Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][C:29]#[C:30][CH2:31][OH:32])[N:15]=[C:14]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH:39]1([N:45]=[C:46]=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[N:13]=[C:14]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[N:15]=[C:16]([O:27][CH2:28][C:29]#[C:30][CH2:31][O:32][C:46](=[O:47])[NH:45][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:17]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCC#CCO
Reactant: O=C=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCC#CCOC(=O)NC1CCCCC1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Under argon, a suspension of 50 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 3), 10 mg of DMAP and 25 μl of cyclohexylisocyanate in 4 ml of chloroform and 3 ml of DMF was stirred for 72 h at 70° C. The mixture was diluted with 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and 2×25 mlf of water. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with a gradient of hexane:ethyl acetate 1:1 to ethyl acetate, then with DCM containing 4% of methanol to give 38 mg of cyclohexylcarbamic acid 4-[6-(5-methylpyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester as a beige foam. LC-MS: tR=4.89 min, [M+1]+=659.33, [M−1]−=657.25.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17].CI>O1CCCC1.CCOCC>[CH3:1][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CI
Product: COCCc1ccccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 37.0 g of potassium t-butoxide in 400 ml dry tetrahydrofuran was cooled to 0° and a solution of 39.2 g of the product from Example 1 in 300 ml tetrahydrofuran was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. After cooling to 0°, 9.3 ml of methyl iodide was added dropwise and the mixture stirred for 15 minutes at 0°. The solution was diluted with ether, washed with water and dried (Na2SO4). Concentration gave a viscous brown oil which was used in the following example, without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:28]4[N:35]=[CH:36][C:37]([C:38](=[O:40])[NH2:39])=[C:27]4[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[O:42]([CH2:44][S:45]([C:48]1[CH:49]=[C:50]([OH:55])[C:51](=[CH:53][CH:54]=1)[OH:52])(=[O:47])=[O:46])[NH2:43]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:42][CH2:44][S:45]([C:48]2[CH:54]=[CH:53][C:51]([OH:52])=[C:50]([OH:55])[CH:49]=2)(=[O:46])=[O:47])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[N:28]4[N:35]=[CH:36][C:37]([C:38](=[O:40])[NH2:39])=[C:27]4[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Reactant: NC(=O)c1cnn2c(C(F)(F)F)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)nc12
Product: NC(=O)c1cnn2c(C(F)(F)F)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)nc12

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was reacted with 4-[[(aminoxy)methyl]sulphonyl]pyrocatechol according to the procedure described in Example 7. After purification of the product with the chromatographic procedure in Example 7 and lyophilization of the product, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4 -dihydroxyphenyl)-sulphonyl]methoxy]imino]acetamido]-3-[[(3-carbamoyl-7-(tri-fluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31](Br)[CH3:32])[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH:31]([C:30](=[O:34])[NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=3)[CH3:32])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: CC(Br)C(=O)Nc1cccc(F)c1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1cccc(F)c1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 300 mg of 1-[bis(4-fluorophenyl)methyl]piperazine and 256 mg of N-(3-fluorophenyl) -2-bromopropionamide was dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and N,N-dimethylformamide, and 100 mg of anhydrous potassium carbonate were added to the resulting solution. The reaction mixture was then stirred at 90° C. for 2 hours. At the end of this time, ethyl acetate was added, and the organic layer was separated. The organic layer was washed three times with water, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel thin layer chromatography using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to give 1-[bis(4-fluorophenyl)methyl]-4-[1-(3-fluorophenylcarbamoyl)ethyl]piperazine.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([CH2:22][C:23](=[N:26]O)[CH2:24][CH3:25])[CH2:21][CH2:20][CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17].[OH-].[Na+].Cl>O1CCCC1.CCOCC.O>[ClH:10].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([CH2:22][CH:23]([NH2:26])[CH2:24][CH3:25])[CH2:21][CH2:20][CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: CCC(CC1(c2ccc(Cl)c(Cl)c2)CCC1)=NO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: CCC(N)CC1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
A solution of trifluoroacetic acid (2.33 ml) in tetrahydrofuran (5 ml) was added to a stirred suspension of sodium borohydride (1.13 g) in tetrahydrofuran (30 ml) over a period of five minutes. A solution of the oxime (1.7 g) prepared as described above in tetrahydrofuran (25 ml) was added dropwise and the mixture heated under reflux for six hours. The mixture was cooled and water (25 ml) and then 5 N sodium hydroxide solution (25 ml) were added. The mixture was extracted with ether and the extract washed with water, dried and evaporated to give a residue which was dissolved in petroleum ether (25 ml). Dry hydrogen chloride gas was passed through the ether solution to give 1-{[1-(3,4-dichlorophenyl)cyclobutyl]methyl}propylamine hydrochloride (m.p. 222°-224° C.). (Formula I R1, R2, R3 and R4 =H; R5 =4-Cl; R6 =3-Cl; R7 =Et and R8 =H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([CH3:24])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH2:23])[CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42]3([C:45](O)=[O:46])[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)([CH3:24])[C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH:23][C:45]([C:42]4([C:40]5[CH:39]=[CH:38][C:37]6[O:33][CH2:34][O:35][C:36]=6[CH:41]=5)[CH2:44][CH2:43]4)=[O:46])[CH:17]=3)=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S(C)(c2ccc(OC)cc2)c2ccc(-c3cc(N)ccc3C)cc2)cc1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(C)(c2ccc(OC)cc2)c2ccc(-c3cc(NC(=O)C4(c5ccc6c(c5)OCO6)CC4)ccc3C)cc2)cc1
Temperature: 65 °C

Procedure:
4′-[Bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamine (−10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.28 g, 11 mmol) were dissolved in chloroform (25 mL) followed by addition of TCPH (4.1 g, 12 mmol) and DIEA (5.0 mL, 30 mmol). The reaction mixture was heated at 65° C. for 48 h. The volatiles were removed under reduced pressure. The residue was distributed between water (200 mL) and ethyl acetate (150 mL). The organic layer was washed with 5% NaHCO3 (2×150 mL), water (1×150 mL), brine (1×150 mL) and dried over MgSO4. Evaporation of the solvent yielded crude 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid 4′-[bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamide as a pale oil, which was used without further purification. ESI-MS m/z calc. 629.0. found 630.0 (M+1) (HPLC purity ˜85-90%, UV254 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[S:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[N:20][C:19]1[CH:21]=[CH:22][C:16]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)cc1Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1Cl

Procedure:
Following a procedure similar to that described in Example 1(i), but using 3-chloro-4-methoxybenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[CH:14](O)=O>>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[CH:14][NH:12][C:7]=2[CH:6]=1)=[O:13])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: O=CO
Product: CCOC(=O)c1ccc2nc[nH]c2c1
Yield: 70.2 %

Procedure:
40 g of 3,4-diaminobenzoic acid ethyl ester (0.22 mol) and 200 mL formic acid were added to a three-necked bottle. After refluxing for 7 h, the reaction was completed. After concentration under reduced pressure, the ice water was poured into the residual solution. The resulting mixture was adjusted to pH 7 with sodium hydroxide. After sucking filtration, the filtrate was extracted with dichloromethane thrice, dried with anhydrous sodium sulfate, and decolored with active charcoal. Then the solution was concentrated under reduced pressure to get a white solid (29.6 g). Yield: 70.2%. MS: 191 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:7]=1.[BH4-].[Na+]>CO.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:6]([CH:8]([OH:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CCC(=O)O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-oxo-butyric acid (0.10 g, 0.20 mmol) in methanol (4 mL) was added sodium borohydride (0.012 g, 0.32 mmol). The reaction was stirred at ambient temperature for 3 hours. The reaction was then diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration in diethyl ether/methylene chloride/hexanes gave the title compound (0.095 g, LRMS: 493.2, 495.3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])(=[O:20])=[O:19].COC1C=CC=CC=1C1C=CN=C(NC2C=CC=C([N+]([O-])=O)C=2)C=1>>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:22]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: COc1ccccc1-c1ccnc(Cl)c1
Agent: COc1ccccc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Product: COc1ccccc1-c1ccnc(Nc2cccc(S(C)(=O)=O)c2)c1

Procedure:
F1 was prepared from A1 (281 mg, 1.28 mmol) and 3-(methylsulfonyl)aniline hydrochloride (267 mg, 1.28 mmol) following the procedure reported for C1. Yield: 210 mg (46%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.18 (s, 3H), 3.80 (s, 3H), 7.02-7.08 (m, 2H), 7.12-7.18 (m, 2H), 7.35-7.45 (m, 2H), 7.50-7.53 (m, 1H), 7.53-7.62 (m, 1H), 7.92 (d, J=8.0 Hz, 1H), 8.12-8.19 (m, 2H), 10.05 (bs, 1H). MS (ES) C19H18N2O3S requires: 354. found: 355 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:21][C:22]([F:35])([F:34])[C:23]1[N:24]=[C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:31]2[CH2:32][CH2:33][N:28]([C:25]3[S:26][CH:27]=[C:23]([C:22]([F:35])([F:21])[F:34])[N:24]=3)[CH2:29][CH2:30]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1csc(N2CCNCC2)n1
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(C(F)(F)F)cs2)CC1)C(F)(F)F
Yield: 48 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(4-trifluoromethyl-thiazol-2-yl)-piperazine (Example 49(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a crystalline white solid (yield 48%). MS (m/e): 531.8 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:37][C:38]1[N:39]=[C:40]([CH3:43])[S:41][CH:42]=1>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH2:37][C:38]4[N:39]=[C:40]([CH3:43])[S:41][CH:42]=4)[CH2:22][CH2:23]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCNCC2)n1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(CN2CCN(c3nc(NCCc4ccc(O)cc4)nc(N(C)CCCc4ccc(Cl)cc4)n3)CC2)cs1
Yield: 50 %

Procedure:
The title compound was prepared in 50% yield via the procedure outlined for example 5 using 4-(2-{[4-[[3-(4-chlorophenyl)propyl](methyl)amino]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]amino}ethyl)phenol and 4-chloromethyl-2-methylthiazole hydrochloride to give an off-white glass: 1H NMR (CDCl3, 400 MHz) δ 7.18 (d, 2H, J=8.0), 7.10-7.02 (m, 2H), 6.98-6.95 (m, 3H), 6.64 (d, 2H, J=8.0), 3.85-3.45 (m, 10H), 3.02 (s, 3H), 2.78-2.68 (m, 5H), 2.55-2.50 (m, 2H), 2.50-2.46 (m, 4H), 1.92-1.80 (m, 2H); low resolution MS (ES+) m/e 594 (MH+); TLC (CH2Cl2/EtOAc/MeOH (5:5:1)): Rf=0.50; Anal. calcd. for C30H37N8OSCl: C, 60.74; H, 6.29; N, 18.89. Found: C, 60.64; H, 6.26; N, 18.81.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18]Cl>>[N:1]1([C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: ClCCCNCCCl
Reactant: Nc1cc2ccccc2cn1
Product: c1ccc2cc(N3CCCNCC3)ncc2c1

Procedure:
3-(1,4-Diazacycloheptan-1-yl)-isoquinoline is prepared from 3-aminoisoquinoline and 2-chloroethyl-3-chloropropylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(Br)n2)CC1
Temperature: 100 °C
Yield: 50.1 %

Procedure:
A mixture of 2-bromo-6-fluoropyridine (500 mg, 2.8 mmol), tert-butyl 1,4-diazepane-1-carboxylate (568 mg, 2.8 mmol) in DIPEA (1.83 g, 14.2 mmol) and ethanol (10 mL) was heated at 100° C. for 16 hours. After it was cooled, the solvent was removed under reduced pressure, and the residue was diluted with EtOAc (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate as a colorless oil (500 mg, 50%). MS (ESI) m/z: 356 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([NH:11]C(=O)OC(C)(C)C)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[C:5]4[S:10][C:9]([NH2:11])=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
Tert-butyl 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylcarbamate (50 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 8.8 mg of 225. MS (Q1) 353 (M)+
Reaction SMILES: C(OC([NH:8][C:9]([CH3:35])([CH3:34])[C@H:10]([NH:15][C:16]([C:18]1[S:22][C:21]2[CH:23]=[C:24]([C:27]#[C:28][C@@H:29]3[CH2:31][C@H:30]3[CH2:32][OH:33])[CH:25]=[CH:26][C:20]=2[CH:19]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:8][C:9]([CH3:35])([CH3:34])[C@H:10]([NH:15][C:16]([C:18]1[S:22][C:21]2[CH:23]=[C:24]([C:27]#[C:28][C@@H:29]3[CH2:31][C@H:30]3[CH2:32][OH:33])[CH:25]=[CH:26][C:20]=2[CH:19]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](NC(=O)c1cc2ccc(C#C[C@@H]3C[C@H]3CO)cc2s1)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)c1cc2ccc(C#C[C@@H]3C[C@H]3CO)cc2s1)C(C)(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a stirring solution of (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.3) in methanol (10 mL) was added 4N HCl in dioxane (10 mL) and the reaction was stirred at room temperature for 2 hr, then at 4° C. overnight. The reaction mixture was concentrated under reduced pressure to yield a residue, which was partitioned between water and MTBE. The aqueous layer was basified with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-amino-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.4, 880 mg, 2.2 mmol, 67%).
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[N:20]=[C:19]([C:21](=[N:25][O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([OH:24])=O)[CH:18]=[CH:17][CH:16]=1)=[O:13].Cl.[NH2:36][CH:37]1[C:62](=[O:63])[N:39]2[C:40]([C:46]([O:48][CH:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[S:47])=[C:41]([CH2:44][CH3:45])[CH2:42][S:43][C@H:38]12>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[N:20]=[C:19]([C:21](=[N:25][O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([NH:36][CH:37]2[C:62](=[O:63])[N:39]3[C:40]([C:46]([O:48][CH:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[S:47])=[C:41]([CH2:44][CH3:45])[CH2:42][S:43][C@H:38]23)=[O:24])[CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1cccc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: Cl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(NC=O)n3)[C@H]2SC1
Yield: 78.1 %

Procedure:
Vilsmeier reagent prepared from phosphorus oxychloride (0.52 ml) and N,N-dimethylformamide (0.44 ml) was suspended in dry tetrahydrofuran (16.5 ml). To the stirred suspension was added 2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 1.67 g) under ice-cooling and then the solution was stirred for an hour at the same temperature to prepare the activated acid solution. To the solution of benzhydryl 7-amino-3-ethylthio-3-cephem-4-carboxylate hydrochloride (2.0 g) and monotrimethylsilylacetamide (5.67 g) in methylene chloride (40 ml) was added the activated acid solution all at once at -20° C., and then the mixed solution was stirred for an hour at -20° to -10° C. To the resultant solution were added water (50 ml) and ethyl acetate (100 ml). The organic layer was separated and washed with 5% aqueous solution of sodium bicarbonate. The solution was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give benzhydryl 7-[2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.5 g), mp. 113° to 123° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:5]=[C:6]([CH2:8][NH:9][C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26]Br)[CH:19]=3)[N:11]=2)[CH:7]=1.O1CCCC1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:5]=[C:6]([CH2:8][NH:9][C:10]3[N:11]=[C:12]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([CH:19]=4)[CH2:24][CH2:25][CH2:26][O:28]2)[N:13]=[CH:14][C:15]=3[Cl:16])[CH:7]=1
Reactant: Oc1cc(Br)cc(CNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cnc2nc1NCc1cc(Br)cc(c1)OCCCc1cccc(c1)N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.9 %

Procedure:
Into a reaction flask were added 3-bromo-5-{[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]methyl}phenol (2.97 g, 5.64 mmol), tetrahydrofuran (30 mL), and a solution of sodium hydroxide in water (33.8 mL, 1.0 M). The reaction mixture was stirred at rt over two days. The mixture was filtered, and then the cake was washed with water, MeOH, and EtOAc successively to provide the desired product (1.33 g, 53%) as an off-white powder. LCMS for C20H18BrClN4O (M+H)+: m/z=444.9, 446.9. 1H NMR (400 MHz, DMSO-d6): δ 9.04 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.36 (s, 1H), 7.10 (m, 1H), 7.07 (m, 1H), 6.92 (d, J=7.9 Hz, 1H), 6.86 (s, 1H), 6.78 (d, J=7.5 Hz, 1H), 4.42 (d, J=5.5 Hz, 2H), 4.18 (t, 2H), 3.60 (m, 1H), 2.65 (m, 2H), 1.65 (m, 2H).