Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=C[N:3]([C:6](N2C=NC=C2)=[S:7])C=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C([O-])(=O)C.[NH4+]>C(#N)C.CO>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[NH:13][C:6]([NH2:3])=[S:7]
Reactant: Nc1ccc2ccccc2n1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC#N
Product: NC(=S)Nc1ccc2ccccc2n1
Reaction time: 1 h
Yield: 41 %

Procedure:
1.496 g (8.394 mmol) N,N′-thiocarbonyldiimidazole was dissolved in 30 mL acetonitrile, and 1.210 g (8.394 mmol) 2-amino-quinoline dissolved in 15 mL acetonitrile was added dropwise at room temperature. After 1 hr a precipitate deposited, and stirring was performed for an additional 12 hr. The solid was filtered off, and without further purification was reacted directly with 1.294 g (16.789 mmol) ammonium acetate in 50 mL methanol for 5 hr at 40° C. After mass spectrometric analysis the solvent was removed under vacuum, and the batch was dissolved in dichloromethane and shaken out with water (1×50 mL). The organic phase was dried over magnesium sulfate and filtered, and the solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel (column Ø=3 cm, h=15 cm), first with dichloromethane as eluent, then with methanol to increase the polarity, and finally with pure methanol. The clean fraction was purified and the solvent was removed under vacuum, resulting in a total of 0.70 g (3.445 mmol, 41%) N-quinolin-2-yl-thiourea.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([F:29])[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=3)[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)c(OC)nc1C
Yield: 69 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:23][C:24]([F:42])([F:41])[C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)=[CH:27][CH:26]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][C:28]2[CH:39]=[CH:40][C:25]([C:24]([F:23])([F:41])[F:42])=[CH:26][CH:27]=2)=[CH:31][CH:32]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]([F:19])[F:20])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)F)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(difluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-[4-(trifluoromethyl)phenoxy]benzoic acid used in Example 41 (41a) to give the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O-])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:26])C=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:26])[C:15]=1[N:12]1[CH2:13][CH2:14][N:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: O=C([O-])N1CCN(C(=O)c2ccccc2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 22.6 %

Procedure:
General procedure C was followed using 4-benzoylpiperazine 10 (47 mg, 0.25 mmol), 3,4,5-trichloropyridine (72 mg, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (19 mg, 23%), m.p. 132-134° C.; umax (CHCl3)/cm−1 3005, 1627, 1435, 1286, 1153, 1010; m/z (ESI) C16H16Cl2N3O requires 336.0665, found [M+H]+ 336.0661.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:10]2[C:6]([S:7][C:8]([C:11]3[C@H:12]([CH3:35])[C@@H:13]4[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]4[C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])=[CH:9]2)=[C:5]([S:36][CH3:37])[N:4]=1.IC[C:40]([NH2:42])=[O:41]>CC(C)=O>[C:40]([CH2:37][S:36][C:5]1[N:4]=[C:3]([S:2][CH3:1])[N:10]2[CH:9]=[C:8]([C:11]3[C@H:12]([CH3:35])[C@@H:13]4[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]4[C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:17])[S:7][C:6]=12)(=[O:41])[NH2:42]
Reactant: CSc1nc(SC)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: NC(=O)CI
Solvent: CC(C)=O
Product: CSc1nc(SCC(N)=O)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Temperature: 25 °C
Reaction time: 336 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[5,7-bis(methylthio)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (107 mg) was dissolved in 2 ml of acetone. 2-Iodoacetamide (353 mg) was added to the solution. The mixture was stirred at room temperature for 14 days. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1:1) to prepare 88 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-carbamoylmethylthio-5-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:15])[C:12](Cl)=[O:13])(=[O:10])=[O:9].O1CCCC1.[CH3:21][NH:22][C:23]1[N:28]=[C:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH:26]=[C:25]([CH3:35])[N:24]=1>C(N(CC)CC)C>[F:34][C:31]([F:32])([F:33])[CH2:30][O:29][C:27]1[CH:26]=[C:25]([CH3:35])[N:24]=[C:23]([N:22]([CH3:21])[C:12]([N:11]([CH3:15])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])=[O:13])[N:28]=1
Reactant: CNc1nc(C)cc(OCC(F)(F)F)n1
Reactant: CN(C(=O)Cl)S(=O)(=O)c1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(F)(F)F)nc(N(C)C(=O)N(C)S(=O)(=O)c2ccccc2Cl)n1

Procedure:
To 18 parts of N-[(2-chlorophenyl)sulfonyl]N-methylcarbamyl chloride in 300 parts of tetrahydrofuran containing 10 parts of triethylamine is added 22 parts of 2-methylamino-4-(2,2,2-trifluoroethoxy)-6-methylpyrimidine. After stirring at reflux for 10 hours, the precipitated salts are filtered off and the filtrate is concentrated to yield N-[N-[4-(2,2,2,-trifluoroethoxy)-6-methylpyrimidin-2-yl]-N-methylaminocarbonyl]-2-chloro-N-methylbenzenesulfonamide.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([Cl:19])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
To a well-stirred solution consisting of 3.1 g. (0.015 mole) of α-(4-isobutylphenyl)propionic acid (ibuprofen) dissolved in 200 ml. of methylene chloride, there were added 3.8 g. (0.030 mole) of oxalyl chloride. The resulting reaction mixture was refluxed for a period of two hours and then cooled to room temperature. The clear colorless solution so obtained was thereafter concentrated in vacuo to dryness to yield a residue that was substantially free of solvent and excess oxalyl chloride. In this way, there was readily obtained substantially pure α-(4-isobutylphenyl)-propionyl chloride in the form of a clear colorless oil. The latter product was used as such in the next reaction step without any purification being necessary. The yield of product was assumed to be quantitative.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=O)=[CH:20][CH:19]=1)#[N:17]>O1CCCC1.C(O)(=O)C>[C:10]1([C:8]2[CH:7]=[CH:6][C:3]3[N:4]([CH3:5])[C:25]([CH2:24][C:21]4[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=4)=[N:1][C:2]=3[CH:9]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CNc1ccc(-c2ccccc2)cc1N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1c(Cc2ccc(C#N)cc2)nc2cc(-c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 24f from 2-amino-4-phenyl-N-methyl-aniline, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran and glacial acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](S)=[N:8][C:7]=2[CH:12]=1.CN(C=O)C.S(Cl)([Cl:20])=O>>[Cl:20][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[N:8]=1
Reactant: COc1ccc2oc(S)nc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2oc(Cl)nc2c1

Procedure:
The mixture containing 5-methoxybenzoxazole-2-thiol was heated in thionyl chloride with a drop of DMF. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried and concentrated. Purification on a silica gel column gave 2-chloro-5-methoxybenzoxazole as a white solid. MS: MH+=184.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([C:9]([C:12]3[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].CO>N.[Pd]>[NH2:2][CH2:1][C:3]1[C:4]2[N:5]([C:9]([C:12]3[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[O:24])[CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(C#N)cccn23)c1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(CN)cccn23)c1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
1-(3-(8-cyanoimidazo[1,2-a]pyridin-3-yl)-5-isopropoxyphenyl)-3-(2,2,2-trifluoroethyl)urea (0.030 g, 0.072 mmol) was taken up in 7N AMMONIA in methanol (20 mL, 140 mmol) and Pd—C (10 mg, 0.094 mmol) added. Reaction was stirred under H2 balloon for 1 hour. Mixture was then filtered through celite and solvent removed. Residue was dried under high vacuum overnight to give title compound as a yellow solid (0.026 g, 0.062 mmol, 86% yield). MS (ES+) C20H22F3N5O2 requires: 421. Found: 422 [M+H]+.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=C1C=C(Br)CCC1
Product: COc1ccccc1C1=CC(=O)CCC1
Yield: 98 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 2-methoxyphenylboronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 80% ethyl acetate/hexanes) yielded the product (166 mg, 98%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.32 (ddd, J=8.3, 7.4, 1.9 Hz, 1H), 7.18 (dd, J=7.7, 1.9 Hz, 1H), 6.96 (dd, J=7.4, 1.1 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.18 (t, J=1.8 Hz, 1H), 3.83 (s, 3H), 2.73 (td, J=6.1, 1.4 Hz, 2H), 2.48 (t, J=6.3 Hz, 2H), 2.14-2.06 (m, 2H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH2:39][C:40]#[N:41])[CH:37]=2)O1>>[CH3:24][N:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:33]5[CH:34]=[N:35][N:36]([CH2:38][CH2:39][C:40]#[N:41])[CH:37]=5)[N:10]4[N:9]=3)=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Reactant: CN1CCC(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Product: CN1CCC(c2ccc(Nc3ncc4ccc(-c5cnn(CCC#N)c5)n4n3)cc2)CC1

Procedure:
(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(1-methyl-piperidin-4-yl)-phenyl]-amine (1.00E2 mg, 0.259 mmol), and 3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-propionitrile (128 mg, 0.518 mmol) were reacted in an analogous manner to Example 881A at 80° C. for 8 h. The reaction mixture was purified via ISCO silica gel chromatography using an amine capped column 50-100% EtOAc in hexanes (32 mg, 29%). LCMS=427.0 (M+H), HPLC rt=1.889 min, 96% purity. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.32 (s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 7.65 (d, J=7.6 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.08 (d, J=4.3 Hz, 1H), 6.91 (d, J=4.7 Hz, 1H), 4.47 (t, J=6.4 Hz, 2H), 3.16 (t, J=6.5 Hz, 2H), 2.87 (d, J=10.8 Hz, 2H), 2.46-2.40 (m, 1H), 2.19 (s, 3H), 1.96 (t, J=10.8 Hz, 2H), 1.76-1.62 (m, 4H).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:11]=[CH2:12].C(N(CC)CC)C>C(OCC)C>[CH3:16][O:15][C:14]([NH:13][CH2:10][CH:11]1[O:9][N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)=[O:17]
Reactant: ON=Cc1ccccc1
Reactant: C=CCNC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)NCC1CC(c2ccccc2)=NO1
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A 24 g. portion of benzaldoxime was chlorinated, isolated and dissolved in diethyl ether. The solution was cooled to 15° C., and 46 g. of methyl allylcarbamate was added. Sixty ml. of triethylamine was then added dropwise, keeping the temperature below 20° C. The mixture was stirred for 3 hours, and filtered. The filtrate was evaporated to dryness, and the residue was washed with water and filtered again. The solids were identified as 32 g. of product, m.p. 102°-103° C., NMR singlets at 3.63 and 5.48 ppm., multiplets at 2.82-3.80, 4.57-5.08, 7.13-7.50 and 7.45-7.77 ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]2=[N:9][C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:25]([F:28])([F:27])[F:26])=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=3)=[CH:11][N:5]2[N:4]=1)#[N:2].CC[OH:31].CS(C)=O.[OH-].[Na+].OO>O>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([NH:18][C:16]1[CH:17]=[C:12]([C:10]2[N:9]=[C:6]3[N:5]([CH:11]=2)[N:4]=[C:3]([C:1]([NH2:2])=[O:31])[CH:8]=[CH:7]3)[CH:13]=[CH:14][C:15]=1[C:25]([F:28])([F:26])[F:27])=[O:24]
Reactant: CCO
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(C#N)ccc3n2)ccc1C(F)(F)F
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(C(N)=O)ccc3n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
An 8 mL vial is charged with N-[5-(6-cyanoimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.019 g, 0.05 mmol), EtOH-DMSO (1.2 mL, 5:1), NaOH (0.1 mL, 1M in water), and H2O2 (0.1 mL, 30% in water). The mixture is stirred for 2 hr at room temp, diluted with water (4 mL), extracted EtOAc (2×) and CH2Cl2 (1 x). Organics are dried, concentrated onto celite and purified on silica (0-100% EtOAc in CH2Cl2) to give the title compound (12 mg, 60% yield). LCMS m/z=406.5 [M+H]+, tR=2.12 min. (compound same as Example 180)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=[O:12])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>CO>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][C:3](=[O:12])[C:2]([F:13])([F:14])[F:1])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(C#Cc1ccccc1)C(F)(F)F
Solvent: CO
Product: O=C(C=C(Nc1cccc(Cl)c1)c1ccccc1)C(F)(F)F

Procedure:
Into a 1-Neck round-bottom flask was added 1,1,1-trifluoro-4-phenyl-but-3-yn-2-one (2.0 g, 0.01 mole), methanol (5 mL) and m-chloroaniline (0.961 mL, 0.0091 mol). The reaction was stirred. TLC (SiO2, hexanes/methylene chloride 1:1) indicated near reaction completion after 1 h. After 1.5 h the product was concentrated in vacuo to afford an orange oil, which was placed on high vacuum overnight, affording a yellow gum. The crude product was chromatographed on Silica gel with hexanes, Methylene Chloride 2:1, and place on high vacuum for 2 h to afford the title compound as a yellow gum; 1H NMR (CDCl3, 400 MHz) δ 5.74 (s, 1 H), 6.67-6.69 (m, 1 H), 6.85 (m, 1 H), 7.08-7.10 (m, 1 H), 7.31-7.39 (m, 4 H), 7.43-7.47 (ft, 1 H), 12.39 (bs, 1 H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[CH2:3].[NH3:11]>>[NH2:11][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: N
Reactant: C=C(C)c1ccc(O)cc1
Product: CC(C)(N)c1ccc(O)cc1

Procedure:
A 0.10-g sample of 4-(1-methylethenyl)phenol is exposed to excess, gaseous ammonia for about 1 day at 50° C. under autogenous pressure in a closed heavy wall glass bottle. The excess ammonia is purged and a quantitative yield of 2-amino-2-(4-hydroxyphenyl)propane is obtained.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>N1C=CC=CC=1.[Cu]Br>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1I
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1ccccc1Oc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg, 1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath and treated with sodium hydride (60% in mineral oil) (66 mg, 1.66 mmol) under argon. The resulting mixture was stirred for 5 minutes, treated with copper (I) bromide (277 mg, 1.93 mmol) and allowed to warm to room temperature over 30 minutes. A solution of 2-iodobenzonitrile (948 mg, 4.14 mmol) in pyridine (2 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (180 mg); MS (ES+) m/e 319 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].I[CH2:26][CH3:27]>O>[CH2:26]([N:11]1[C:10](=[O:15])[C:9](=[CH:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[S:13][C:12]1=[O:14])[CH3:27]
Reactant: CCI
Reactant: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)SC(=Cc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a mixture of 5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione (3.50 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60% in oil, 0.62 g) at room temperature. The reaction mixture was stirred at room temperature for 30 min. and iodoethane (6.55 g) was added to the reaction mixture. The mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 3-ethyl-5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione as yellow crystals (3.81 g, yield 98%). Recrystallization thereof from acetone-hexane gave yellow prism crystals. melting point: 217-218° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)([CH3:15])[C:12](=[O:14])[N:13]=1.Cl>CCOC(C)=O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH3:15])([CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:12](=[O:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC2(C)SC(N[C@H]3CC4CCC3C4)=NC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(CC2CCNCC2)SC(N[C@H]2CC3CCC2C3)=NC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A mixture of tert-butyl 4-((2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)methyl)piperidine-1-carboxylate (1.42 g, 3.37 mmol, 1.0 eq) in 50 mL of a 4.7 M HCl solution in EtOAc was stirred at room temperature. After 4 h, the reaction mixture was concentrated in vacuo. Aqueous Na2CO3 (2.0 M, 20 mL) was then added, and water was removed in vacuo. The residue was then triturated with 10% MeOH—CH2Cl2 (6×100 mL), and the combined triturating solution were concentrated in vacuo. The crude product was dissolved in CH2Cl2, filtered, and concentrated in vacuo to afford the title compound as a light orange solid (1.08 g). MS (ESI, pos. ion) m/z: 322 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=3)[C:14](=[O:24])[O:13][N:12]=2)=[N:8][O:9][N:10]=1.Cl[S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].C(N(CC)CC)C>ClCCl>[Br:23][C:18]1[CH:17]=[C:16]([N:15]2[C:14](=[O:24])[O:13][N:12]=[C:11]2[C:7]2[C:6]([NH:5][CH2:4][CH2:3][NH:2][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:27])=[O:28])=[N:10][O:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
A 22 L flask was charged with 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (661 g, 1.57 mol) and 8.5 L dichloromethane. After cooling to −15° C. with an ice/salt bath, the solution of tert-butyl [chlorosulfonyl]carbamate (prepared as above) was added at a rate so that the temperature did not exceed −10° C. (addition time 7 min). After stirring for 10 min, triethylamine (1085 mL, 7.78 mol) was added at a rate so that the temperature did not exceed −5° C. (addition time 10 min). The cold bath was removed, the reaction was allowed to warm to 10° C., split into two portions, and neutralized with 10% conc HCl (4.5 L each portion). Each portion was transferred to a 50 L separatory funnel and diluted with ethyl acetate to completely dissolve the white solid (˜25 L). The layers were separated, and the organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford an off-white solid. The solid was triturated with MTBE (2×1.5 L) and dried to a constant weight to afford a white solid. A total of 4113 g starting material was processed in this manner (5409 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.6 Hz, 1H), 6.58 (t, J=5.7 Hz, 1H), 3.38 (dd, J=12.7, 6.2 Hz, 2H), 3.10 (dd, J=12.1, 5.9 Hz, 2H), 1.41 (s, 9H).