Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:46]([CH3:48])[CH3:47]>CN(C)C=O.O>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:46]([CH3:48])[CH3:47])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=1
Reactant: CC(C)I
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 2-iodopropane (226 μl, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (287 mg, 66%).
Reaction SMILES: [CH:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(#N)C>[N:46]1([C:12]([C:9]2[CH:8]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[S:11][CH:10]=2)=[O:14])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: C1CCCNCC1
Reactant: O=C(O)c1csc(C2CCCCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1csc(C2CCCCC2)c1)N1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
5-(Cyclohexyl)-thiophene-3-carboxylic acid (0.03 g, 0.14 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.42 mmol), HATU (0.15 mmol) and azepane (0.14 mmol) were added and the reaction stirred at room temperature overnight. The resulting solution was purified directly by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.022 g). LCMS m/z 292.22 [M+H]+ RT=13.57 min (Analytical Method 1). 1H NMR δ (ppm) (CHCl3-d): 7.2 (s, 1H), 6.95 (s, 1H), 3.7-3.4 (m, 4H), 2.8 (m, 1H), 2.1 (m, 2H), 1.9-1.2 (m, 16H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:11])([O-])[O-:9].[K+].[K+].[Br:14][C:15]1[CH:16]=[C:17](C(OC)=O)[C:18](CBr)=[CH:19][CH:20]=1>CN(C)C=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:8]([OH:9])=[O:11])=[C:17]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Br)cc1Oc1ccccc1
Yield: 68.2 %

Procedure:
Phenol (8 g, 85 mmole) and potassium carbonate (11.7 g, 85 mmole) in 150 mL of N,N-dimethylformamide was reacted with methyl 4-bromo-α-bromo-2-toluate (20 g, 65 mmole) by the procedure of Example 2, step a and folloed with alkaline hydrolysis by the procedure of Example 2, step b to give the crude 4-bromo-2-phenoxybenzoic acid (13 g) which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)Cl.[N+:28]([C:31]1[CH:48]=[CH:47][C:34]2[NH:35][C:36]3[C:37](=[CH:40][NH:41][C:42](=[O:46])[C:43]=3[C:44]#[N:45])[S:38](=O)[C:33]=2[CH:32]=1)([O-:30])=[O:29]>CN(C)C=O>[N+:28]([C:31]1[CH:48]=[CH:47][C:34]2[NH:35][C:36]3[C:37](=[CH:40][NH:41][C:42](=[O:46])[C:43]=3[C:44]#[N:45])[S:38][C:33]=2[CH:32]=1)([O-:30])=[O:29]
Reactant: N#Cc1c2c(c[nH]c1=O)S(=O)c1cc([N+](=O)[O-])ccc1N2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1c2c(c[nH]c1=O)Sc1cc([N+](=O)[O-])ccc1N2
Reaction time: 0.25 h

Procedure:
To a solution of 27 parts of triphenylphosphine in a mixture of 195 parts of acetonitrile with 400 parts of carbon tetrachloride is added 12 parts of a 1:1 solvate of 2,3-dihydro-8-nitro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile 10-oxide with N,N-dimethylformamide. The resultant mixture is heated at the boiling point under reflux with stirring for 15 minutes, then chilled. The precipitate which forms is isolated by filtration and recrystallized from a mixture of N,N-dimethylformamide and methanol to give 2,3-dihydro-8-nitro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile solvated 2:1 with N,N-dimethylformamide which melts above 305°. The solvent of crystallization can be removed by heating at around 200° in vacuo.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.ClC1N=CN=C(N)C=1OC[C:47]([F:50])([F:49])[F:48]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH2:36][C:47]([F:50])([F:49])[F:48])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc(Cl)c1OCC(F)(F)F
Reactant: COc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: Nc1ncnc(N2CCC(c3nc(-c4ccnc(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1OCC(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine using 6-chloro-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine instead of 6-Chloro-5-methoxy-pyrimidin-4-ylamine. LC-MS: (M+1=571, obsd.=571).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[S:13][C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOC(C)=O>[C:1]1([C:7]([C:9]2[S:13][C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)c1cnc(C#Cc2ccccc2)s1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cnc(C#Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of phenyl-(2-phenylethynyl-thiazol-5-yl)-methanol (Example 234, 157 mg, 0.539 mmol) in dichloromethane (5.0 mL) was added pyridinium dichromate (243 mg, 0.647 mmol) and the reaction was stirred at room temperature for about 18 hours. The mixture was then diluted with EtOAc (15 mL), filtered over Celite® and washed with EtOAc. The solution was concentrated under reduced pressure and purified by preparative TLC, eluting with 20% EtOAc in hexanes, to afford the titled compound, phenyl-(2-phenylethynyl-thiazol-5-yl)-methanone (135 mg, 87%) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](C)[CH:13]=1)=[C:5]2[CH2:20][C:21]([OH:23])=[O:22].BrC1C=C([Cl:31])C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:31])[CH:13]=1)=[C:5]2[CH2:20][C:21]([OH:23])=[O:22]
Reactant: Clc1cccc(Br)c1
Reactant: Cc1cccc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Product: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 18, step 1) and 3-bromochlorobenzene.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1>C(O)C(C)C>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([NH:11][C:8]2[NH:9][CH2:10][CH2:6][N:7]=2)[CH:3]=1
Reactant: Nc1cc(Br)c2[nH]cnc2c1
Solvent: CC(C)CO
Product: Brc1cc(NC2=NCCN2)cc2[nH]cnc12
Yield: 157.9 %

Procedure:
4-bromo-6-aminobenzimidazole (0.4 g, 1.9 mmol) and ISA (1.2 g, 8.9 mmol) was dissolved in isobutanol and stirred at reflux for 12 h. Column chromatographic separation of the reaction mixture (NH3 sat'd 20% MeOH/EtOAc) provided 0.41 g (1.5 mmol, 78%) of the product. The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.24 g (32%) of the product as a light brown solid: mp 217-218° C.; Anal. Calc. for C10H10N5Br.1.0C4H4O4 requires C, 42.44; H, 3.56; N, 17.68. Found: C, 42.28; H. 3.58; N, 17.40.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:19]([NH:23][CH2:24][CH:25](OCC)OCC)=[CH:20][C:21]#[N:22]>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][C:10]=1[C:19]1[NH:23][CH:24]=[CH:25][C:20]=1[C:21]#[N:22]
Reactant: CCOC(CNC(=CC#N)c1cc(C(F)(F)F)ccc1Cl)OCC
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To TFA (4 mL) at 5° C. the crude 3-[2-chloro-5-(trifluoromethyl)phenyl]-3-[(2,2-diethoxyethyl)amino]prop-2-enenitrile was added. After stirring at room temperature for 30 min, the reaction mixture was concentrated and then diluted with EtOAc and saturated solution of sodium hydrogen carbonate. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. Column chromatography on silica gel (0 to 20% EtOAc/hexane) afforded the title compound (584 mg, 45% 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.[Cl-].[Na+].O>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(C=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CNc1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.7 %

Procedure:
To a solution of 4-fluoroaniline (2.00 mL, 21.1 mmol) and dimethoxyacetaldehyde (60% solution in water, 3.30 mL, 21.9 mmol) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (6.70 g, 30.0 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 12 hours, followed by the addition of brine (50 mL) then extraction with ethyl acetate (3×100 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography to afford N-(2,2-dimethoxyethyl)-4-fluoroaniline (2.30 g, 57%): MS (ES+) m/z 200.6 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[S:28][C:27]([C:29](O)=O)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:54](=[N:57][OH:58])([NH2:56])[CH3:55].O>CN(C=O)C>[CH3:3][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[S:28][C:27]([C:29]5[O:58][N:57]=[C:54]([CH3:55])[N:56]=5)=[N:26][C:25]=4[C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:36][CH:37]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: CC(C)(c1cc(-c2cccc(-c3sc(C(=O)O)nc3-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)c(-c3cccc(-c4cc(C(C)(C)S(C)(=O)=O)cc5cccnc45)c3)s2)n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of acid from step 1 in DMF (0.05M) was added CDI (1.1 eq) and, after 5 min, acetamidoxime (1.1 eq). The reaction mixture was stirred at rt for 1 h and 18 h at 110° C. The reaction mixture was cooled to rt and poured into water. The residue was purified by flash chromatography (toluene:EtOAc, 45:55) to afforded the title compound and decarboxylated analog EXAMPLE 73 (more polar product).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1CCCCC1.[C:31](=[O:33])=[O:32]>C1COCC1>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[C:31]([OH:33])=[O:32])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A solution of (4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (2.31 g, 8.33 mMol) in anhydrous THF (50 mL) at −78° C. was treated with a 1.4 M solution of sec-butyllithium in cyclohexane (13 mL, 18.33 mMol), at a rate which did not allow the internal temperature to exceed −60° C. The solution was stirred at −78° C. for 15 minutes, then allowed to warm to −40° C. and stirred for 2.5 hours. The reaction was treated with gaseous CO2, stirred 30 minutes while warming to −20° C., then quenched with saturated ammonium chloride. The mixture was warmed to room temperature, and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated in-vacuo. The residue was triturated with hot heptane to yield 1.9 g of white powder as product. NMR (500 MHz, DMSO) δ 12.89 (s, 1H), 8.24 (d, 1H, J=9 Hz), 7.84 (s, 1H), 7.21 (d, 1H, J=7 Hz), 1.51 (s, 9 Hz). Yield=72%.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25](OCC)=[O:26])=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:19][C:25](=[O:26])[C:24]1[CH:30]=[CH:31][C:21]([NH2:20])=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(N)cc1
Temperature: 140 °C
Yield: 121.9 %

Procedure:
A 1-liter round bottom flask was fitted with a reflux condenser, Dean Stark trap and heating mantle and charged with 54 g (0.20 mole) of 1-octadecanol, 33 g (0.20 mole) ethyl 4-aminobenzoate, 8 g of p-toluenesulfonic acid and 500 ml of mixed xylenes. The flask was flushed with nitrogen and sealed under a nitrogen balloon. The reaction system was heated to reflux with a pot temperature of about 140° C. and allowed to reflux for about 1/2 hour before a 25 ml-aliquot of xylenes-ethanol mixture was removed through the Dean-Stark trap. Every 5-10 minutes, another 25 ml aliquot of the xylenes-ethanol mixture was removed until a total of 400 ml had been withdrawn from the reaction mixture and the pot attained a temperature of 150° C. Remaining volatiles were removed under 29 inches of Hg vacuum at 70° C. in a vacuum oven to give 95 g of an off-white waxy material melting at 60°-70° C., with an infrared spectrum showing the amino-aromatic ester with a long-chain aliphatic tail.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18]O)[CH2:11][CH2:10]1.[CH2:20]([NH:23][CH:24]1[CH2:32][CH2:31][C:27]2[N:28]=[CH:29][S:30][C:26]=2[CH2:25]1)[CH2:21]C>>[CH2:20]([N:23]([CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[CH:24]1[CH2:32][CH2:31][C:27]2[N:28]=[CH:29][S:30][C:26]=2[CH2:25]1)[CH3:21]
Reactant: CCCNC1CCc2ncsc2C1
Reactant: COc1ccccc1N1CCN(CCCCO)CC1
Product: CCN(CCCCN1CCN(c2ccccc2OC)CC1)C1CCc2ncsc2C1
Yield: 25 %

Procedure:
Compound 30 is prepared from 30A and 1C as described for 1. The salt of oxalic acid is crystallized from ethanol/diethylether.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[O:29])=[CH:23][CH:22]=1)C)(C)(C)C>C(OC(=O)C)C.Cl>[ClH:37].[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([N:16]3[C:17]4[C:13](=[C:12]([O:11][CH2:10][CH2:9][NH:7][CH3:6])[CH:20]=[CH:19][CH:18]=4)[CH:14]=[CH:15]3)=[CH:22][CH:23]=2)=[O:29])=[CH:32][C:33]=1[C:38]([F:41])([F:39])[F:40]
Reactant: CN(CCOc1cccc2c1ccn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCOc1cccc2c1ccn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 123.6 %

Procedure:
In 5 ml of a 4N hydrogen chloride ethyl acetate solution, 200 mg (0.33 mmol) of [2-(1-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-1H-indol-4-yloxy)ethyl]-methylcarbamic acid tert-butyl ester was dissolved and the solution was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and then the obtained residue was triturated with ethyl acetate to obtain 110 mg (66%) of 1-(4-chloro-3-(tri-fluoromethyl)phenyl)-3-{4-[4-(2-methylamino-ethoxy)-indol-1-yl]phenyl}urea hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[CH3:31][O:32][CH:33]([O:36][CH3:37])[CH2:34][NH2:35]>C(O)CCC.CO.CCCCC>[Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[N:6]=[C:7]([NH:35][CH2:34][CH:33]([O:36][CH3:37])[O:32][CH3:31])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: COC(CN)OC
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3NC(=S)C2)cc1
Solvent: CO
Solvent: CCCCC
Solvent: CCCCO
Product: COC(CNC1=Nc2cc(Cl)c(Cl)cc2N=C(c2ccc(-n3c(C)nc4cnccc43)cc2)C1)OC

Procedure:
A mixture 7,8-dichloro-2,3-dihydro-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (1.36 g, 3.0 mmol), aminoacetaldehyde dimethyl acetal (630 mg, 6.0 mmol) and red mercuric oxide (650 mg, 3.0 mmol) in n-butanol (15 ml) was heated at reflux for 2.5 hours. The mixture was cooled, diluted with methanol (50 ml) and filtered through Hyflo filter aid. The solvents were removed under reduced pressure to give a foam, which was suspended in pentane and sonicated for 5 minutes. The pentane was removed in vacuo to give the title compound, 1.10 g (70%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:25][N:24]=[C:23]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[S:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]([N:48]=[C:49]=[S:50])(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]([C:49]([NH:48][C:40](=[O:47])[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[S:50])[N:24]=[C:23]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[S:22]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)[Si](OCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (1.00 g, 1.79 mmol) in 20 mL of anhydrous THF was added benzoyl isothiocyanate (0.29 mL, 2.15 mmol). The reaction was allowed to stir overnight at reflux then cooled and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a yellow foam, 0.677 g, 52%.
Reaction SMILES: [F:1][C:2]([F:25])([O:7][C:8]([F:24])([C:20]([F:23])([F:22])[F:21])[C:9]([F:19])([F:18])[O:10][C:11]([F:17])(Cl)[C:12]([F:15])([F:14])Cl)[C:3]([O:5][CH3:6])=[O:4].II>[Zn].COCCOCCOC>[F:1][C:2]([F:25])([O:7][C:8]([F:24])([C:20]([F:21])([F:22])[F:23])[C:9]([F:19])([F:18])[O:10][C:11]([F:17])=[C:12]([F:14])[F:15])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)(Cl)C(F)(F)Cl
Agent: II
Agent: [Zn]
Solvent: COCCOCCOC
Product: COC(=O)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)=C(F)F
Temperature: 140 °C

Procedure:
A mixture of 10 g crude methyl perfluoro-7,8-dichloro-4-methyl-3,6-dioxaoctanoate, 5 g zinc dust, 50 ml anhydrous diethylene glycol dimethyl ether and 0.1 g iodine was heated to 140° C., and then distilled. The distillate was washed with water and the product chromatographed to yield appreciable amounts of CF2 =CFOCF2CF(CF3)OCF2COOCH3. The structure of the final product was proven by IR spectroscopy and by conversion with bromine to CF2BrCFBrOCF2CF(CF3)OCF2COOCH3. The structure of the vinyl ether was further confirmed by its boiling point, 75° C. at 50 mm of Hg, and its NMR spectrum.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1
Product: Fc1ccc(CNc2nc(-n3ccnc3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-(2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1)#[CH:2].C1CCCCC1.[CH3:23][C:24]1([CH3:31])[O:29][CH2:28][C:27](=[O:30])[CH2:26][O:25]1>C1COCC1.CCOCC>[CH3:23][C:24]1([CH3:31])[O:29][CH2:28][C:27]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=2)([OH:30])[CH2:26][O:25]1
Reactant: CC1(C)OCC(=O)CO1
Reactant: C#Cc1ccc(CCCCCCCC)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCCCCCCc1ccc(C#CC2(O)COC(C)(C)OC2)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
To a solution of the product of Step A (0.05 g; 0.233 mmol) in anhydrous THF (2 ml) 2 M n-butyllithium in cylohexane (0.13 ml; 0.26 mmol) was added drop wise at −15° C. under N2. After stirring for 15 min at −15° C., 2,2-dimethyl-1,3-dioxan-5-one (0.034 g; 0.26 mmol) was added and the resulting mixture was allowed to warm up to room temperature, diluted to 15 ml with Et2O and washed with H2O (2×10 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 95; 5) to give the title compound (0.03 g; 63%) as colourless oil. 1H-NMR (CDCl3) 7.33 (d, 2H, J=8.09 Hz); 7.09 (d, 2H, J=8.09 Hz); 4.11 (d, 2H, J=11.76 Hz); 3.83 (d, 2H, J=11.76 Hz); 3.99 (s, 1H); 2.57 (t, 2H, J=7.88 Hz); 1.56 (t, 3H, J=6.94 Hz); 1.49 (s, 3H); 1.46 (s, 3H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.96 Hz).