Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:29][CH2:30][CH3:31])=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:57]=[N+:58]=[N-:59])(CCCCCCCC)CCCCCCCC)CCCCCCC>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:59][N:58]=[N:57][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:31]
Reactant: CCCCCCCC[Sn](CCCCCCCC)(CCCCCCCC)N=[N+]=[N-]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 117.5 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 1-[(2′-cyanobiphenyl-4-yl)-methyl]-2-ethoxybenzimidazole-7-carboxylate [BEC] (228 kg) obtained in Reference Example 5, the residue containing trioctyltin azide [TOTA] obtained in Reference Example 6 and toluene (1148 L) was heated for about 40 hours under reflux (115-120° C.). The reaction solution was cooled and concentrated under reduced pressure. To the residue were added ethanol (764 kg) and sodium nitrite solution (135 kg/460 L) and the solution was adjusted to pH 4.5-5.5 with concentrated hydrochloric acid (about 224 kg). To the solution was added ethyl acetate (735 L) and the solution was adjusted to pH 0.5-1.5 with concentrated hydrochloric acid (about 100 L). To the solution was added hexane (1005 L) and the solution was adjusted to pH 3.5±0.5 with 4% sodium hydroxide solution. The solution was cooled to 10° C. or less and stirred for 1 hour. The crystals were separated and washed with a mixture of ethyl acetate (106 L) and hexane (310 L), followed by hexane (410 L) to give wet MET (396.6 kg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=4[O:31][CH3:32])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Product: COc1ccc(OC)c(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Yield: 50.6 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,5-dimethoxyphenyl)boronic acid (0.356 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.291 g (51%) of (±)-[7-(2,5-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][C:30]1[O:31][C:32]([CH3:39])=[CH:33][C:34]=1[S:35](Cl)(=[O:37])=[O:36]>N.CO>[CH3:29][C:30]1[O:31][C:32]([CH3:39])=[CH:33][C:34]=1[S:35]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)c(C)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2,5-Dimethylfuran-3-sulfonyl chloride (19 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.2 mg). MS m/z 347 [M+H]+.
Reaction SMILES: C(=O)([O:10][C:11]1[C:16]2[NH:17][C:18](=[O:20])[S:19][C:15]=2[C:14]([C:21](=[O:24])[CH2:22]Br)=[CH:13][CH:12]=1)OCC1C=CC=CC=1.[CH2:26]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[CH2:26]([N:33]([CH2:22][C:21]([C:14]1[C:15]2[S:19][C:18](=[O:20])[NH:17][C:16]=2[C:11]([OH:10])=[CH:12][CH:13]=1)=[O:24])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)CBr)c2sc(=O)[nH]c12
Reactant: c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN(CCCCCCOCCCCc1ccccc1)Cc1ccccc1)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a solution of benzyl 7-(bromoacetyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl carbonate (50 mg) in dry DMF (1 ml) stirring under nitrogen was added N-benzyl-6-(4-phenylbutoxy)hexan-1-amine (Tetrahedron Letters. 1994, 35, 9375) (60 mg) and N,N-diisopropylethylamine (32 μl). After stirring at 40° C. for 2 h, 2N HCl was added and the mixture extracted with ethyl acetate. The solution was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a 5 g silica SPE cartridge, eluting with a stepped gradient of 2% to 10% methanol-dichloromethane mixtures to give the title compound (50 mg). LCMS RT=3.14 min.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[O:20][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Oc1ccc(F)c(F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(F)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 3,4-difluorophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:29]=3[F:28])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1ccc(F)cc1F
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(F)cc3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 28.3 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 2,4-difluoro aniline (0.047 g, 0.364 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.035 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.09 (s, 2H), 7.11 (t, J=8.4 Hz, 1H), 7.30 (s, 1H), 7.41 (t, J=8.7 Hz, 1H), 8.39-8.45 (m, 3H), 9.91 (s, 1H), 11.01 (br s, 1H), 11.55 (br s, 1H); MS [M]+: 504.22.
Reaction SMILES: [Mg].BrCC.Br[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([CH3:15])[N:14]=2)[CH:11]=1.[CH2:16]=[O:17].Cl>O1CCCC1.II>[CH3:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([CH2:16][OH:17])=[CH:11][N:10]2[CH:12]=1
Reactant: Cc1cn2cc(Br)ccc2n1
Reactant: C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: Cc1cn2cc(CO)ccc2n1
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
In a nitrogen atmosphere, 78.56 g of magnesium was added to 2 l of tetrahydrofuran and 0.3 g of iodine and 18 ml of bromoethane were added to the obtained mixture to prepare a Grignard reagent. A solution of 170.5 g of 6-bromo-2-methylimidazo[1,2-a]pyridine and 162 ml of bromoethane in 500 ml of tetrahydrofuran was slowly dropped into the above reaction mixture. After the completion of the dropping, the obtained mixture was heated under reflux for 30 minutes and then cooled with ice. Formaldehyde gas generated by heating a container containing 242 g of paraformaldehyde to 200° C. was introduced into the reaction mixture by the use of a nitrogen stream. After 30 minutes, dilute hydrochloric acid was added to the resulting mixture and the obtained mixture was filtered to remove insolubles. The filtrate was alkalinized with concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1 to 10:1)] to give 120 g of the title compound as a pale-yellow solid (yield: 91.9%).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30]CCCCCC)=[O:29])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.F[C:40]1[CH:50]=[CH:49][C:43]([O:44][CH2:45][C@@H:46]2[CH2:48][O:47]2)=[CH:42][CH:41]=1>>[CH2:7]([C:49]1[CH:50]=[CH:40][CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C@@H:46]([OH:47])[CH2:48][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]([CH2:25][CH2:26][CH2:21][CH2:22][CH2:23][CH3:24])[C:28]([NH2:30])=[O:29])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:37][CH:38]=1)[CH:6]=[CH2:5]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Solvent: O=CO
Product: C=CCc1ccccc1OC[C@@H](O)CNCCc1ccc(NC2CCN(S(=O)(=O)c3ccc(N(CCCCCC)C(N)=O)cc3)CC2)cc1
Yield: 36.9 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N′-hexylurea formate (0.172 g 0.314 mmol) was reacted (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.06 g, 0.315 mmol) according to Procedure G to give the title compound (0.04 g, 0.058 mmol).
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].O.[CH2:8]1[CH2:12]O[CH2:10][CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:2]1([CH:4]=[CH2:4])[CH2:8][CH2:4][CH:2]([CH:1]2[CH2:12][CH2:12][CH:8]([CH2:9][CH2:10][CH2:1][CH2:2][CH3:3])[CH2:9][CH2:10]2)[CH2:3][CH2:3]1)[CH2:10][CH2:9][CH2:8][CH3:12]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: C=CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 17.84 g of KOtBu in 100 ml of THF is added dropwise at 0C to a suspension of 53.20 g of 4,4,′-dipentylbicyclohexyl-4-carbaldehyde and 56.80 g of methyltriphenylphosphonium bromide in 300 ml of THF. The mixture is stirred at RT overnight, water is added, and the mixture is extracted with MTB ether. The combined organic phases are subjected to conventional work-up, giving 4,4′-dipentyl-4-vinylbicyclohexyl.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:14](O)[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=C[C:21]([S:24](O)(=O)=O)=CC=1.SCO>C(O)(C)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:14]([S:24][CH3:21])[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCS
Solvent: CC(C)(C)O
Product: CSC1CN(C)C(=O)N1c1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a three-necked flask provided with a magnetic stirring bar, dry-ice/acetone condenser and a gas inlet tube were charged 70 grams of 3-(5-t-butyl-3-isoxazolyl)-1-methyl-4-hydroxy-2-imidazolidinone, 5.0 grams of p-toluene sulfonic acid and 700 milliliters of t-butanol. A slow stream of gaseous mercaptomethanol was introduced into the stirred reaction mixture, a total 54 grams of mercaptomethanol being added over a 3 hour period. After 17 hours stirring at room temperature. HPLC and TLC analyses indicated unreacted starting material as the major component. Stirring was continued an additional 24 hours after which time HPLC analysis indicated about 50 percent conversion of starting material to desired product. The reaction mixture was then neutralized by the additiono of 10 grams of potassium carbonate in 15 milliliters of water and excess mercaptomethanol was removed by bubbling nitrogen gas through the reaction mixture. Evaporation of solvent, afforded a semi-solid gummy residue. The residue was dissolved in methylene chloride and adsorbed onto 840 grams of silica gel in a two liter sintered glass funnel. The silica gel was eluted with hexane:methylene chloride, methylene chloride and methylene chloride:methanol and the eluent fractions (about 500 milliliters) were analyzed by TLC or HPLC. Combination of appropriate fractions afforded 58 grams of material identified as the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=2[N:7]=1.[I-:16].[Na+]>CC(C)=O>[I:16][CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=2[N:7]=1
Reactant: FC(F)(F)c1ccc2sc(CCl)nc2c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc2sc(CI)nc2c1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
To a stirred solution of 10.79 g (42.97 mmol) of 2-(chloromethyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound 3) in 86 mL of acetone was added 7.40 g (49.42 mmol) of sodium iodide. The resulting reaction mixture was heated to 55° C. for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water, the layers separated, and the organic layer washed with water (1×). The recovered organic layer was then treated with 1.0 M Na2S2O3 and stirred vigorously for 15 minutes. The layers were then separated and the organic layer washed sequentially with water (1×) and brine (1×). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 14.28 g (97% crude yield) of 2-(iodomethyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound 5) that was used without further purification: 1H NMR (CDCl3, 300 MHz): δppm 8.26 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 4.80 (s, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:4]1[CH:3]=[CH:2][S:6][C:5]=1[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]2[CH2:20][CH2:19]2)[CH:13]=[CH:12][C:11]=1[CH3:22])=[O:8]
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1sccc1-c1ccccc1Cl
Temperature: 115 °C
Yield: 64.9 %

Procedure:
5-Bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide (80 mg, 0.21 mmol) and 2-chlorophenylboronic acid (50 mg, 0.32 mmol) in toluene (0.7 mL) was purged with argon and ethanol (0.14 mL), 2 M aq. K3PO4 (0.21 mL, 0.42 mmol), and Pd(PPh3)4 (12 mg, 0.010 mmol) was added. The resulting mixture was heated at 115° C. for 2 h. After cooling to rt, the mixture was diluted with EtOAc (100 mL), washed with brine and dried over anyhd. sodium sulfate. The solution was filtered and concentrated under vacuum to afford a yellow solid which was triturated with MeOH (2 mL), filtered to collect the solid and rinsed with additional MeOH (2×0.5 mL) and dried under vacuum to afford 56 mg of a white solid as the title compound (Example 136). HPLC Ret time=3.56 min. LCMS [M+H]+ 411.21.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[N:28]1([C:33](N)=[NH:34])C=CC=N1>CN(C=O)C>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:33]([NH2:34])=[NH:28])[CH:4]=4)[C:18]=23)[CH:25]=[CH:24][CH:23]=1
Reactant: N=C(N)n1cccn1
Reactant: NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 200 mg (0.537 mmol) of 3-(3aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 1.79%; see Step 90.5), 79 mg (0.539 mmol) of 1H-pyrazole-1-carbamidine monohydrochloride and 2 ml of DMF is stirred at RT for 65 hours and then concentrated by evaporation under a high vacuum. Crystallization of the residue from diethyl ether, filtration and washing the filter residue with diethyl ether yield 4-(3-chlorophenylamino)-3-(3-{guanidino-methyl}-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine.1.05 hydrochloride having a water content of 1.76%; m.p. 270° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](O)=[O:32])=[C:29]([CH3:34])[CH:28]=[N:27]1.O1CCCC1.S(Cl)(Cl)=O>CN(C)C=O.CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[CH:28][C:29]=5[CH3:34])=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1cnn(C)c1C(=O)O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cnn(C)c1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 66.8 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol), 1,4-dimethyl-1H-pyrazole-5-carboxylic acid (154 mg, 1.1 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (1 drop), thionyl chloride (0.08 mL, 1.1 mmol) and N,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner as in Example 203, the title compound (300 mg, 67%) was obtained as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:17])[C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1>[Ni].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:17])[C:11]([CH3:15])([CH3:16])[CH:12]([CH3:13])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)C(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Agent: [Ni]
Solvent: Cc1ccccc1
Product: CC(C)C(C)(C)C(=O)CCc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
5 g of Raney nickel are added to a solution of 33.1 g (0.132 mol) of 1-(4-chloro-phenyl)-4,4,5-trimethyl-1-hexen-3-one in 200 ml of toluene and the mixture is stirred in an autoclave for 5 hours at 80° C. under a hydrogen pressure of 80-100 bar. After this, the reaction mixture is filtered and concentrated under reduced pressure. 28.3 g (85% of theory) of 1-(4-chlorophenyl)-4,4,5-trimethyl-hexan-3-one are obtained in the form of a yellow oil. ##STR23##
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].Cl[CH2:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16]>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:4][CH2:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16]
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: CN(C)C(=O)CCl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NCC(=O)N(C)C)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
A mixture of 2,4-dimethyl-6-nitroaniline (5.00 g, 30.1 mmol), 2-chloro-N,N-dimethylacetamide (18.3 g, 150 mmol), K2 CO3 (6.24 g, 45.2 mmol), and KI (499 mg, 3.01 mmol) in DMF (100 mL) was heated at 120° C. for 7 h, then at 130° C. for 14 h. The cooled mixture was quenched with H2O (200 mL) and extracted with CH2 Cl2 (3×150 mL). The combined organic layers were dried over Na2 SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=252 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].I[CH3:34].P([O-])([O-])([O-])=O>ClCCl.C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([O-:20])=[O:19])=[C:8]([C:10]3[N+:11]4[C:12](=[CH:15][N:16]([CH3:34])[CH:17]=4)[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4cncn34)C[C@H]12
Reactant: CI
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4cn(C)c[n+]34)C[C@H]12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 100 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 1.5 ml of dry dichloromethane was added 1.37 ml of iodomethane, and the mixture was stirred under the atmosphere of argon in the darkness at room temperature for 24 hours. Unreacted reagent was removed under reduced pressure. The residue thus obtained was dissolved in 4 ml of THF and 4 ml of 1/15 M phosphate buffer (pH 6.8), and 160 mg of 10% Pd-C was added. The reactor was purged with hydrogen, the reaction mixture was stirred at room temperature for 3.5 hours. The catalyst was collected by filtration on Celite and washed with water. The filtrate was washed with ethyl acetate, and purified by column chromatography on DIAION HP-20 and COSMOSEAL 40C18-PREP (water:methanol=20:1) to give 4.8 mg of the title compound.
Reaction SMILES: [CH:1]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:30]>C1(C)C=CC=CC=1>[Br:30][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OC(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCc1ccc(OC(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4-(Benzhydryloxy)phenyl)methanol (500 mg, 1.72 mmol) was dissolved in toluene (20 ml) and pyridine (139 uL, 1.72 mmol) was added. The solution was cooled to 0° C. PBr3 (163 uL, 1.72 mmol) was added dropwise over 15 min. The resulting mixture was stirred at room temperature for 1 h. It was then washed with saturated K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to obtain ((4-(bromomethyl)phenoxy)methylene)dibenzene as an oil, (450 mg, 74%). This intermediate was used in the following reaction.