Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=O)(C)(C)C.[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH3:80])[C:63]=1[N:64]1[CH2:70][CH2:69][CH:68]([OH:71])[C:67]([NH:73]C(=O)C(F)(F)F)([CH3:72])[CH2:66][CH2:65]1.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C1COCC1.CO.O>[NH2:41][C:42]1[S:46][C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])=[N:44][C:43]=1[C:55]([NH:58][C:59]1[CH:60]=[N:61][N:62]([CH3:80])[C:63]=1[N:64]1[CH2:70][CH2:69][C@H:68]([OH:71])[C@:67]([NH2:73])([CH3:72])[CH2:66][CH2:65]1)=[O:57]
Reactant: Cn1ncc(N)c1N1CCC(O)C(C)(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@H](O)[C@@](C)(N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(5-hydroxy-4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide (200 mg, 0.55 mmol) and ammonium formate (700 mg, 2.74 mmol) in MeOH (10 mL) under nitrogen was added 10% palladium on carbon (50 mg, 0.13 mmol). The mixture was heated at 65° C. for 2 hr before being cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between water (10 mL) and DCM (50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxy-4-methylazepan-4-yl)-2,2,2-trifluoroacetamide as a red gum (140 mg). A solution of PyBOP (330 mg, 0.62 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (160 mg, 0.45 mmol) in DCM (3 mL) was stirred at room temperature for 30 min. A solution of N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxy-4-methylazepan-4-yl)-2,2,2-trifluoroacetamide (140 mg, 0.41 mmol) and DIPEA (140 μL, 0.83 mmol) in DCM (2 mL) was added and the mixture was stirred at room temperature for 18 hr. Additional DCM (50 mL) was added and the mixture washed with water (20 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was dissolved in a mixture of THF (2 mL), MeOH (2 mL) and water (1 mL) and potassium carbonate (200 mg, 1.44 mmol) was added. The reaction mixture was heated at 60° C. for 18 hr, cooled to room temperature, filtered and concentrated under reduced pressure. The residue was then dissolved in DCM (3 mL) and trifluoroacetic acid (1 mL) added. The mixture was stirred at room temperature for 2 hr, concentrated under reduced pressure and purified via preparative HPLC to give 424 as the monoformate salt as a white solid (5 mg, 2% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 8.56 (s, 1H), 7.57 (s, 1H), 7.53-7.44 (m, 1H), 7.15 (t, J=8.8 Hz, 2H), 3.86-3.72 (m, 5H), 3.45-3.35 (m, 2H), 3.26-3.14 (m, 1H), 2.15-1.90 (m, 4H), 1.46 (s, 3H). LCMS (ES+) m/z 478 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[N:23][C:22]([NH2:25])=[N:21]1>>[Cl:16][C:17]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[N:23][C:22]([NH:25][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:21]1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ncn(Cc2ccc(Cl)cc2Cl)n1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4ccc(Cl)cc4Cl)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2,4-dichloro-benzyl)-1H-[1,2,4]triazol-3-ylamine (ART-CHEM). The title compound was obtained as a colorless solid (Yield=67%). MS ISP (m/e): 424.1 (100) & 426.0 (81) [(M+H)+].
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]([CH:20]2[CH2:22][CH:21]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8][CH2:7]1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:29]1[C:1]([CH2:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][N:13]([CH:20]3[CH2:22][CH:21]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8][CH2:7]2)=[N:2][N:31]=[N:30]1
Reactant: N#CCCCN1CCC(CN(C(=O)C(F)(F)F)C2CC2c2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N(CC1CCN(CCCc2nnn[nH]2)CC1)C1CC1c1ccccc1)C(F)(F)F

Procedure:
A mixture of N-((1-(3-cyanopropyl)piperidin-4-yl)methyl)-2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetamide (260 mg, 0.661 mmol), sodium azide (129 mg, 1.982 mmol), ammonium chloride (159 mg, 2.97 mmol) in N,N-dimethylformamide (DMF) (20 mL) was heated to 110° for 16 hours. Added sodium azide (129 mg, 1.982 mmol) and ammonium chloride (159 mg, 2.97 mmol) and heated to 110° for 16 hours. Concentrated and HPLC purification (reverse phase) was performed. A 7 minute gradient was run (10% AcCN/H2O, 0.1% Formic Acid to 50% ACN/H2O, 0.1% Formic Acid). Obtained 36 mg N20984-94-2(oil) [M+H]+=437.3
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([CH2:24][N:25]=C=O)(=O)=O)=CC=1.COCCOC.CC(C)([O-])C.[K+]>O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:24]#[N:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Yield: 58.3 %

Procedure:
1-tert-Butyloxycarbonyl-4-piperidone (13 g) and p-toluenesulfonylmethylisocyanate (16.6 g) were added to 1,2-dimethoxyethane (90 ml) and ethanol (10 ml). The solution was cooled in ice, potassium tert-butoxide (8.3 g) was added thereto under stirring and the mixture was stirred at room temperature for 6.5 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and the resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 4-cyanopiperidine-1-carboxylic acid tert-butyl ester (8.0 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of 3-bromoaniline (3.21 g, 18.60 mmol) in dry tetrahydrofuran (45 mL) were added triethylamine (2.82 g, 27.91 mmol) and phenylacetyl chloride 93.45 g, 22.30 mmol) at 0° C. The reaction warmed to room temperature and stirred for 4 h. The reaction mixture was treated with 2.0 N aqueous hydrochloric acid (20 mL) at 0° C. and diluted with ethyl acetate (300 mL). The organic layer was washed with water (20 mL), saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford crude N-(3-bromophenyl)-2-phenylacetamide (4.84 g, 86% yield) which was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:10]([CH2:12][CH3:13])[NH2:11])=[O:9])[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>N1C=CC=CC=1>[CH3:35][O:34][C:32]([NH:11][N:10]([C:8]([C:6]1[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])[CH2:12][CH3:13])=[O:33]
Reactant: CCN(N)C(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: CCN(NC(=O)OC)C(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [6-chloro-2-(N-ethyl-hydrazinocarbonyl)-4-methyl-pyridin-3-yl]-amide (11-a) (177 mg) was dissolved in pyridine (2 mL), methyl chloroformate (100 μL) was added and the reaction mixture was stirred at room temperature. After 30 min, 1 h and 1.5 h, methyl chloroformate (each 50 μL) was added. After 14 h stirring at room temperature, the reaction mixture was quenched with water and 3× co-evaporated with toluene. The residue was dissolved in water and ethyl acetate, the layers were separated and the aqueous layer was extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate=3:1, Rf=0.10) to afford 135 mg of the title compound (11) of the present invention of the formula
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10]C(=O)[C:7]=12.C(N1C2C(=CC=CC=2)C=C1C)CCCCCCC.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:5]([Cl:13])=[C:4]([Cl:14])[C:3]=1[Cl:15])[C:11]([OH:12])=[O:10]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: CCCCCCCCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)c1Cl

Procedure:
Proceeding in the same manner as that described in part A of Example 6 above, 14.3 g (0.05 mole) of tetrachlorophthalic anhydride, 16.0 g (0.052 mole) of 76.5 percent active 1-n-octyl-2-methylindole and 13.3 g (0.10 mole) of aluminum chloride were interacted to obtain 2-[(1-n-octyl-2-methyl-3-indolyl)carbonyl[-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: R°=R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =(CH2)7CH3 ; Y1 =H), a pale orange solid melting at 132°-134° C. The infrared spectrum, showing a maximum at 1745 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum was in accord with the structure.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O-])=O.C(N(CC)CC)C.[CH3:30][O:31][CH2:32]Cl>CN(C=O)C.C(=O)([O-])O.[Na+]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:30][O:31][CH3:32])=[O:21]
Reactant: O=C(O)CCCCCCc1ccc2ccccc2c1[N+](=O)[O-]
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.3 %

Procedure:
7-(1-Nitro-2-naphthyl)heptanoic acid (2 g) and triethylamine (2.02 g) were dissolved in DMF (10 ml) followed by addition of chloromethyl methyl ether (0.802 g), and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with cold saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness. Using the residue, 10% palladium-on-carbon (0.23 g), and ethanol (23 ml), a catalytic hydrogenation reaction was carried out at atmospheric temperature and pressure for 18 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to provide methoxymethyl 7-(1-amino-2-naphthyl)heptanoate (2.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([Cl:25])=[C:15]([Cl:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(Cl)c(Cl)cc21
Product: CC1c2cc(Cl)c(Cl)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dichloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8](=[S:28])[NH:9][C:10]=2[C:11]2[C:20]([F:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl[C:30]1[S:31][C:32]([CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:33][N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[F:21][C:20]1[C:11]([C:10]2[N:9]=[C:8]([S:28][C:30]3[S:31][C:32]([CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:33][N:34]=3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=23)=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]=[CH:15]2
Reactant: Nc1nccn2c(=S)[nH]c(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Reactant: CS(=O)(=O)Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cnc(Sc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c3c(N)nccn23)s1
Temperature: 100 °C

Procedure:
A 10 mL microwave vessel was charged with a solution of 8-amino-1-(8-fluoro-2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazine-3-thione (24 mg, 0.000062 mol), 2-chloro-5-[(methylsulfonyl)methyl]-1,3-thiazole (0.026 g, 0.00012 mol), potassium carbonate in DMF (1.7 mL, 0.022 mol). The reaction mixture was heated in the microwave at 100° C. for 10 min. The reaction mixture was heated again at 120° C. for 10 min in the microwave to get full consumption of SM. Reaction mixture was purified by Gilson HPLC eluting with 10→65% acetonitrile: H2O to afford the title compound as an off white solid. 1H NMR (400 MHz, CDCl3): δ=2.85 (s, 3H), 4.36 (s, 2H), 7.34 (d, J=4.80 Hz, 1H), 7.48-7.59 (m, 4H), 7.67 (s, 1H), 7.74-7.78 (m, 2H), 8.04 (d, J=8.84 Hz, 1H), 8.24 (dd, J=8.21, 1.39 Hz, 2H), 8.31 (dd, J=8.72, 1.39 Hz, 1H). MS (ES+): m/z 563.18 (100) [MH+]. HPLC: tR=2.89 min (Open Lynx polar—5 min).
Reaction SMILES: [O:1]=[C:2]([N:19]1[C:27]2[C:22](=[C:23]([C:34]3[O:35][C:36](=[S:39])[NH:37][N:38]=3)[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:2]([N:19]1[C:27]2[C:22](=[C:23]([C:34]3[O:35][C:36](=[S:39])[NH:37][N:38]=3)[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(-c3n[nH]c(=S)o3)cc(-c3ccncc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(-c3n[nH]c(=S)o3)cc(-c3ccncc3)cc21
Yield: 62.8 %

Procedure:
To (S)-tert-butyl 1-oxo-3-phenyl-1-(6-(pyridin-4-yl)-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)indolin-1-yl)propan-2-ylcarbamate 58.0 (80 mg) was added 3 mL dichloromethane and 1.5 mL trifluoroacetic acid. Stirring was continued for a few hours until deprotection was complete. Reaction was concentrated, basified with NaHCO3 and extracted with 30% isopropanol in chloroform six times to afford 41 mg (63%) 58.D.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:7]([O:9][C:10](=O)[C:11]=1[Cl:12])=[O:8].Cl.[CH3:15][NH2:16].O>C(O)(=O)C>[Cl:5][C:6]1[C:7]([N:16]([CH3:15])[C:10](=[O:9])[C:11]=1[Cl:12])=[O:8]
Reactant: CN
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
Sodium ethoxide (3.56 g, 50 mmol) was added to a solution containing 2,3-dichloromaleic anhydride (5.56 g, 33.3 mmol) and methylamine hydrochloride (3.50 g, 55.0 mmol) in 40 mL of acetic acid. The mixture was stirred under a CaCl2 drying tube at 25° C. for 16 hours and then refluxed for 4 hours. The cooled mixture was poured into water (350 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with 100 mL portions of saturated aqueous NaHCO3, water and brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 3.82 g (64%) of 2,3-dichloro N-methylmaleimide as white crystals. Concentration of the mother liquor and chromatography of the residue by radial preparative layer chromatography (Chromatotron, Harrison Research), gave an additional 0.81 g of 2,3-dichloro N-methylmaleimide, raising the yield to 77%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]([S:26]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:24][CH3:25])[CH:6]=1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[S:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:37][C:38]3[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=3)=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:6]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(Br)cc1
Reactant: Cc1cccc(N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(Nc2cccc(C)c2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
[3-(2-{[(4-Bromo-benzenesulfonyl)-ethyl-amino]-methyl}-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester (0.183 g, 0.31 mmol), m-toluidine (0.04 mL, 0.38 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.009 g, 0.02 mmol) were combined in 1,4-dioxane (3.6 mL). Cesium carbonate (0.505 g, 1.55 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.028 g, 0.03 mmol) were added, and the mixture was purged with N2 for 15 minutes and then stirred at 70° C. overnight under N2. Once no starting material was seen by analytical LCMS, the mixture was filtered through Celite. The filter cake was washed with EtOAc, and the filtrate was concentrated and purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)([N:13]=[N+:14]=[N-:15])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)([N:13]=[N+:14]=[N-:15])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(N=[N+]=[N-])(c1ccc(C)cc1)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C(N=[N+]=[N-])(C(=O)O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl bis(4-methylphenyl)azidoacetate (2.07 g, 7.01 mmol) in tetrahydrofuran(15 mL) was added 2 M aqueous sodium hydroxide (3.86 ml, 7.71 mmol). The mixture was stirred at room temperature for 18 hours, and then the solvents were removed in vacuo. The residue was dissolved in ethyl acetate and washed with 1M HCl and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound as a waxy solid which was used as is.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2](=[O:8])/[CH:10]=[CH:9]/[O:11][CH2:12][CH3:13])[CH3:7]
Reactant: C=COCC
Reactant: CCOC(=O)C(=O)Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CCO/C=C/C(=O)C(=O)OCC
Temperature: 55 °C
Yield: 69.7 %

Procedure:
Reference: Dujardin, G; Rossignol, S.; Brown, E. Synthesis, 1998, 763-770. Add ethyl chlorooxoacetate (67 mL, 600 mmol) to a solution of palladium acetate (1.35 g, 6 mmol), ethyl vinyl ether (315 mL, 3.3 mol), and triethylamine (125 mL, 900 mmol) at ambient temperature. Heat to 55° C. for 24 hours, cool to room temperature, then partition the reaction mixture between diethyl ether and water. Concentrate under reduced pressure the organic layer to obtain (E)-4-ethoxy-2-oxo-but-3-enoic acid ethyl ester (72 g, 70%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J=13.2 Hz, 1H), 6.15 (d, J=13.2 Hz, 1H), 4.29 (q, J=7.6 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 1.34 (m, 6H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[N:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.[CH:27](=[O:29])[CH3:28].Cl>O1CCCC1>[CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:16][C:17]([CH:27]([OH:29])[CH3:28])=[CH:18][CH:19]=3)=[N:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC=O
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3cccs3)s2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)O)s3)s2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 185.6 %

Procedure:
A solution of Example 24D (0.35 g, 1.1 mmol) in tetrahydrofuran (14 mL) was cooled to −78° C. under a nitrogen atmosphere and was treated with n-butyllithium (2.5M in hexanes, 0.925 mL, 2.31 mmol) drop wise over 5 minutes. After stirring at −78° C. for 10 min, acetaldehyde (0.309 mL, 5.5 mmol) was added and the reaction was allowed to warm to −30° C. The reaction was stirred for 10 min at −30° C. and 1N HCl (20 mL) was added. The resulting bilayer was stirred at 25° C. for 5 min and was extracted with ethyl ether (80 mL). The organic phase was washed with brine (20 mL), dried (Na2SO4), filtered, and evaporated to provide 0.74 g of a light brown oil. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 35% ethyl acetate in hexanes to provide 0.34 g (86%) of the title compound as a pale green oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.48 (d, J=3.68 Hz, 1H) 7.39 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.96 (dd, J=3.68, 0.74 Hz, 1H) 5.78 (d, J=5.15 Hz, 1H) 4.88-5.06 (m, 1H) 4.63 (heptet, J=5.88 Hz, 1H) 1.43 (d, J=6.25 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (ESI) m/z 363 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N:6]1([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][NH:24][C:25](=[O:31])[CH2:26][S:27][CH2:28][CH2:29][OH:30])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[N:6]1([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][NH:24][C:25](=[O:31])[CH2:26][S:27][CH2:28][CH2:29][O:30][C:1](=[O:4])[CH2:2][CH3:3])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
0.09 ml of propionyl chloride was added to a mixture of 0.40 g of N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 1.02 ml of pyridine, and the resulting mixture was allowed to stand at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into ice-water, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting mixture, after which it was extracted with chloroform. The extract was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.39 g (yield 85%) of the title compound as an oil.