Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:14]5[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Yield: 61 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (120 mg, 0.316 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (76 mg, 0.35 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (100 mg, 62%) as a white solid: ESI MS m/z 519 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH2:11][CH2:10]2)[NH:4][N:3]=1.CN(C)[CH:26]=[CH:27][C:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=O.[ClH:37]>C(O)(=O)C.C(O)(C)C>[ClH:37].[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[C:6]([C:7]#[N:8])=[C:2]4[N:1]=[CH:26][CH:27]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[N:3]4[N:4]=3)[CH2:10][CH2:11]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: COc1cccc(CN2CCN(c3[nH]nc(N)c3C#N)CC2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1cccc(CN2CCN(c3nn4c(-c5cccnc5)ccnc4c3C#N)CC2)c1

Procedure:
A mixture of 5.0 g of 3-amino-5-[4-[(3-methoxyphenyl)methyl]-1-piperazinyl]-1H-pyrazole-4-carbonitrile (prepared as described in Example 19) and 2.9 g of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (U.S. Pat. No. 4,281,000, Example 1) in 25 ml of glacial acetic acid was heated at reflux for 3 hours. The work procedure of Example 21 was followed to obtain a gummy solid. The solid was dissolved in isopropanol and was treated with 20 ml of 2.9N ethanolic hydrochloric acid. The yellow precipitate formed was collected by filtration, washed with isopropanol and dried in vacuo. The product was recrystallized from ethanol/water and gave 2.5 g of the desired product as a yellow solid, mp >250° C.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([CH3:22])[C:16]1=[NH2+:23].[OH-].[Na+].[Cl:26][CH2:27][C:28](OC)=O>C(O)C>[Cl:26][CH2:27][C:28]1[N:23]=[C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[C:20]([CH3:21])[N:15]2[N:14]=1
Reactant: COC(=O)CCl
Reactant: Cc1ncc(C)n(N)c1=[NH2+]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C)n2nc(CCl)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A mixture of 1-amino-3,6-dimethylpyrazin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (2.0 g, 5.9 mmol) and sodium hydroxide (480 mg, 12 mmol) in ethanol (20 mL) was stirred at 60° C. for 1 h; methyl 2-chloroacetate (1.34 g, 12.4 mmol) was then added slowly. The reaction mixture heated at reflux for 4 h, then the solvent was removed. The product was purified by column chromatography to give 2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine as a yellow solid (420 mg). MS (ESI): m/z 197 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1CC[CH2:48][CH2:47]1>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:6][CH2:48][CH2:47][CH2:39]3)=[O:38])=[O:23])[CH2:25][CH2:26]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C1CCNC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (249 mg) described in Example 769 and pyrrolidine (40 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (138 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].CO[C:9]1[CH2:13][CH2:12][CH2:11][N+:10]=1[CH3:14].[CH3:15][NH:16][CH3:17]>C1C=CC=CC=1>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:15][N:16]([CH3:17])[C:9]1[CH2:13][CH2:12][CH2:11][N+:10]=1[CH3:14]
Reactant: COC1=[N+](C)CCC1
Reactant: CNC
Agent: COS(=O)(=O)[O-]
Solvent: c1ccccc1
Product: CN(C)C1=[N+](C)CCC1

Procedure:
22.5 g of 2-methoxy-1-methyl-1-pyrrolinium methyl sulfate are added dropwise (with stirring) to a solution of 6.76 g of dimethylamine in 45 ml of benzene. The resulting admixture is subsequently boiled under reflux for 1 hour. The obtained heavy phase is separated off, extracted twice by shaking with diethyl ether and freed from solvent residues in a vacuum. 19.4 g (81.4% of theory) of the title compound (as a red-brown oil) are thus obtained.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Si:7]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][C:27]=1[Cl:34])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[Si:7]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:28][C:27]=1[Cl:34])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCI
Reactant: CC(C)(C)[Si](OCc1ccc([Mg]Br)cc1Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCc1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(Cl)c1
Temperature: 60 °C

Procedure:
Then, 1-iodopentane (910 mg) was added to a suspension of copper bromide-dimethyl sulfide complex (62 mg) in hexamethylphosphoric triamide (0.3 ml) under a nitrogen atmosphere, and the mixture was heated to 60° C. Thereto was dropwise added the above-mentioned solution (5 ml) of 4-((tert-butyldiphenylsilyloxy)methyl)-3-chlorophenyl magnesium bromide in tetrahydrofuran over 10 min after removal of unreacted magnesium. After completion of the dropwise addition, the reaction mixture was refluxed under heating for 2 hr. Aqueous ammonium chloride was added to the reaction mixture and the resulting product was extracted three times with hexane. The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane) to give the objective compound (914 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14]>>[Cl-:10].[CH3:11][N:12]([CH2:8][P+:3]([CH2:1][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])([CH2:4][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[CH2:6][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 25 %

Procedure:
A solution of 80% THPC (59.55 g, 0.25 mol) and 1,3-dimethylurea (88.12 g, 1 mol) was heated to reflux in an oil bath, held at reflux for 4 hrs., allowed to cool, and stripped to dryness in a rotary evaporator. The residue (130.67 g) was shaken with acetonitrile (100 ml) and filtered, giving 29.40 g (25.0%) of tetrakis(1,3-dimethylureidomethyl)phosphonium chloride (I, R=R'=CH3, R"=H, X=Cl) as a white, crystalline solid, mp 189°-190° C. dec. The remainder, a heavy oil, yielded no more product nor water even when subjected to azeotropic distillation with toluene and more 1,3-dimethylurea.
Reaction SMILES: [CH:1]([N:3]1[C:8]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=O)=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2].[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[N:30]([CH3:31])[N:29]=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12>>[CH:1]([N:3]1[C:8]([C:9](=[N:13][O:14][CH3:15])[C:10]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]4[N:30]([CH3:31])[N:29]=[N:28][N:27]=4)[CH2:22][S:23][C@H:18]23)=[O:12])=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)C1=CSCCN1C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)C1=CSCCN1C=O

Procedure:
2-(4-Formyl-(2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 2.3 g.) was allowed to react with 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.3 g.) in a similar manner to that of Example 1 to give the captioned compound (2.5 g.), pale yellow powder, mp. 150° to 155° C. (dec.).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][OH:43])[CH2:39][CH2:40]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: NCCCCN1CCN(CCO)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCN(CCO)CC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[4-(4-amino-butyl)-piperazin-1-yl]-ethanol by the procedure analogous to Example 1. MS (APCl, m/z): 527 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:18]([C:19]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
A mixture of 4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin-3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoic acid (50 mg, 0.11 mmol), methanesulfonamide (15 mg, 0.16 mmol), EDCI (31 mg, 0.16 mmol) and DMAP (20 mg, 0.16 mmol) in DCM (20 mL) was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with HCl (2.0 M, 20 mL) and brine (50×2 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase Combiflash (35%-38% MeCN in 0.5% NH4HCO3) to give the target product (11.0 mg, 19%) as an off-white solid. LCMS (ESI) Method A: RT=5.83 min, m/z: 543.5 [M+H]+. 1H-NMR (500 MHz, MeOH-d4): δ 7.31-7.29 (m, 4H), 7.23-7.19 (m, 5H), 7.14-7.11 (m, 1H), 6.69-6.66 (m, 1H), 4.51 (s, 1H), 4.08 (d, J=6.5 Hz, 2H), 3.39-3.34 (m, 2H), 3.32-3.13 (m, 5H), 2.94-2.90 (m, 1H), 1.99-1.96 (m, 1H), 0.84-0.80 (m, 2H), 0.58-0.54 (m, 2H).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[F:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:19]O>>[F:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9]([O:11][CH3:19])=[O:10]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (16 mL, 0.22 mol) was added dropwise to cooled (0° C.) methanol (250 mL). After the addition the resulting anhydrous methanolic HCl solution was poured into a flask containing 2-fluoro-5-nitrobenzoic acid (13.77 g, 74.39 mmol). The mixture so obtained was stirred overnight at rt. The reaction mixture was concentrated and the residue collected was purified by flash chromatography using a gradient [silica, 5-30% (700 mL), then 30-50% (1 L)], giving methyl 2-fluoro-5-nitrobenzoate.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cc(F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2,5-difluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.70 mg, 40.1% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.40–7.30 (m, 4H), 7.20 (m, 2H), 7.17 (s, 1H), 6.97 (m, 2H), 6.58 (m, 1H), 6.51 (m, 1H), 5.27 (apparent dd, 1H, J=5.1, 8.2 Hz), 3.13 (apparent d, J=9.7 Hz, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.34 (apparent sept, partially hidden, J=7.1 Hz, 1H), 2.17 (m, 3H), 1.90–1.80 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 493.1, (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=[O:22])(=[O:15])=[O:14])=[O:11])[N:3]=1.Cl>C(O)C.[OH-].[Na+].O>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([OH:23])=[O:22])(=[O:15])=[O:14])=[O:11])[N:5]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccsc2C(=O)O)n1

Procedure:
A solution of 1.0 g of methyl 3-[[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-2-thiophenecarboxylate in 10 ml of ethanol and 1 ml of 50% sodium hydroxide in water was stirred overnight at room temperature. To this was added icewater and aqueous hydrochloric acid until acidic, and the precipitate was filtered and washed first with acetone and then with methylene chloride. The product, 0.8 g, melted at 127°.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NCC)C.Br[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)/[CH:18]=[CH:19]\[C:20]([O:22][CH3:23])=[O:21]>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>[C:17]1(/[C:18](/[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19]\[C:20]([O:22][CH3:23])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:15][CH:16]=1
Reactant: COC(=O)/C=C\c1cccc(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: COC(=O)/C=C(/C#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.158 g of cuprous iodide and 0.424 g of phenylacetylene were added to 25 ml of a diethylamine solution containing 1.000 g of methyl (Z)-3-bromocinnamate and 0.029 g of bis(triphenylphosphine)dichloropalladium. The mixture was then stirred for 1 hour at room temperature, after which the solvent was distilled off under reduced pressure. Water was added to the residue, and the resulting mixture was extracted twice with benzene. The combined benzene extracts were washed with water, dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel (70-230 Tyler mesh, 25 g). Those fractions eluted with a 39:1 by volume mixture of hexane and ethyl acetate were collected to afford 1.043 g of the title compound, melting at 73°-75° C. (after recrystallisation from hexane).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[CH2:5].[F-].[Cs+].[F:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])=[O:28])[CH:21]=[CH:22][C:23]=1[F:24]>CS(C)=O>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])=[O:28])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: C=C(O[Si](C)(C)C)c1ccc(Cl)cc1
Reactant: O=C(C=Cc1ccc(F)c(F)c1)c1ccccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(4-chlorophenyl)ethylene (7.0 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(4-chlorophenyl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [IH:1].[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:14][C:15](SC)=[NH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CC(O)(C)C>[IH:1].[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:14][C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[NH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: CSC(=N)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: I
Solvent: CC(C)(C)O
Product: N=C(NC(c1ccccc1)c1ccc(Cl)cc1)N1CCCC1

Procedure:
A mixture of 7.0 g (0.017 mole) of methyl N-(4-chlorobenzhydryl)carbamimidothioate hydroiodide and 2.85 g (0.04 mole) of pyrrolidine in 20 mls of t-BuOH is heated at reflux overnight. The t-BuOH is removed in vacuo and the crude guanidine hydroiodide is crystallized from methanol-ether. The crude product is recrystallized from methanol-t-butanol to yield pure N-(4-chlorobenzhydryl)-1-pyrrolidinecarboximidamide hydroiodide; mp 218°-220° (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13]Cl)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: O=C(CCl)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)CC(=O)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-Chloro-4-(2-chloroacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (2.3 g, 8.8 millimoles), prepared as described in Example 4a was dissolved in 100 ml CH2Cl2, to which solution was added diethylamine (6.5 g; 88.0 millimoles). The resulting solution was allowed to stir at room temperature for 18 hours after which the solvent was removed. The residue was extracted with diethyl ether. The ethereal solution was washed with three portions of H2O, with brine, and was dried over Na2So4, filtered and evaporated, thereby affording crude 7-chloro-4-(2-diethylaminoacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine as a viscous oil. The crude material was reduced with LiAlH4 (0.55 g; 14.6 millimoles) in diethyl ether by the general procedure of Example 5. The dihydrochloride salt was prepared, thereby affording a 52% yield of the title compound; mp 113° C (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: OCc1c(F)cccc1F
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1COc1ccccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2 ml (18.0 mmol) of (2,6-difluorophenyl)methanol in 15 ml of dry tetrahydrofuran stirred at 0° C. was admixed with 865.9 mg (21.6 mmol) of sodium hydride (60% in mineral oil), followed by 1.72 ml (18.0 mmol) of 2-bromopyridine. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was diluted with water (15 ml) and extracted with dichloromethane (2×20 ml). The organic phase was removed, dried with a phase separation cartridge and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 800 mg (15% of theory, 77% pure) of the target compound.
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30](O)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=1.CN1C=CN=C1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:33][C:34]3[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Reactant: Cc1ncccc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cn1ccnc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
(4bR,7R,8aR)-4b-benzyl-7-hydroxy-6-oxo-7-phenyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxylic acid (21 g, 49.2 mmol), 3-amino-2-picoline (5.8 g, 52.2 mmol) and 1-methylimidazole (20 mL, 246.2 mmol) were dissolved in anhydrous acetonitrile (105 mL). 1-Propanephosphonic acid cyclic anhydride (50 wt % in ethyl acetate) (47 mL, 78.8 mmol) was slowly added to control the mild exotherm. The mixture was stirred at 25° C. until the reaction was completed (less than an hour). Ethyl acetate (86 mL) was added to the mixture. The mixture was washed with water (4×100 mL). The organic phase was dried with MgSO4 and concentrated to dryness. The title product (22.3 g, 89% yield) was obtained as a light-yellow foam. 1H NMR (DMSO): δ 1.95 (m, 2H), 2.10 (m, 3H), 2.35 (s, 3H), 2.75 (m, 3H), 3.0 (d, 1H), 3.05 (m, 2H), 5.70 (s, 1H), 6.15 (d 1H), 6.60 (m, 2H), 7.10 (m, 3H), 7.25 (m, 2H), 7.30 (m, 5H), 7.65 (d, 1H), 7.70 (s, 1H), 8.15 (s, 1H), 9.85 (s, 1H).