Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4]([O:7][CH2:8][CH2:9][N:10]([CH3:17])[S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])(=[O:6])=[O:5])[CH2:2][CH3:3].N1CC[CH2:20][C@@H:19]1CO>>[CH2:14]([S:11]([N:10]1[CH2:17][CH2:20][CH2:19][C@@H:9]1[CH2:8][O:7][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])(=[O:13])=[O:12])[CH2:15][CH3:16]
Reactant: OC[C@H]1CCCN1
Reactant: CCCS(=O)(=O)OCCN(C)S(=O)(=O)CCC
Product: CCCS(=O)(=O)OC[C@H]1CCCN1S(=O)(=O)CCC

Procedure:
Prepared as described for 2-(N-methylpropylsulfonamido)ethyl propane-1-sulfonate (example 76, step 1 using (R)-1-pyrrolidin-2-yl-methanol instead of 2-(methylamino)ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][C:14]2[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].CCN(CC)CC.Cl>CCOC(C)=O>[CH3:39][S:40]([O:21][CH2:20][C:18]1[CH:17]=[C:16]([O:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:15]=[C:14]([CH2:13][N:12]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[S:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[OH:38])(=[O:11])=[O:10])[CH:19]=1)(=[O:42])=[O:41]
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cc(CO)cc(Oc2ccc(F)cc2)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dichloro-N-(4-fluorobenzyl)-N-(3-(4-fluorophenoxy)-5-(hydroxymethyl)benzyl)-2-hydroxybenzenesulfonamide (1.1 g, 1.895 mmol) and methanesulfonyl chloride (0.147 mL, 1.895 mmol) in EtOAc at −30° C. was added Et3N (0.4 mL, 2.87 mmol) under Ar atm. The mixture was stirred for 1 h, but only a small amount of product was produced. Thus, additional methanesulfonyl chloride (0.25 mL) and Et3N (0.6 mL) were added at −30° C. The mixture was slowly warmed to rt, stirred at rt for 2 h and treated with 1N aq HCl and EtOAc. The EtOAc layer was separated, washed with water, dried over MgSO4 and concentrated in vacuo to obtain the desired product as a viscous material (˜1.4 g). This material was used directly for the next step without further purification. 1H NMR (CDCl3): δ 7.61 (d, J=2.8 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.07-6.89 (m, 8H), 6.82 (d, J=1.6 Hz, 2H), 6.63 (s, 1H), 5.06 (s, 2H), 4.37 (s, 2H), 4.34 (s, 2H), 2.97 (s, 3H; MS: (M−H)−=656.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:22][C:19]([F:20])([F:21])[C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nnc(N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.83 mmol 4-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml of dichloromethane was treated with 6.6 mmol trifluoroacetic acid and stirred for 2 hours at room temperature. The reaction mixture is concentrated to give the title compound as yellowish gum. MS (m/e): 239.1 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]([NH2:20])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18](=[S:30])[NH2:20]
Reactant: NC(=O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=S)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A mixture of 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carboxylic acid amide (1.74 g, 6.0 mmol), Lawesson's reagent (4.85 g, 12.0 mmol), toluene (150 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with 20-50% (v/v) ethyl acetate in n-heptane to afford 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carbothioic acid amide (1.38 g, 4.50 mmol). A mixture of 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carbothioic acid amide (921 mg, 3.00 mmol), 1,3-dichloroacetone (571 mg, 4.50 mmol) in toluene (30 ml) was stirred at 40° C. for 18 h. The reaction mixture was concentrated in vacuo, and the obtained crystals were washed with 10% dichloromethane (v/v) in n-heptane to give 7-chloro-3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-1H-indole (587 mg, 1.55 mmol).
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]([F:44])([F:43])[C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[N:22]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:23]([CH:26]=O)=[N:24][N:25]=2)[N:12]=[N:11]1.[OH-].[Na+]>ClCCCl>[F:4][C:5]([F:44])([F:43])[C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[N:22]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:23]([CH:26]=[N:2][OH:3])=[N:24][N:25]=2)[N:12]=[N:11]1
Reactant: O=Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)n1Cc1ccccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: ON=Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 35.1 %

Procedure:
Add hydroxylamine hydrochloride (7 mg) to a 0° C. solution 5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-4-(2-chloro-benzyl)-4H-[1,2,4]triazole-3-carbaldehyde (50 mg) in 1,2-dichloroethane (1 mL). Stir 60 hours while allowing reaction to slowly warm to RT. Quench reaction by slowly adding 1 N NaOH (1 mL). Extract with CH2Cl2 (2×2 mL) and dry. Purification via silica gel chromatography using 3:1 to 1:1 hexanes:EtOAc gradient gives the desired product (18 mg, 35%). MS (IS) 606.1 (M+1); Rf=0.52 (1:1 hexanes:EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=O)[O:14][CH:13]([CH3:18])[C:12]=3[CH:19]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[S:29])[O:14][CH:13]([CH3:18])[C:12]=3[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1OC(=O)Nc2ccc(-c3cccc(F)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC1OC(=S)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
A solution of 6-(3-fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.15 g, 0.58 mmol) in toluene was treated with Lawesson's reagent according to the procedure in example 9 to yield 6-(3-fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-thione (0.08 g, 50%) as an off-white solid (0.08 g, 50%): mp 173-174° C.; 1H-NMR (DMSO-d6) δ 12.27 (s, 1H), 7.70 (dd, 1H, J=8.2, 2.0 Hz), 7.62 (s, 1H), 7.46-7.56 (m, 3H), 7.15-7.22 (m, 1H), 7.11 (d, 1H, J=8.3 Hz), 5.64 (q, 1H, J=6.6 Hz), 1.67 (d, 3H, J=6.6 Hz); MS (ESI) m/z 272 [M−H]−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][SH:7].Cl[C:9]1[CH:19]=[C:13]2[N:14]([CH3:18])[CH2:15][CH2:16][CH2:17][N:12]2[C:11](=[O:20])[N:10]=1>>[CH3:18][N:14]1[CH2:15][CH2:16][CH2:17][N:12]2[C:11](=[O:20])[N:10]=[C:9]([S:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:19]=[C:13]12
Reactant: SCc1cccs1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(SCc1cccs1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E62 starting from thiophen-2-ylmethanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][C:9]1[CH:34]=[C:33]([CH3:35])[C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:11]([CH3:36])[C:10]=1[CH3:37].[Na].[F:39]/[C:40](=[CH:49]\[CH:50]=[C:51](/[CH3:54])\[CH:52]=O)/[C:41](/[CH3:48])=[CH:42]/[C:43]([O:45][CH2:46][CH3:47])=[O:44]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:34]=[C:33]([CH3:35])[C:12](/[CH:13]=[CH:54]/[C:51](/[CH3:52])=[CH:50]/[CH:49]=[C:40](\[F:39])/[C:41](/[CH3:48])=[CH:42]/[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:11]([CH3:36])[C:10]=1[CH3:37]
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Reactant: CCOC(=O)/C=C(C)/C(F)=C/C=C(\C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C(F)=C/C=C(C)/C=C/c1c(C)cc(OC)c(C)c1C
Temperature: -30 °C

Procedure:
A solution of 6.06 ml. (14.4 mmol) of n-butyllithium (2.3 M in hexane) was added dropwise under argon, at -72° C., to a stirred suspension of 4.61 g. (10 mmol) of 4-methoxy-2,3,6-trimethylbenzyl triphenylphosphonium chloride in 25 ml. of dry tetrahydrofuran. After addition of reagent was complete the mixture was stirred at -30° C. until an orange solution was formed. The resulting solution was first cooled to -72° C. and then treated dropwise with a sodium of 2.03 g. (9.0 mmol) of ethyl (E,Z,E)-4-fluoro-3,7-dimethyl-8-oxo-2,4,6-octatrienoate in 10 ml. of dry tetrahydrofuran. The reaction mixture was gradually allowed to come to 25° C. and further stirred at this temperature under argon for 2.0 hours. It was poured onto 100 ml. of cold water and extracted with methylene chloride (4×100 ml.). The combined organic extracts were washed with water (2×100 ml.) dried over anhydrous magnesium sulfate and concentrated to give 6.4 g. of oily crude product. This material was filtered through 300 g. of florisil and eluted with methylene chloride to yield 2.97 g. of yellow crystalline substance, which on crystallization from ether-petroleum ether (~1:9) afforded ethyl (E,Z,E,E)-9-(4-methoxy-2,3,6-trimethylphenyl)-4-fluoro-3,7-dimethyl-2,4,6,8-nonatetraenoate as yellow crystals, mp 92°-96° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][NH2:5].N#N.[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](OC)=[O:22]>C[O-].[Na+].C1COCC1>[NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][NH:5][C:10](=[O:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]
Reactant: NCC(O)CN
Reactant: COC(=O)CCCCCCCCCCCO
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC(O)CNC(=O)CCCCCCCCCCCO
Yield: 75.7 %

Procedure:
A 100-ml two-necked flask equipped with a stirrer and dropping funnel was charged with 9.39 g (104 mmol) of 1,3-diamino-2-propanol and 0.047 g (0.87 mmol) of sodium methoxide. While heating and stirring the contents at 80° C. in an N2 atmosphere, a THF solution of 4.00 g (17.4 mmol) of methyl 12-hydroxydodecanate was added dropwise over 2.5 hours. Precipitate formed was washed with water and recrystallized from ethyl acetate-methanol (4:1 v/v), thereby obtaining 3.80 g (yield: 75%) of the title compound (IIh-12) as colorless powder.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:33][N:32]=4)=[O:24])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(F)cn1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCc1ccc(F)cn1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Yield: 502.6 %

Procedure:
Stir mixture of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid (0.767 g, 0.0.21 m mol), C-(5-fluoro-pyridin-2yl)-methylamine (0.041 g, 0.25 mmol), and EDC (0.063 g, 0.33 mmol) in dry CH2Cl2 (15 mL) under N2 and add DMAP (0.061 g, 0.50 mmol.). Stir the resulting mixture at ambient temperature for 72 h Dilute the reaction mixture to 50 mL with CH2Cl2, wash with H2O, 1N NaOH, and brine sequentially. Dry the organic layer (MgSO4), filter and evaporate to give 0.189 g of crude product. Chromatograph on the ISCO using a 12 g column and eluting with Hexane-EtOAc (0-100%) to gives the title compound 0.60 g as a foam:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([F:18])[CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[C:19](=[O:22])([O-])[O-].[K+].[K+]>N1CCOCC1.C(Cl)Cl>[F:18][C:13]1[CH:12]=[C:11]([C:8]2[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][N:9]=2)[CH:16]=[CH:15][C:14]=1[N:4]1[CH2:5][CH2:19][O:22][CH2:2][CH2:1]1
Reactant: CC(=O)NCC1CC(c2ccc(F)c(F)c2)=NO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC(=O)NCC1CC(c2ccc(N3CCOCC3)c(F)c2)=NO1
Temperature: 140 °C

Procedure:
To a resealable tube containing (+/-)-N-[[4,5-dihydro-3-(3,4-difluorophenyl)-5-isoxazolyl]methyl]acetamide (Step 3, Example 3) (1.70 g) in morpholine (5.83 mL) is added potassium carbonate (1.16 g) and heated to 140° C. for 48 hours. The reaction is diluted with CH2Cl2 (50 mL) and washed with H2O (3×50 mL) and saline (50 mL). The organic phase is dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh), eluting with methylene chloride/methanol (98.5/1.5). The appropriate fractions are combined (Rf =0.30, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound. The racemic material is separated on chiral HPLC (Chiralpak AD column, eluting with 8:2:1.5 heptane/isopropanol/chloroform) to give the individual enantiomers, the title compound having mp 179-180° C., [α]25D -71° (DMSO).
Reaction SMILES: Cl[C:2]1[C:18]2[C:6](=[C:7]([CH3:21])[C:8]3[NH:9][C:10]4[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=4[C:16]=3[CH:17]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1>>[CH3:20][O:19][C:13]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[C:7]([CH3:21])=[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:22][CH:23]5[CH2:24][C:25]([CH3:32])([CH3:31])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]5)[C:18]4=[CH:17][C:16]=3[C:15]=2[CH:14]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: COc1ccc2[nH]c3c(C)c4ccnc(Cl)c4cc3c2c1
Product: COc1ccc2[nH]c3c(C)c4ccnc(NC5CC(C)(C)NC(C)(C)C5)c4cc3c2c1
Temperature: 150 °C
Yield: 71 %

Procedure:
The mixture of 1-chloro-9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole (1.0 g; product known, already published) and 4-amino-2,2,6,6-tetramethylpiperidin (1.0 g) is heated at 150° C. for 21 h. Excess amino is eliminated by evaporation under reduced pressure. Water is added to the residue obtained to form a solid. This solid is filtered, washed with water, then recrystallized from xylene to yield the expected (9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazol-1-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (1.0 g, 71% yield) in the form of yellow microcrystals (melting point: 223-225° C.). NMR in agreement.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C:21]1[S:22][CH:23]=[C:19]([CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:26][S:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)(=[O:29])=[O:28])[C:6]([OH:36])=[O:5])=[O:25])=[CH:16][CH:15]=2)[N:20]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCc2csc(N)n2)cc1)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(CCc2ccc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)cs1

Procedure:
Ester 21-5 (200 mg, 0.377 mmol) was dissolved in 2 mL CH2Cl2, and 2 mL TFA was added. After 4 h at RT the mixture was concentrated, azeotroped with toluene, and purified by flash chromatography (silica, 28:10:1:1 EtOAc/EtOH/NH4OH/H2O) providing 21-6 as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.C(N(CC)CC)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:26]1(=[O:28])=[O:27]>CN(C)C=O>[O:27]=[S:26]1(=[O:28])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[C:35](=[O:36])[N:25]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: NCC1CCc2ccccc2O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCNCC1CCc2ccccc2O1
Temperature: 60 °C

Procedure:
The mixture of 5.4 g (0.033 mol) (-)-2-aminomethylchroman (example 92f; αD =-122.8), 6.1 g (0.06 mol) triethylamine, 9.5 g (0.03 mol) N-(4-bromobutyl) saccharin and 80 ml anhydrous dimethyl formamide was heated to 60° C. for 4 h. The solvent was evaporated at 0.01 torr. The residue (13.5 g) was dissolved in toluene/ethyl acetate (5:1) and chromatographed on silica (300 g). The fraction (5.8 g) obtained by elution with toluene/ethyl acetate 1:1 was rechromatographed on 150 g of silica, providing 3.7 g of chemically pure 2-(N-[4-(1,1-Dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl)chroman.
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([NH2:22])(=[O:21])[CH:19]=[CH2:20].[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.CC(C)=O>[CH2:1]([NH:22][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: C=CC(N)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: C=CC(=O)NCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 250 ml capacity conical flask 13 g cetyl chloride (0.05 M), 3.5 g acrylamide (0.05 M) and 50 ml acetone were placed to obtain a clear solution. The solution was stirred with a magnetic needle at room temperature. 6.5 g anhydrous aluminium chloride (0.05 M) was added and the reaction mixture was stirred at room temperature. After 5 to 10 minutes of stirring, vigorous evolution of hydrogen chloride took place which ceased after about 5 minutes. Temperature of the reaction mixture was raised to 40 to 50° C. It was then cooled to room temperature and poured into 500 ml cold water. White product was precipitated. The product was isolated and purified by reprecipitation from acetone into cold water.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1>ClCCl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([NH:41][C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:43])[CH:38]=[CH:39][CH:40]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 3-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (3-methoxy-phenyl)-amide as a white solid. (Yield 45 mg, 64%).
Reaction SMILES: C[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:14](C1C=C2C(=CC=1)C=NC=C2)(C)(C)C>>[CH3:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:13]=1
Reactant: Cc1cccnc1-c1ccccn1
Reactant: CC(C)(C)c1ccc2cnccc2c1
Product: Cc1ccnc(-c2ccccn2)c1

Procedure:
3-methyl-2,2'-bipyridine; 6-tert-butylisoquinoline;
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH:20]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:18](=[O:40])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>CC(C)=O>[CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH2:20])[C:18](=[O:40])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Reaction time: 16 h

Procedure:
Methyl 3-benzyl-7-tritylamino-3-cephem-4-carboxylate (111 mg) was dissolved in acetone (1.5 ml.) and the solution cooled to -20°. p-Toluene sulphonic acid (40 mg) in acetone (0.5 ml) was added dropwise over a few minutes and the solution left at 0° for 16 hours. Thin layer chromatography (TLC) still showed some unchanged starting material was present. A further quantity of p-toluene sulphonic acid (10 mg) was added and the solution left at room temperature for 4 hours. Ethyl acetate was added and the solution washed with dilute aqueous sodium bicarbonate and brine. Evaporation of the dried organic layer afforded methyl 3-benzyl-7-amino-3-cephem-4-carboxylate contaminated with trityl alcohol.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:34]>CO>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:34]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Yield: 15.5 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mol) is dissolved with stirring in methanol (40 ml) with cooling in an ice-water bath. Sodium methoxide (2.42 g, 31 mmol) is added slowly. After 15 mins a solution of trifluoroacetic anhydride (1.8 ml, 12.5 mmol) in methanol (30 ml) is added dropwise over 25 min. After 30 min the reaction mixture is filtered and evaporated under reduced pressure. Water is added and the resulting solid is collected and washed with water and ether, to give (tolyl)diphenylsulphoxonium hexafluorophosphate (0.85 g, 76%) identical to authentic material.