of ethyl 2,4-dibromo-3-methoxybenzoate (105 g) and potassium carbonate (131 g) in dimethyl formamide and the resultant suspension was stirred at room temperature overnight. Water was added and the mixture was extracted into ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography eluted with a mixture of ethyl acetate and cyclohexane to give as the minor component ethyl 4-bromo-3-methoxy-2-(methylsulphenyl)-benzoate (4.5 g) as a white solid, NMR (CDCl3) 1.5(t,3H), 2.6(s,3H), 4.05(s,3H), 4.5(q,2H), 7.35 (m,2H).
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN.O1CCCC1.C[CH2:22][N:23](C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH3:22])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cccc([N+](=O)[O-])c1Br

Procedure:
To a solution of 2-bromo-3-nitrobenzoic acid (0.974 g, 3.96 mmol) in DMF (3 mL) was added methylamine, 2.0 m solution in tetrahydrofuran (2.97 mL, 5.94 mmol), 1,1′-dimethyltriethylamine (1.38 mL, 7.92 mmol) and (1H-benzo[d]-[1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (2.47 g, 4.75 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel column using DCM/EtOAc-DCM (1:1) as eluent to give 2-bromo-N-methyl-3-nitrobenzamide: LC-MS (ESI) m/z 261.0 [M+H]+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)O
Reaction time: 3.75 h

Procedure:
Boc-Gly-L-Phe-L-Leu-OH (44 mg, 0.1 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexaflurophsophate (14 mg, 0.104 mmol) are dissolved in dry DMF (1 mL). DIEA (20 μL, 0.115 mmol) is added and about 0.5-1.0 mL of this solution is transferred to a test tube containing amino derivatized ELAMS™. The tube is sealed, vortexed for about 3.5-4 hours and the ELAMS™ pelleted and washed with DMF (3×) and methylene chloride (2×). The ELAMS™ are then deprotected with a solution of 50% trifluoroacetic acid (TFA) in methylene chloride for 30 min., washed with methylene chloride (2×), ethanol (2×) and methylene chloride (2×), and dried at 55° C. for about 1 hour. The identifier tag from each ELAMS™ is detected and recorded.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C.Cl.[CH3:21][C:22]1([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CCOC(C)=O.O>[CH2:1]([N:25]1[CH2:26][CH2:27][C:22]([CH3:21])([C:28]([NH2:30])=[O:29])[CH2:23][CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CC1(C(N)=O)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C(N)=O)CCN(Cc2ccccc2)CC1
Reaction time: 16 h
Yield: 97.8 %

Procedure:
Benzyl chloride (1.90 g) and sodium carbonate (1.59 g) were added to a DMF (70 ml) suspension of 4-methylpiperidine-4-carboxamide hydrochloride (2.24 g), and stirring was performed at room temperature for 16 hours. After adding water to the reaction liquid, extraction was performed with EtOAc. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (MeOH/chloroform) to obtain 1-benzyl-4-methylpiperidine-4-carboxamide (2.85 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][C:4]=5[C:10]([F:13])([F:12])[F:11])=[O:9])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)o1
Yield: 67.3 %

Procedure:
In the same manner as in Example 18-4 and using 2-methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic acid (110 mg, 0.564 mmol), tetrahydrofuran (8 mL), oxalyl chloride (98.0 μL, 1.13 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (74.0 mg, 67%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:28])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])O.[Na+]>ClCCCl.C(N(CC)CC)C>[Cl:28][C:3]1[C:2]2[N:1]=[C:30]([OH:32])[N:12]([CH2:13][CH2:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:19][CH2:20]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCNc2c(N)c(Cl)nc3ccccc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(CCn2c(O)nc3c(Cl)nc4ccccc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 0.60 g of tert-butyl 4-[2-(3-amino-2-chloro-4-quinolylamino)-ethyl]-1-piperidinecarboxylate and 0.44 g of triphosgene in 10 ml of 1,2-dichloroethane, 0.41 ml of triethylamine was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with 1,2-dichloroethane. The extract was washed with saturated brine, and dried, and the solvent was evaporated. The residue was washed with diisopropyl ether to give 0.57 g of colorless crystals. Recrystallization from 1,2-dichloroethane gave colorless crystals having the melting point of from 222 to 223° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](C)[CH:6]=[CH:5][C:4]=1[C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.Cl[CH2:35]Cl>[Ti](Cl)(Cl)(Cl)Cl>[OH:19][C:12]1([C:15]([F:16])([F:18])[F:17])[CH2:11][C:10]([CH3:20])([CH3:21])[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:35])[C:3]=2[O:2][CH3:1])[CH:13]1[NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1c(C)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]c(=O)ccc12

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 315 mg of 5-aminoquinolin-2(1H)-one. 12 mg of the title compound is obtained by reaction of 370 mg of the imine with 8.3 ml of titanium tetrachloride (1 M in dichloromethane) in 20 ml of dichloromethane.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([NH:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][C:8]([Cl:11])=[N:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[ClH:11].[ClH:11].[NH2:1][CH2:4][C:5]1[C:6]([NH:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][C:8]([Cl:11])=[N:9][CH:10]=1
Reactant: CC(C)(C)CNc1nc(Cl)ncc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CNc1nc(Cl)ncc1CN
Product: Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1.47 g (15.77 mmol) (5-azidomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine and 1.67 g (6.35 mmol) of triphenylphosphine in 20 ml of THF and 0.08 ml of H2O is stirred at r.t. for 24 h. Then the solvent is removed and the residue dissolved in 40 ml EtOH and 17 ml NH3 (25%). This reaction mixture is stirred for 48 h at r.t. and again the solvent is removed. The residue is dissolved in diethylether and twice extracted with 25 ml of 1N HCl. Both acidic extracts were combined and once more extracted with diethylether, then the acidic layer is evaporated under vacuo. The solid residue was triturated with diethylether yielding (5-Aminomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine 2HCl as slightly yellow crystalls.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][OH:20])=[O:17])=[N:14][CH:15]=1.O[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][O:20][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:17])=[N:14][CH:15]=1
Reactant: CCOC(=O)CO
Reactant: Cc1cc(C(=O)NCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)COCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Yield: 34.9 %

Procedure:
A solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-N-(hydroxymethyl)-4-methylpyridine-2-carboxamide (421 mg, 0.935 mmol) obtained from Example 85, ethyl hydroxyacetate (106 μl, 1.12 mmol), p-toluenesulfonic acid monohydrate (18 mg, 0.094 mmol) in benzene (10 ml) was heated to reflux for 30 minutes. The reaction solution was returned to room temperature, and then was concentrated under reduced pressure. Saturated aqueous sodium hydrogencarbonate was added to the resulting concentration residue, and the mixture was extracted from ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with 35% ethyl acetate/hexane was concentrated under reduced pressure, to obtain the title compound (175 mg, 0.326 mmol, 35%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:11]=2[C:12]#[N:13])[CH:5]=[N:6][C:7]=1[F:8].[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:23]3[CH:24]=[C:25]4[N:32]([CH3:33])[CH2:31][CH2:30][N:26]4[C:27](=[O:29])[N:28]=3)=[CH:14][C:11]=2[C:12]#[N:13])[CH:5]=[N:6][C:7]=1[F:8]
Reactant: N#Cc1cc(CO)ccc1Oc1cnc(F)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cnc(F)c(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 2-((5,6-difluoropyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile (131 mg, 0.5 mmol) in THF (4 mL), NaH (30.0 mg, 0.750 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (93 mg, 0.500 mmol).
Reaction SMILES: [C:1]([N:4]([CH3:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]([CH3:20])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[S:30][CH:31]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:28]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1
Yield: 31.2 %

Procedure:
A solution of 2,2,2-trichloroethyl {4-[acetyl(methyl)amino]phenyl}carbamate (200 mg, 0.589 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (144 mg, 0.589 mmol), diisopropylethylamine (0.103 ml, 0.589 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (80.0 mg, 31.3%) as a solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([C:11]2[C:12]3[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=3[S:14][C:15]=2[CH2:16]OS(C)(=O)=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C=O)C.O>[N:1]([CH2:16][C:15]1[S:14][C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[C:11]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
Sodium azide (179 mg, 2.76 mmol) was added to a solution of methanesulfonic acid 3-phenylbenzo[b]thiophen-2-ylmethyl ester (828 mg, 1.84 mmol) in DMF (10 mL) and the mixture stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-35% DCM in cyclohexane) affording the title compound as a clear oil (244 mg, 50%). LCMS (Method C): RT 4.46 min [M+H-N2]+ 237.8
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[C:46]([C:50]1[O:54][N:53]=[C:52]([NH2:55])[CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl>[C:46]([C:50]1[O:54][N:53]=[C:52]([NH:55][C:38]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[N:10]4[CH:11]=[CH:12][C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[CH:8][C:9]4=[N:15][CH:14]=3)=[CH:17][C:18]=2[C:23]([F:26])([F:25])[F:24])=[O:44])[CH:51]=1)([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: Nc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 144.7 %

Procedure:
Dissolve 4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-2-trifluoromethyl-phenylamine (0.4 g, 1.1 mmol) in DCM (40 mL) under nitrogen. Add triethylamine (0.39 mL, 2.5 equiv.) followed by careful addition of triphosgene (0.13 g, 0.4 equiv.). After 15 minutes at room temperature, add 5-tert-butyl-isoxazol-3-ylamine (0.19 g, 1.2 equiv.) and stir for 2 days at room temperature. Quench with water then dilute with ethyl acetate. Wash organics with 1 N NaOH followed by aqueous saturated sodium chloride. Dry organics over MgSO4 then filter and concentrate. Purify by reverse phase (5% MeCN:0.03% HCl in water→65% MeCN:0.03% HCl in water). Dilute product containing fractions with ethyl acetate then wash with 1 N NaOH followed by aqueous saturated sodium chloride. Dry the organics over MgSO4 then filter and concentrate to give the freebase (0.33 g off-white solid, 56%). MS (ES), m/z 521.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:17]([NH:19][CH3:20])=[O:18]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:15]=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[CH:21]=[C:22]([Cl:24])[CH:23]=2)[CH:9]=1
Reactant: CNC(=O)c1cc(Cl)cc(CBr)c1
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: CNC(=O)c1cc(Cl)cc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
(Step 3) To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-(bromomethyl)-5-chloro-N-methylbenzamide (0.28 g), and the mixture was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate. The solvent was removed, and the obtained precipitate was dissolved in methanol and crystallized from ethyl acetate. The obtained crystals were recrystallized from methanol-ethyl acetate to give the title compound (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.[NH2:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[OH:38].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[OH:38][C@@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@H:32]1[NH:31][C:20]([C:10]1[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1)=[O:21]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83587.3 %

Procedure:
To a suspension of 0.300 mg 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid in 1 ml dichloromethane was added 0.137 mL 1-chloro-N,N,2-trimethyl-propenylamine and the mixture was stirred at ambient temperature for 30 min. The resulting slightly yellow solution was added to a solution of 130 mg (1R,2R)-2-amino-cyclohexanol and 0.224 ml N,N-diisopropylethylamine in 3 ml dimethylformamide and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate of 95:5 to 50:50 to yield 324 mg of the title compound as white solid. MS (EI): 430.3 (M+H).
Reaction SMILES: [C:1]([C:3]([C:10]#[N:11])=[C:4](Cl)[C:5]([F:8])([F:7])[F:6])#[N:2].FF.[SH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(=O)C.[K+]>O.C(O)C>[CH2:19]([O:18][C:16]([C:15]1[S:14][C:4]([C:5]([F:8])([F:7])[F:6])=[C:3]([C:10]#[N:11])[C:1]=1[NH2:2])=[O:17])[CH3:20]
Reactant: CCOC(=O)CS
Reactant: N#CC(C#N)=C(Cl)C(F)(F)F
Agent: CC(=O)[O-]
Agent: FF
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1N

Procedure:
Combine 1,1-dicyano-2-chloro-2-(trifluoromethyl)ethylene (0.554 mmol) (prepared by the method of Middleton, J. Fluorine Chem., 20, 1982, p 397-418) and ethanol in a 50 ml flask. Add ethyl 2-mercaptoacetate (0.554 mmol) and potassium acetate (0.831 mmol) and heat to 60-70° C. for 30-40 minutes. Cool the reaction and add water. Product crystallizes as yellowish needles. Filter crystals and wash with 1:1 ethanol/water. Dry solid under reduced pressure to give the title compound as light yellow crystals: 1H NMR (400 MHz, CDCl3) δ 5.88 (s, 2H), 4.36 (q, 2H, J=7.2 Hz), 1.38 (t, 3H, J=7.0 Hz), MS found (M−1) 262.9.