Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][C:14](=[O:17])[CH2:15][CH3:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(O)CC)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOc1cc(C(CC(=O)CC)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Reaction time: 5 h
Yield: 80.5 %

Procedure:
A mixture of N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxypentyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.35 g, 3.06 mmol), pyridinium chlorochromate (1.32 g, 6.12 mmol) and celite (0.6 g) in methylene chloride (35 mL) was stirred for 5 hours. The mixture was filtered through celite and the filtrate was washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. Solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 9:1) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxopentyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.08 g, 81%) as a white solid: mp 137-139° C.; 1H NMR (CDCl3) δ 9.53 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.07-7.04 (m, 2H), 6.83 (d, J=8.8 Hz, 1H), 5.76-5.70 (dd, J=5.2, 10.1 Hz, 1H), 4.12 (q, J=6.9 Hz, 2H), 4.02-3.90 (dd, J=10.1, 17.9 Hz, 1H), 3.83 (s, 3H), 3.26-3.17 (dd, J=5.2, 17.9 Hz, 1H), 2.49 (q, J=7.3 Hz, 2H), 2.26 (s, 3H), 1.46 (t, J=6.9 Hz, 3H), 1.02 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3) δ 208.03, 170.02, 169.15, 167.86, 149.12, 148.33, 137.34, 135.76, 131.39, 131.22, 124.64, 120.00, 117.87, 115.29, 112.50, 111.27, 64.38, 55.89, 49.94, 43.51, 36.10, 24.92, 14.71, 7.52; Anal. Calcd. for C24H26N2O6: C, 65.74; H, 5.98: N, 6.39. Found: C, 65.74; H, 6.34; N, 6.38.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH:17]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH:23]2[NH:1][C:2]3[CH:7]=[C:6]([Cl:8])[C:5]([S:9](=[O:11])(=[O:12])[NH2:10])=[CH:4][C:3]=3[S:13](=[O:15])(=[O:14])[NH:16]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: O=CC1CCCCC1
Product: NS(=O)(=O)c1cc2c(cc1Cl)NC(C1CCCCC1)NS2(=O)=O

Procedure:
2-Amino-4-chloro-5-sulfamoylbenzenesulfonamide was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 274-276° C.
Reaction SMILES: C(OCC(F)(F)C(F)(F)C(F)([F:12])CO)CCC.[CH2:18]([C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@@H:40](O)[CH2:41][O:42][CH2:43][C:44]([F:58])([F:57])[C:45]([F:56])([F:55])[C:46]([F:54])([F:53])[CH2:47][O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:34][CH:33]=2)=[N:30][CH:31]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:18]([C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@H:40]([F:12])[CH2:41][O:42][CH2:43][C:44]([F:58])([F:57])[C:45]([F:56])([F:55])[C:46]([F:54])([F:53])[CH2:47][O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:34][CH:33]=2)=[N:30][CH:31]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)CO
Reactant: CCCCCCCCc1cnc(-c2ccc(OC[C@@H](O)COCC(F)(F)C(F)(F)C(F)(F)COCCCC)cc2)nc1
Product: CCCCCCCCc1cnc(-c2ccc(OC[C@H](F)COCC(F)(F)C(F)(F)C(F)(F)COCCCC)cc2)nc1

Procedure:
The title compound was prepared essentially as described in Examples 3 and 4 by combining 5-butoxy-2,2,3,3,4,4-hexafluoropentanol (3.1 g, 11.7 mmol, prepared essentially by the method described in U.S. Pat. No. 5,399,291 (Janulis et al.)) with (S)-5-octyl-2-[4-(2,3-oxiranylpropoxy)phenyl]pyrimidine (2.0 g, 5.87 mmol) to produce 5-octyl-2-[4-((S)-2-hydroxy-3-(-5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)propoxy)phenyl]pyrimidine. This chiral (S)-hydroxy compound (2.0 g, 3.3 mmol) was treated with diethylaminosulfur trifluoride (1.06 g, 6.6 mmol) to produce the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(C)C=CC=CC=1>[C:22]([C:16](=[CH:15][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: COc1ccc(N)cc1OC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1ccc(OC)c(OC)c1
Temperature: 100 °C

Procedure:
A mixture of 7.66 g of 4-aminoveratrole, 8.49 g of ethyl ethoxymethylenecyanoacetate, and 20 ml of toluene was heated at 100° C. for 90 min. The toluene was evaporated to give a solid, mp 150-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([C:17]#[N:18])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[OH:25][NH:24][C:17]([C:13]1[C:14]2[CH:15]=[CH:16][C:7]([NH:6][CH2:5][C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[O:2][CH3:1])=[N:8][C:9]=2[CH:10]=[CH:11][CH:12]=1)=[NH:18]
Reactant: COc1ccccc1CNc1ccc2c(C#N)cccc2n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1CNc1ccc2c(C(=N)NO)cccc2n1
Yield: 90 %

Procedure:
A stirred suspension of 2-(2-methoxy-benzylamino)-quinoline-5-carbonitrile (example 136, step B) (289 mg, 1.0 mmol), hydroxylamine hydrochloride (257 mg, 3.7 mmol) and sodium carbonate (212 mg, 2.0 mmol) in EtOH (4 ml) and water (4 ml) was heated under reflux conditions for 17 h, water (5 ml) was added, the precipitate was collected by filtration, washed with water and heptane and dried to yield the crude product as solid which was further purified by crystallization (diethyl ether/MeOH) to yield N-hydroxy-2-(2-methoxy-benzylamino)-quinoline-5-carboxamidine as off-white solid (290 mg, 90%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O1CCCC1.[OH-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3I)nc2c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-c3ccccc3)nc2c1
Yield: 26.5 %

Procedure:
To a mixture of 0.78 g of 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of phenylboronic acid, 5 ml of tetrahydrofuran and 0.14 g of dichlorobis(triphenylphosphine)palladium (II), 3 ml of 10% aqueous solution of sodium hydroxide was added and heated to reflux for three hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.18 g of 2-(3-phenyl pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 32”).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH3:12][N:13]([CH3:19])[C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>>[CH3:12][N:13]([CH3:19])[C@H:14]1[CH2:18][CH2:17][N:16]([C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:15]1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: CN(C)[C@H]1CCNC1
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Yield: 51.5 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (548 mg, 3.58 mmol) reacted with (3S)-(−)-3-dimethylamino-pyrrolidine (490 mg, 4.29 mmol) to give 460 mg (52%) of 3-[(3S)-3-dimethylamino-pyrrolidin-1-ylcarbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.OS(O)(=O)=O.[OH-].[Na+].[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:17])=[O:8])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(Br)cs1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (4 g, 19 mmol) in MeOH (100 mL) was added H2SO4 (5 mL) dropwise at 25° C. The solution was stirred for 12 h at 50° C. and was poured into ice-H2O and the pH was adjusted to ˜11 with aqueous NaOH. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly (4.27 g, quant.): LCMS (ES) m/z 222 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([O:15]C(C)C)=[O:14])[CH2:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OP(O)(O)=O>O1CCOCC1.[OH-].[K+].CO>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A mixture of isopropyl N-benzylpyrrolidin-2-one4-carboxylate (Example 33, 3.93 g) in dioxane (80 mL), aqueous KOH (2 N, 40 mL) and MeOH (60 mL) was stirred at room temperature for 1 hour. The mixture was then cooled with ice, acidified to pH=4 with H3PO4 and left in a refrigerator overnight. The precipitate was filtered and the filtrate was concentrated to give a yellow oil. The oil was contaminated with dioxane, and therefore was dissolved in aqueous KOH. The solution was extracted with CHCl3 (2×20 mL), and the aqueous layer was acidified with HCl (3 N). It was extracted with CHCl3 (4×30 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give N-benzylpyrrolidin-2-one-4carboxylic acid as a pale yellow oil (2.89 g): 1H NMR (300 MHz) δ 10.77 (br s, CO2H), 7.34 (m, 5 H), 5.17 (d, J=14.9 Hz, 1 H), 4.02 (dd, J=9.4, 3.2Hz, 1 H), 3.98 (d, J=14.1 Hz, 1 H), 2.12-2.71 (m, 4 H); 13C NMR (75 MHz) δ 176.47, 174.32, 135.25, 128.78, 128.46, 127.90, 58.63, 45.69, 29.57, 22.83; MS (FAB), m/e 220 (100, M+H), 174 (40); HRMS (FAB) m/e calcd for (C12H13NO3+H) 220.0974, found 220.0984.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[C:5]=2[C:4](O)=[N:3][CH:2]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:4]1[C:5]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:8]=3[NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2[nH]c3cnccc3c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1ncnc2[nH]c3cnccc3c12
Temperature: 75 °C

Procedure:
A mixture of 9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-4-ol (264 mg, 1.4 mmol) and triethylamine (750 μL) in 5 mL POCl3 was heated at 75° C. for 18 hours. Toluene was added to the cooled reaction mixture and the solvents were then removed in vacuo to give the title compound as a brown oil (290 mg). LC-MS (1) Rt 1.25 min; m/z (ES+) 205/207.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[C:19]([O:24][CH:25]2[CH2:30]CNCC2)=[N:20][CH:21]=[N:22][CH:23]=1)=[O:16].C[Si](C)(C)[O:33][CH2:34][CH2:35]CCO>>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[C:19]([O:24][CH2:25][CH2:30][CH2:35][CH2:34][OH:33])=[N:20][CH:21]=[N:22][CH:23]=1)=[O:16]
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cncnc1OC1CCNCC1
Reactant: C[Si](C)(C)OCCCCO
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cncnc1OCCCCO

Procedure:
Following the procedure described in Example 1, and substituting Compound 4 in Step (1) with 4-((trimethylsilyl)oxy)butan-1-ol (30B2) (100 mg, 0.617 mmol), the title compound 30 (32 mg, 0.0760 mmol) was obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([C:29]5([OH:28])[CH2:31][CH2:30]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1(O)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (78 mg, 69.1%), MS (ISP) m/z=416.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (100 mg, 0.272 mmol) and 1-hydroxycyclopropanecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([NH:30][CH3:31])=[O:29])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([NH:30][CH3:31])=[O:29])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: CNC(=O)c1cccc(Nc2nc(Nc3ccc4c(c3)CCN(CCOC)CC4)ncc2Cl)c1
Yield: 38 %

Procedure:
In an analogous procedure to Example 651, part c, 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were combined to yield 3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (29.56 mg, 38% yield) as a beige amorphous solid. 1H-NMR (CDCl3) δ 8.07 (s, 1H), 7.97 (s, 1H), 7.75 (m, 1H), 7.52 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.22 (m, 1H), 6.97 (t, J=7.9 Hz, 1H), 5.99 (br s, 1H), 3.54 (m, 2H), 3.35 (s, 3H), 2.90 (m, 5H), 2.81 (m, 1H), 2.74 (m, 6H). LC/MS (ESI+)=481 (M+H). MP=102.5° C. dec.
Reaction SMILES: [C:1]([C:3](=[C:8](SC)[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:13]([NH2:15])[CH3:14]>C(COC)OC>[C:1]([C:3](=[C:8]([NH:15][CH2:13][CH3:14])[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: CCN
Reactant: COC(=O)C(C#N)=C(SC)SC
Solvent: COCCOC
Product: CCNC(SC)=C(C#N)C(=O)OC
Yield: 90 %

Procedure:
To a suspension of 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester (8.12 g, 1 eq) in dimethoxyethane (14 mL) was added a solution of ethylamine (2.16 g, 1.2 eq.) in dimethoxyethane (6.5 mL). The suspension turned to solution, and a white solid began to precipitate. After about 10 min the solvent was removed and the residue was filtered with diethyl ether to yield 2-cyano-3-ethylamino-3-methylthio-2-propenoic acid, methyl ester (7.2 g): mp 86°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([F:12])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)=[O:11])[CH:3]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)n1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.10 g (0.58 mmol) 4-chloro-6-methyl-pyridine-2-carboxylic acid and 80 mg (0.58 mmol) 5-fluoro-2,3-dihydro-1H-indole in 0.17 mL (1.2 mmol) TEA and 2.0 mL DMF were combined with 0.19 g (0.58 mmol) TBTU and stirred overnight at RT. The reaction mixture was diluted with water, the precipitated solid was suction filtered and dried.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]2[CH:34]=[C:22]3[C:23](=[O:33])[N:24]([CH3:32])[C:25]4[N:26]([CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=4)[C:21]3=[N:20]2)=[CH:16][CH:15]=1)(=[O:13])[CH3:12].[Cl:37]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[C:11]([C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]2[C:34]([Cl:37])=[C:22]3[C:23](=[O:33])[N:24]([CH3:32])[C:25]4[N:26]([CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=4)[C:21]3=[N:20]2)=[CH:16][CH:15]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1ccc(Cn2cc3c(n2)N2CC(C)(C)N=C2N(C)C3=O)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1ccc(Cn2nc3c(c2Cl)C(=O)N(C)C2=NC(C)(C)CN23)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
1.0M LiHMDS (2.5 mL, 2.5 mmol) in THF is added dropwise into a solution of 7,8-dihydro-2-(4-acetylbenzyl)-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (580 mg, 1.65 mmol) and hexachloroethane (782 mg, 3.32 mmol) in methylene chloride (8 mL) at −20° C. The reaction mixture is stirred at −20° C. for 30 min, and then quenched with acetic acid (60 μL). Solvents are removed under reduced pressure and the obtained residue is purified on a basic alumina oxide column to give 273 mg of product (yield: 43%). MS (ESI) m/z 386.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:24][C:25]1[N:26]=[C:27]([CH3:33])[NH:28][C:29]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:24][C:25]1[N:26]=[C:27]([CH3:33])[NH:28][C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C(F)(F)F)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (27.9 mg, 0.081 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (13.0 mg, 0.081 mmol) and HATU (30.8 mg, 0.081 mmol) in DMF (1.5 ml) was added diisopropylethyl amine (0.028 ml, 0.162 mmol) and the mixture was stirred for 1 hour at rt. The mixture was purified via reverse phase HPLC and neutralized to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-2-methyl-1H-imidazole-5-carboxamide (25 mg, 0.051 mmol, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05-8.14 (m, 2H), 7.77 (s, 1H), 7.71 (s, 1H), 7.47 (d, 1H), 7.33 (t, 1H), 4.49 (d, 2H), 2.21 (s, 3H). LC-MS (ES+) m/z 486.94, [M+H].
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:30]=[CH:29][C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:17][S:18][C:14]=2[CH:13]=1)[CH2:4][CH2:5]O)[CH3:2].CCN(S(F)(F)[F:37])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH2:5][F:37])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:30]=[CH:29][C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:17][S:18][C:14]=2[CH:13]=1)[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN(CCO)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CCF)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 10.6 %

Procedure:
To 540 mg (11.37 mmol) 2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol in 6 ml CH2Cl2 were added 0.22 ml (1.7 mmol) DAST at −78° C. After stirring at that temperature for 3.5 h, additional 0.2 ml (1.6 mmol) DAST were added and the mixture was slowly warmed to RT over night. The solution was added to a cooled aqueous solution of Na2CO3 and extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. Column chromatography CH2Cl2:MeOH 95:5 yielded 79.3 mg (16%) Ethyl-(2-fluoro-ethyl)-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine as brown oil, MS: 441 (MH+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:7]=2[CH:22]=1.[C:25]([O:30][CH3:31])(=[O:29])[C:26]([CH3:28])=O>>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:26]([C:25]([O:30][CH3:31])=[O:29])[CH3:28])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:7]=2[CH:22]=1
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2Cl)=NC1
Reactant: COC(=O)C(C)=O
Product: COC(=O)C(C)=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-(trifluoromethyl)-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 7-(trifluoromethyl)-2-[[1-(methoxycarbonyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=C[CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[N:22]1C=CC=C2C(N)CCC=12>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[N:22][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: NC1CCc2ncccc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCc3ncccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.48, 7.73, 7.66, 7.14, 5.82, 4.54, 3.22-3.07, 2.79, 2.70-2.57, 1.94 1.36-1.27; HRMS (FAB) calcd for C16H20N4+H 269.1766, found 269.1763.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[CH3:30][N:31]([CH2:33][C:34](Cl)=[O:35])[CH3:32]>>[CH3:30][N:31]([CH2:33][C:34]([N:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:23])=[CH:19][CH:18]=1)[CH3:22])=[O:35])[CH3:32]
Reactant: CN(C)CC(=O)Cl
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)CN(C)C)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and dimethylamino-acetyl chloride, the title compound was prepared as light yellow crystals (46% yield). MS: m/e=498(M+H+).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>>[F:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: F[C@@H]1CCNC1
Product: Cn1ncc([N+](=O)[O-])c1N1CC[C@@H](F)C1
Yield: 58 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (R)-3-fluoropyrrolidine gave (R)-5-(3-fluoropyrrolidin-1-yl)-1-methyl-4-nitro-1H-pyrazole as a yellow solid (153 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 5.48-5.31 (m, 1H), 3.79 (s, 3H), 3.73-3.57 (m, 2H), 3.48-3.37 (m, 2H), 2.46-2.27 (m, 2H)