Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[CH:25]1([CH2:24][C:4]([CH3:5])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[O:12])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)C(C)c1ccccc1
Reactant: BrCC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(CC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A solution of 2-phenyl-propionic acid methyl ester (3.0 g, 18.27 mmol) in tetrahydrofuran (25 mL) at −78° C. was treated dropwise with the lithium hexamethyldisilazide (21.9 mL, 1M in tetrahydrofuran, 21.9 mmol) and stirred for 1 hour. Bromomethyl-cyclohexane (3.09 mL, 21.92 mmol) was added to the reaction and the reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 2.5% ethyl acetate in hexane, and 5% ethyl acetate in hexane to give the title compound (4.02 g, 84%). 1H NMR (300 MHz, CDCl3): δ ppm 1.11 m, 10 H) 1.55 m, 4 H) 1.80 m, 1 H) 2.04 m, 1 H) 3.64 m, 3 H) 7.29 (m, 5 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7]2[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:35]([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:36][CH2:37][CH2:38][CH3:39].N12CCCN=C1CCCCC2.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7]2[CH:15]=[C:14]([C:16](=[O:17])[NH:43][S:40]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11]
Reactant: CCCCCS(N)(=O)=O
Reactant: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
3-(3,4-Dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic acid (160 mg) was dissolved in dry dimethylformamide (2 ml). Carbonyl-diimidazole (111 mg) was added and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added n-pentanesulfonamide (108 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (122 mg) and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was cooled in ice, and the pH thereof was adjusted to pH 4 with 1N hydrochloric acid. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was eluted by silica gel column chromatography (hexane:ethyl acetate=1:1) . The resulting residue was crystallized from hexane-ethyl acetate to give 3-(3,4-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)benzo[b]thiophene (118 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[OH-].[Li+]>CO.O>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ncccc1OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ncccc1OCC(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.3 mmol) in N,N-dimethylformamide (2.0 ml) was added at 22° C. sodium hydride (55% in oil, 64 mg) and stirring was continued until gas evolution ceased. The suspension was cooled to 0° C. and treated with trifluoroethyl trifluormethanesulfonate (728 mg) and stirring was continued at 22° C. for 2 hours. The mixture was partitioned between saturated sodium hydrogen-carbonate solution and ethyl acetate, and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using n-heptane and ethyl acetate (3:1) as the eluent to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester as a pale green oil. Mass (calculated) C9H8F3NO3 [235.16]; (found) [M+H]+=236. b) A solution of 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg, 0.9 mmol) in methanol (1 ml) was treated with a solution of lithium hydroxide (78 mg, 3.3 mmol) in water (0.1 ml) and stirring was continued at 22° C. for 2 hours. The solution was evaporated and the residue triturated with 1N aqueous hydrochloric acid. The suspension was filtered, the residue washed with water and dried to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid as a colorless solid. Mass (calculated) C8H6F3NO3 [221.14]; (found) [M−H]−=220.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[(2-methoxy-2-oxoethyl)(methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 38) (315 mg, 0.70 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene. The residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium citrate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil (273 mg)
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:25][CH2:24][N:6]2[C:7]3[CH:19]=[C:18](C(F)(F)F)[CH:17]=[CH:16][C:8]=3S[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1.[CH:27](Cl)(Cl)Cl.CO>>[CH3:1][N:2]([CH3:26])[CH:3]1[CH2:25][CH2:24][N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:27][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1
Reactant: ClC(Cl)Cl
Reactant: CN(C)C1CCN2c3cc(C(F)(F)F)ccc3Sc3ccccc3C2C1
Solvent: CO
Product: CN(C)C1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
2-dimethylamino-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyridino[ 1,2-d]-dibenzo[b,f](1,4)-thiazepine (2-equatorial), (oil); Rf = 0.45 in chloroform:methanol (8:2).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:26][CH3:27])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:25]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:35][C:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:26]([CH3:27])[C:42]([C:36]2([CH3:35])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:43])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:25]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2cccc3c2OCCO3)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)C1(C)CCCCC1)[C@H](CC1CCCCC1)CN1CCN(c2cccc3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 0.7 g (1.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2,3dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.3 g (1.87 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.85 g (91%) of the title compound as a white solid; mp=219-220° C.; MS(+)ESI m/z=498 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:20])(=[O:19])[NH2:18].[C:21]([OH:33])(=[O:32])[CH2:22][C:23]([CH2:28][C:29]([OH:31])=[O:30])([C:25]([OH:27])=[O:26])[OH:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:19])(=[O:20])[NH2:18].[C:21]([O-:33])(=[O:32])[CH2:22][C:23]([CH2:28][C:29]([O-:31])=[O:30])([C:25]([O-:27])=[O:26])[OH:24]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
1.5 g of 4-(4-chloro-3-sulfamoylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol were reacted in the manner described in example 8 with 1 g of ground citric acid and worked up.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]1=[O:27].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]2=[O:27])=[O:37])=[CH:31][CH:30]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCN(CC)C(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-diethylaminocarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 284°-285° C.
Reaction SMILES: Cl.OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N.CCN(C(C)C)C(C)C.C1CN([P+]([O:39][N:40]2[N:48]=[N:47][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:39][N:40]1[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]=[N:48]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: On1nnc2ccccc21
Reaction time: 0.5 h

Procedure:
Nvan—(N-Fmoc-2-n-decylaminoethyl) vancomycin (100 mg, 48 umol, 1-0 eq) was dissolved in 1 mL DMF and glucosamine hydrochloride was added (31 mg, 144 mmol, 3.0 eq). The mixture was stirred vigorously for 30 minutes (the glucosamine hydrochloride did not fully dissolve), DIPEA (60 uL, 344 umol, 7.2 eq) was added and the mixture stirred vigorously for a further 30 minutes. A solution of benzotriazole-t-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP, 50 mg, 96 umol, 2.0 eq) and 1-hydroxybenzotriazole (14 mg, 104 umol, 2.2 eq) in 500 uL DMF was prepared. The PyBOP solution was added in 5 batches of 60 uL at intervals of 5 minutes to the vigorously stirred suspension of the other reaction components. The reaction was stirred an additional 30 minutes then precipitated into acetonitrile. The solid was collected by centrifugation, taken up in 1 mL N,N-dimethylformamide and treated with 200 uL piperidine for 30 minutes. Precipitation into ether was followed by centrifugation and the solid washed with acetonitrile. Reverse-phase preparative HPLC (10-70% acetonitrile in water containing 0.1% trifluoroacetic acid over 120 minutes) gave a compound of formula III where R15 is —CH2CH2—NH—(CH2)9CH3 and R22 is —N-(D-glucosamine as its trifluoroacetate salt.
Reaction SMILES: [Cl:1](O)(=O)(=O)=O.[S:6]1[CH:10]=[CH:9][N:8]2[CH2:11][CH:12]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[NH:17]C(=O)C)[N:13]=[C:7]12.[ClH:24]>>[ClH:1].[ClH:24].[NH2:17][C:16]1[CH:15]=[C:14]([CH:12]2[CH2:11][N:8]3[C:7]([S:6][CH:10]=[CH:9]3)=[N:13]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1cccc(C2CN3C=CSC3=N2)c1
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: Cl
Product: Nc1cccc(C2CN3C=CSC3=N2)c1

Procedure:
A 2.80 g. (0.0078 mole) portion of 3'-(5,6-dihydroimidazo[2,1-b]thiazol-6-yl)acetanilide perchlorate (Example 7) is converted to the free base and then dissolved in 15 ml. of 6N hydrochloric acid. The solution is stirred at reflux for 1.6 hours and then evaporated at reduced pressure. The residue is azeotroped with 2-propanol and crystallized from 95% ethanol/-2-propanol to give 1.69 g. (75%) of crystalline product, melting point 242°-244°C. Anal. Calcd. for C11H13Cl2N3S: C, 45.54; H, 4.52; Cl, 24.43; N, 14.48; S, 11.05. Found: C, 45.39; H, 4.66; Cl, 24.26; N, 12.27; S, 10.83.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([OH:30])=O)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([N:34](CC)C(C)C)(C)[CH3:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N)C>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([NH:34][CH2:31][CH3:32])=[O:30])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)O)n4)n3Cc3ccccc3)n12
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2ccccc2)n1
Reaction time: 0.03 h

Procedure:
To a solution of 3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]propanoic acid (8.0 mg, 0.020 mmol, prepared as in Example 95, Step 1) in DMF (0.40 mL) was added N,N-diisopropylethylamine (14 μL, 0.080 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (14 mg, 0.036 mmol, Aldrich). After stirring for 2 minutes, ethylamine (11 μL, 0.20 mmol, neat, Aldrich) was introduced, and the reaction was stirred for 15 minutes. The reaction was diluted with MeOH, and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.3 mg, 39%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Br)=[N:6][CH:7]=1.[CH3:10][NH:11][CH3:12]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:11]([CH3:12])[CH3:10])=[N:6][CH:7]=1
Reactant: CNC
Reactant: BrCc1ccc(Br)cn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Place 5-bromo-2-bromomethyl-pyridine (1.7 g, 6.7 mmol, 1 eq) (Bioorg. Med. Chem. Lett. 1994, 4(1), 99) in a 250 mL round bottom short neck flask, dissolve in 100 mL of THF, cool to 0° C. and treat with a 2 M N,N-dimethylamine solution in THF (9 mL, 18 mmol, 2.7 eq). After 2 hours, concentrate the reaction, dilute with 50 mL of CH2Cl2, and wash with 20 mL of water. Dry the organics and concentrate to give 0.90 g (64%) of the title compound as a brown oil. MS (ES), m/z 217 (M+1).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])[C:4]=2[CH2:3][O:2]1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:14]([NH:13][S:10]([C:9]2[C:4]3[CH2:3][O:2][CH2:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])=[O:15])[N:19]=1
Reactant: O=C=NS(=O)(=O)c1cccc2c1COC2
Reactant: COc1cc(C)nc(N)n1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2COC3)n1
Reaction time: 1.75 h

Procedure:
A 7.0 ml portion of the methylene chloride solution of 1,3-dihydrobenzo[c]furan-4-sulfonyl isocyanate prepared in Example 4 was added to a stirred suspension of 0.78 g of 4-methoxy-6-methylpyrimidin-2-amine in 20 ml of methylene chloride. After several minutes the amine dissolved, followed by formation of a precipitate. After stirring for 1.75 hours, the solid was collected, washed with methylene chloride and 1-chlorobutane, then dried to give 1.4 g of 1,3-dihydro-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzo[c]furan-4-sulfonamide, m.p. 190°-194°(d).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH3:47][S:48]([N:51]=[C:52]=[O:53])(=[O:50])=[O:49]>C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:52]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:53]
Reactant: CS(=O)(=O)N=C=O
Reactant: Nc1c(Cl)cccc1Cl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CS(=O)(=O)NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 72 h

Procedure:
A solution was prepared containing 3.2 g (0.02 mole) of 2,6-dichloroaniline in 30 ml benzene, and one drop each of triethylamine and dibutyltin dilaurate. A second solution of 2.4 g (0.02 mole) of methanesulfonylisocyanate in 6 ml of benzene was added to the first solution. The temperature of the reaction mixture was allowed to rise to 35° C. The mixture was then allowed to stand for three days.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([O:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][C:15]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([O:13][C:14]1[C:15]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH2:2])=[CH:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=C(c1ccccc1)c1cccc(-c2ccccn2)c1OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1cccc(-c2ccccn2)c1OCc1ccccc1
Temperature: -3 °C
Reaction time: 1 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (1.31 g, 3.67 mmol, 3.67 mmol, 2.0 equiv) in THF (15 mL) was cooled to ˜−3° C. and 2.5M n-BuLi in hexanes (1.4 mL, 3.5 mmol, 1.9 equiv) was added dropwise at <2° C. The yellow light suspension was allowed to warm to room temperature and stirred 1 hr. The mixture was cooled to ˜3° C. and a solution of 12 (0.67 g, 1.84 mmol, 1.0 equiv) in THF (5 mL) was added at <5° C. The mixture was allowed to warm to room temperature and stirred 3 hr. TLC (25% EtOAc/heptanes) showed the reaction was complete. The mixture was quenched by addition saturated NH4Cl solution (5 mL). The mixture was partitioned between EtOAc (75 mL) and H2O (5 mL). The organic phase was washed with brine (25 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a yellow-orange oil (crude weight=1.41 g). The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (15 g) packed in hexanes. The column was eluted with hexanes (100 mL), 5% EtOAc/hexanes (200 mL) and 10% EtOAc/hexanes (200 mL). Product fractions were concentrated under reduced pressure and the residue dried under high vacuum for 1 hr to give 0.64 g of 13 as a colorless, viscous oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:39])[C:16]2[O:22][C:21]3[C:23]([Cl:35])=[CH:24][C:25]([N:27]([C:31](=[O:34])[CH2:32]Cl)[CH2:28][CH2:29]Cl)=[CH:26][C:20]=3[CH2:19][S:18](=[O:37])(=[O:36])[C:17]=2[CH:38]=1)=[O:12]>CN(C=O)C>[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:39])[C:16]2[O:22][C:21]3[C:23]([Cl:35])=[CH:24][C:25]([N:27]4[CH2:28][CH2:29][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:32][C:31]4=[O:34])=[CH:26][C:20]=3[CH2:19][S:18](=[O:36])(=[O:37])[C:17]=2[CH:38]=1)=[O:12]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccccc4)CC3=O)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Benzylamine (0.17 mL, 1.581 mmol) was added to a solution of Example 57k (0.4 g, 0.79 mmol) in DMF (5 mL) and stirred at 80° C. for 5 h. The reaction mixture was concentrated, treated with water and extracted with chloroform. The organic layer was washed with water, brine, dried and concentrated to obtain the crude title compound which was purified using flash chromatography (silica gel, 1% methanol/chloroform). Yield: 125 g, (29.2%); 1H NMR (DMSO-d6,): δ 2.68 (s, 3H, CH3), 2.8 (t, 2H, CH2), 3.2 (s, 2H, CH2), 3.63 (s, 2H, CH2), 3.7 (t, 2H, CH2), 3.88 (s, 3H, OCH3), 5.31 (s, 2H, CH2), 7.29-7.38 (m, 5H, Ar), 7.66 (s, 1H, Ar), 7.73 (s, 1H, Ar), 8.16 (s, 1H, Ar), 8.19 (s, 1H, Ar); MS: m/e (ES+) 541 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][O:4][NH2:5].[CH2:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([NH:20][C:21]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=NCc1ccccc1
Reactant: NOCC(O)CN1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1)NOCC(O)CN1CCCCC1

Procedure:
O-(2-hydroxy-3-piperidino-propyl)-hydroxylamine (2,53 g, 0,0145 mol) was dissolved in 40 ml abs. chloroform and 1,8 ml (0,0145 mol) benzyl isocyanate was added thereto while stirring. The mixture was stirred for 2 hours, the solution was evaporated and the residue was crystallized from ethanol-ether mixture. Yield: 2,1 g (47%). Mp.: 100-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1.ClCCC(C1C=CC=C(Cl)C=1)O.[I-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCI)c1cccc(Cl)c1
Agent: OC(CCCl)c1cccc(Cl)c1
Agent: [I-]
Agent: [Na+]
Product: O[C@H](CCI)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 94 %

Procedure:
1-(3-Chlorophenyl)-3-iodopropan-1-ol: To 3-chloro-1-(3-chlorophenyl)propan-1-ol (2.85 g, 13.90 mmol) was added sodium iodide (2.66 M in dry acetone) (21 mL, 55.9 mmol) and the mixture was placed under nitrogen and brought to reflux for overnight. After overnight stirring, the solvent was removed under reduced pressure. The residue was taken up in Et2O and water and the phases separated. The organic layer was washed further with water and brine. The organic layer was then dried (Na2SO4), filtered and evaporated to give the desired product as colorless oil (3.9 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[F:11].[Cl-].[NH4+:13]>CO.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:13])=[CH:4][C:3]=1[F:11]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)c(F)c1
Temperature: 60 °C
Yield: 43 %

Procedure:
Iron powder (28.1 g, 0.502 mol) was added as small portions to 1,2-difluoro nitrobenzene (20.0 g, 0.126 mol) in methanol (200 ml) and heated to 60° C. Ammonium chloride (48.4 g, 0.91 mol) in water (100 ml) was added drop wise and the reaction mixture refluxed for 5 hr. The reaction mixture was filtered over Celite and washed with methanol. Methanol was removed, and the aqueous layer was extracted with ethylacetate, washed with brine, dried over sodium sulphate and concentrated to yield 1,2-difluoro-4-aminobenzene (7 g, 43%).