Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[OH-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1>O1CCOCC1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:2][N:3]2[CH2:4][CH:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][CH2:8]2)=[S:26])=[CH:20][CH:19]=1
Reactant: NN1CC=C(c2ccccc2)CC1
Reactant: Fc1ccc(N=C=S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(NC(=S)NN2CC=C(c3ccccc3)CC2)cc1
Reaction time: 5 h
Yield: 64.4 %

Procedure:
To a stirred solution of N-amino-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.05 g) in a mixture of dioxane (10 ml) and water (5 ml) was added 1N sodium hydroxide solution (5 ml) under ice-bath cooling, and then a solution of 4-fluorophenyl isothiocyanate (1.15 g) in dioxane (5 ml) was added thereto. The mixture was stirred for 5 hours under ice-bath cooling. The reaction mixture was evaporated in vacuo and the residue was extracted several times with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give a crude product, which was recrystallized from ethyl acetate to give N-[[(4-fluorophenyl)thiocarbamoyl]amino]-4-phenyl-1,2,3,6-tetrahydropyridine (1.05 g).
Reaction SMILES: [CH2:1]([CH:19]([N:38]=[N+:39]=[N-:40])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:41][N:42]([CH3:46])[CH2:43][C:44]#[CH:45].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.C(O)(C)(C)C>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:19]([N:38]1[CH:45]=[C:44]([CH2:43][N:42]([CH3:46])[CH3:41])[N:40]=[N:39]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)N=[N+]=[N-]
Reactant: C#CCN(C)C
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)n1cc(CN(C)C)nn1
Reaction time: 96 h
Yield: 91.4 %

Procedure:
A solution of dilinoleyl methyl azide (500 mg, 0.90 mmol) and 3-dimethylamino-1-propyne (75 mg, 0.90 mmol) in H2O and tert-butyl alcohol (1:1, 12 mL) was treated with sodium ascorbate (0.090 mmol, 17.94 taken from a 1M solution in water), followed by CuSO4.5H2O (2.3 mg, dissolved in 30 μL of water) and stirred (96 h). The solution was then diluted with H2O (50 mL) and extracted with CH2Cl2 (3×), dried (Na2SO4), filtered, concentrated and purified via column chromatography (2%→4% MeOH/CH2Cl2) to yield the title compound as a colorless oil (524 mg, 91%). 1H NMR (400 MHz, CDCl3, δH) 7.76 (br. s, 1H), 5.47-5.25 (m, 8H), 4.48 (p, 1H), 3.80 (br. s, 2H), 2.75 (app. t, 4H), 2.49 (s, 6H), 2.15-2.00 (m, 8H), 1.91-1.75 (m, 4H), 1.40-1.12 (m, 34H), 1.11-0.98 (m, 2H), 0.85 (t, 6H). FW 637.08, C42H76N4.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C[Al](C)C.C([O:18][C:19]([C:21]1[C:22]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=3)=[CH:26][C:23]=2[S:24][CH:25]=1)=O)C.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:19]([C:21]2[C:22]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=4)=[CH:26][C:23]=3[S:24][CH:25]=2)=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1csc2cc(Oc3ccnc(N)n3)ccc12
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(C(=O)Nc4cccc(C(F)(F)F)c4)csc3c2)n1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
In a dried vessel, 66 mg (0.41 mMol) 3-trifluoromethyl-aniline are dissolved in 7 ml degassed toluene and cooled to 10° C. Then 650 μl Me3Al (2 M in toluene; 1.3 mMol) are added via syringe. After 45 min at rt, a solution of 100 mg (0.317 mMol) 6-(2-amino-pyrimidin-4-yloxy)-benzo[b]thiophene-3-carboxylic acid ethyl ester (Step 12.5) in 2.5 ml THF is added and the reaction mixture is stirred for 40 min in an oil bath of 110° C. The solution is cooled in an ice-bath and hydrolyzed with 15 ml of a sat. NH4Cl. After 10 min stirring, the mixture is filtered through Celite, the solid washed extensively with EtOAc and water, the aq. phase separated from the filtrate and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc/hexane 9:1) and crystallization from CH2Cl2/hexane gives the title compound: MS: [M+1]+=431; TLC(EtOAc/hexane 9:1): Rf=0.24.
Reaction SMILES: [F:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[OH-].[NH4+:12]>C(O)C>[F:1][C:2]1[C:3]([NH2:12])=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[Cl:8]
Reactant: Nc1nc(Cl)c(F)c(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(N)c(F)c(Cl)n1
Temperature: 100 °C
Yield: 65 %

Procedure:
5-Fluoro-4,6-dichloro-2-pyrimidineamine (4) (204 mg, 1 mmol) and ammonium hydroxide (15 ml) were charged to a sealed tube and ethanol (1.5 ml) added. The tube was heated at 100° C. for 24 hours. The solution was concentrated. The residue was absorbed on silica gel and chromatographed (elution with ethyl acetate), yielding (5) as a white powder (118 mg, 65%): MS (70 eV, EI) m/z (relative intensity) 162 (M+, 100), 43 (92), 164 (33), 127 (29), 135 (16). Exact Mass Calcd for C4H4N4ClF: 162.0108. Found: 162.0100.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[C:40]=2[N:41]=[CH:42][N:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[C:40]=2[N:41]=[CH:42][N:43]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1-n1nnc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1-n1nnc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
Sodium hydride (57.7 mg, 1.44 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide (Intermediate AU3) (300 mg, 0.60 mmol) in anhydrous THF (7 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 7-chloro-3-o-tolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (148 mg, 0.60 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to give (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(3-o-tolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)propanamide (410 mg, 100%). 1H NMR (400 MHz, CDCl3) δ0.97 (s, 9H), 2.19 (s, 3H), 3.67-3.85 (m, 4H), 4.26 (d, 2H), 6.14 (t, 1H), 7.31-7.54 (m, 10H), 7.60-7.68 (m, 5H), 8.18-8.23 (m, 2H), 8.66 (s, 1H), 8.91 (s, 1H); m/z (ES+), (M+H)+=708.61; HPLC tR=4.02 min
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCC(=O)O.[NH2:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15](=[O:17])[NH2:16].N[C@H](C(O)=O)CCC(=O)N>>[NH3:1].[NH2:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15](=[O:17])[NH2:16]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Product: N

Procedure:
The polymer of Example 15 is converted to the Glu/Gln co-polymer. Polymeric glutamic acid (20 gm) is suspended in 100 ml o heated to 50° C. Concentrated aqueous ammonia (30%) is added while monitoring the pH of the solution. At pH=5.0, the mixture is stirred for an additional 10 min. while making small adjustments to pH 5.0 and the solution is freeze dried to obtain 20.4 gm of a white powder. The partial ammonium salt is then heated to 80° C. in a vacuum oven for conversion to the Glu/Gln co-polymer. Yield: 18.6 gm. Elemental analysis for N shows this preparation to contain 8% Gln. Titrations to higher pH with ammonia yield higher % Gln in the final co-polymer.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>CO.C(OCC)(=O)C>[ClH:22].[ClH:22].[O:21]=[S:17]1(=[O:20])[CH2:16][CH2:15][CH:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S1(=O)CCC(N2CCNCC2)CC1
Yield: 99.5 %

Procedure:
To a stirred solution of 4-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (8.02 g, 25 mmol) in methanol at 45° C. (150 mL) was added 4 N hydrochloric acid in 1,4-dioxane (100 mmol, 25 mL, Aldrich). The mixture was stirred at 45° C. for 7 h until thin layer chromatography (5% methanol in ethyl acetate) indicated that the reaction was complete. The solvent was removed under reduced pressure to give 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride as a white solid (7.24 g, 99.5%). LR-MS: 218 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>S(=O)(=O)(O)O.O>[C:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1)(=[O:12])[CH3:11]
Reactant: Cc1cc(O)ccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
43.0 g (0.30 mol) of 4-chloro-3-methylphenol, 34 ml (0.36 mol) of acetic anhydride and a few drops of concentrated sulfuric acid were stirred for 2 h at 60° C. in a 250 ml flask equipped with a reflux condenser. The reaction mixture was cooled to room temperature, poured into 200 ml of water and stirred for 1 h at room temperature. The mixture was then extracted with 400 ml of diethyl ether. The organic phase was dried over magnesium sulfate and the ether was distilled off. The raw product is subsequently distilled under reduced pressure (b.p. 65-68° C., 20 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])[C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][OH:33].[NH2:34]O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:34]=[CH:32][O:33][N:30]=3)=[CH:25][C:24]=2[F:31])[C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CN([C@H](CCC(F)(F)F)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Reactant: NO
Reactant: CO
Solvent: O
Product: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(-c2ncon2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 47.5 °C
Yield: 96 %

Procedure:
(2R)-2-[[(4-Chlorophenyl)sulfonyl][(4-cyano-2-fluorophenyl)methyl]amino]-5,5,5-trifluoropentanamide (399 g) and methanol (1.6 L) were charged to a reactor followed by hydroxylamine (50% solution in water, 93 mL, 1.8 eq). The mixture was heated to 45-50° C. until complete reaction by HPLC (<0.15 relative AP starting material). Water (0.5 L) was charged slowly, keeping the batch temperature between 30-50° C. The batch was allowed to stand until crystallization started and then water (2.7 L) was charged. The batch was cooled to 15-20° C. and filtered. The cake was washed with 2:1 MeOH:water (2 L) and then dried under vacuum at 50° C. to give the title compound as white solid (415 g, 96% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43-1.64 (m, 1H) 1.77-1.93 (m, 1H) 1.93-2.17 (m, 2H) 4.41 (dd, J=8.48, 6.03 Hz, 1H) 4.60 (d, J=17.14 Hz, 1H) 4.94 (d, J=16.77 Hz, 1H) 5.81-5.98 (m, 2 H) 7.19-7.27 (m, 1H) 7.37-7.47 (m, 2H) 7.52 (d, J=4.14 Hz, 2H) 7.64 (d, J=8.67, Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 9.71-9.83 (m, 1H). IR (KBr): 3491, 3379, 1680, 1651, 1592, 1433, 1343.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH2:6])[CH:5]=1.CC([O-])(C)C.[K+].F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Br:22])[CH:15]=1.OS([O-])(=O)=O.[K+]>CS(C)=O>[N:1]1[N:2]=[CH:3][N:4]([NH:6][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Br:22])[CH:15]=2)[CH:5]=1
Reactant: Nn1cnnc1
Reactant: N#Cc1ccc(F)cc1Br
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Nn2cnnc2)cc1Br
Reaction time: 1 h

Procedure:
To a solution of 4H-1,2,4-triazol-4-amine (4.204 g, 50.0 mmol) in DMSO (50 mL) was added KOtBu (5.51 g, 50.0 mmol). The mixture was stirred for 0.5 hours at room temperature before 4-fluoro-2-bromobenzonitrile (5.00 g, 25.0 mmol) was added and stirring was continued for 1 hour. The mixture was poured into crushed ice and neutralized with 2M KHSO4 solution. The precipitate was filtered off and recrystallised from MeOH to give CAB05094 (4.82 g, 73%) as a light yellow crystalline solid. Mp. 234-236° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.66 (dd, J=8.6, 2.4 Hz, 1H), 6.79 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 8.86 (s, 2H), 10.45 (s, 1H); 13C NMR (100.6 MHz, DMSO-d6) δ 105.0, 111.5, 115.4, 117.8, 126.0, 136.2, 143.9, 151.8; LRMS (APCI−): m/z 261.8 (100%, [C9H579BrN5]−), 263.8 (90%, [C9H581BrN5]−); HRMS (ES+) calcd for C9H779BrN5 [M+H]+: 263.9879. found 263.9870;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[O:6][CH2:5]2.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[OH:11])[C:7](=[O:12])[O:6][CH2:5]2
Reactant: O=[N+]([O-])O
Reactant: O=C1OCc2cc(O)c(O)cc21
Agent: O=S(=O)(O)O
Product: O=C1OCc2cc(O)c(O)c([N+](=O)[O-])c21
Temperature: 25 °C

Procedure:
To a solution of 5,6-dihydroxy-3H-isobenzofuran-1-one (0.4 g) in sulfuric acid at −30° C. was added 5 M nitric acid in sulfuric acid (0.55 ml). The reaction mixture was let to warm up to room temperature and then poured into ice water. The product was filtered and recrystallized from acetic acid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][NH:16][C:15](=[S:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]1.FC(F)(F)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O.O>CN(C)C=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:15](=[S:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 39 mg, 0.975 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (202 mg, 0.567 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (141 μL, 1.131 mmol) in N,N-dimethylformamide at −25° C. After 15 min, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% hexanes→30% ethyl acetate/hexanes) gave the title compound (105 mg). MS 439.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:39]([CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:40])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCCC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 33.8 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclopentanecarbonyl chloride (0.04 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 70 (43 mg, 33% yield) as a white fluffy solid. LC-MS (M+H=439, obsd.=439).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[S:7][C:6]=2[C:17]=1[Cl:18].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2cc(-c3ccccc3C)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1-c1cc2cc(O)c(Cl)c(Cl)c2s1
Yield: 73.2 %

Procedure:
A mixture of 4.0 g of 6,7-dichloro-5-methoxy-2-(2'-methylphenyl)benzo[b]thiophene and 40 g of pyridine hydrochloride is heated at 200°-205° for 3 hrs. To the cooled mixture is added 250 ml of water and the aqueous mixture is extracted with three 200 ml-portions of ethyl ether. The organic layers are combined, washed dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization of the residue from ether-pentane gives 2.8 g of 6,7-dichloro-5-hydroxy-2-(2'-methylphenyl)benzo[b]thiophene, mp 106°-107°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH:14]([CH3:16])[CH3:15].Cl.[CH3:19][O:20][NH2:21]>C(O)C>[CH:14]([C:13]1[N:21]([O:20][CH3:19])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)([CH3:16])[CH3:15]
Reactant: CC(C)C(=O)Nc1cnc2ccccc2c1Cl
Reactant: CON
Agent: Cl
Solvent: CCO
Product: COn1c(C(C)C)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of N-(4-chloroquinolin-3-yl)-2-methylpropanamide (6.0 g, 24 mmol), O-methylhydroxylamine hydrochloride (2.5 g, 0.030 mol), and ethanol (75 mL) was heated at reflux for five hours, allowed to cool to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and the solution was washed with saturated aqueous sodium carbonate (2×50 mL) dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 4.9 g of 2-isopropyl-1-methoxy-1H-imidazo[4,5-c]quinoline as a dark oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[O:17].FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]1[O:17][CH:2]2[CH:3]=[CH:4][C:5]3[C:10]([N:1]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]1=2)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: c1ccc2ncccc2c1
Reactant: O=Cc1cccs1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC2OC(c3cccs3)c3ccccc3N2c2ccccc21
Yield: 57 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 2-Thiophenecarboxaldehyde (0.084 g, 70 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-(thiophen-2-yl)-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as inseparable mixture of diastereomers as a yellow solid (0.091 g, 57% yield, dr determined by NMR analysis of crude reaction mixture is 1:1).
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].[C:35](Cl)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:35])=[O:18])[C:11]([F:12])([F:13])[F:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(+) or (−)-Methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (tr=3.5 min—from Example 35-B) (54 mg, 0.114 mmol) was dissolved in ethanol (2.0 mL). This solution was added to a mixture of acetyl chloride (1.0 mL) in ethanol (20.0 mL) at 0° C. This mixture was gradually warmed to room temperature and stirred for 16 hr. The reaction solution was basified with saturated sodium bicarbonate solution and the majority of the ethanol was removed in vacuo. The resulting reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This material was purified using FCC eluting with ethyl acetate/heptane (0-60%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.89 (br.s., 1H) 11.09 (br. s., 1H) 8.26 (s, 1H) 7.83-8.06 (m, 1H) 7.49-7.73 (m, 1H) 7.38 (t, J=2.78 Hz, 1H) 6.91-6.96 (m, 1H) 6.74 (s, 1H) 3.98-4.36 (m, 2H) 3.73-3.97 (m, 2H) 3.04-3.06 (s, 3H) 2.47-2.50 (s, 3H) 0.97-1.08 (m, 3H) HRMS calcd. for C24H21F3N4O4 (M+H)+ 487.1548. found 487.1576.