Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:45])([P:37]([O:42][O:43][CH3:44])([O:39][O:40][CH3:41])=[O:38])[P:29]([O:34][O:35][CH3:36])([O:31][O:32][CH3:33])=[O:30])=[O:22])[C:19](=[O:20])[N:6]2[C:7]([C:16]([OH:18])=[O:17])=[C:8]([CH2:11][O:12][C:13](=[O:15])[NH2:14])[CH2:9][S:10][C@H:5]12)=[N+]=[N-].[H][H]>[Pt]=O>[NH2:1][C:4]1([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:45])([P:37]([O:42][O:43][CH3:44])([O:39][O:40][CH3:41])=[O:38])[P:29]([O:34][O:35][CH3:36])([O:31][O:32][CH3:33])=[O:30])=[O:22])[C:19](=[O:20])[N:6]2[C:7]([C:16]([OH:18])=[O:17])=[C:8]([CH2:11][O:12][C:13](=[O:15])[NH2:14])[CH2:9][S:10][C@H:5]12
Reactant: COOP(=O)(OOC)C(O)(CCCCNC(=O)C1(N=[N+]=[N-])C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@@H]21)P(=O)(OOC)OOC
Reactant: [H][H]
Agent: O=[Pt]
Product: COOP(=O)(OOC)C(O)(CCCCNC(=O)C1(N)C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@@H]21)P(=O)(OOC)OOC

Procedure:
The 7-azido-7-{[5-hydroxy-5,5-bis(dimethoxyphosphono)-1-pentylamino]-carbonyl}-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, obtained as described in Example 30, is hydrogenated at atmospheric pressure with hydrogen in the presence of platinum oxide as catalyst and gives 7-amino-7-{[5-hydroxy-5,5-bis(dimethoxyphosphono)-1-pentylamino]-carbonyl}-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. Reaction of the latter with 2-thienylacetyl chloride and pyridine yields 7-(2-thienyl-acetamido)-7-{[5-hydroxy-5,5-bis(dimethoxyphosphono)-1-pentylamino]-carbonyl}-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[P:17]([O:24][CH2:25][CH2:26][C:27]#[N:28])[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[C:27]([CH2:26][CH2:25][O:24][P:17]([C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:8]=1)[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)#[N:28]
Reactant: N#CCCOP(Cl)N1CCOCC1
Reactant: O=[N+]([O-])c1nc[nH]n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCOP(c1nc([N+](=O)[O-])n[nH]1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a stirred solution of 3-nitro-1,2,4-triazole (2.57 g, 22.57 mmol) and triethylamine (12.58 mL, 9.14 g, 90.28 mmol) in CH2Cl2 (40 mL) was added dropwise Chloro(2-Cyanoethoxy)morpholinophosphine (5.82 g, 22.57 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a yellow oil (5.98 g, 79%). 31P NMR (CDCl3) δ 126.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:18][C:19](=[O:36])[C@@H:20]([CH2:28][S:29]([C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([OH:17])=O)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.ON1C(=O)CCC1=O>[C:32]([S:29]([CH2:28][C@@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C@H:14]([C:15](=[O:17])[NH:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41])[CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:12]=1)=[O:36])(=[O:30])=[O:31])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)O)c1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1
Reaction time: 17 h
Yield: 87.2 %

Procedure:
89 g (170 mmol) of (S)-1-(t-butoxycarbonyl)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionic acid, 1 g (8.5 mmol) of N-hydroxysuccinimide, 35.5 g (155 mmol) of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-butane-1,2-diol and 800 ml of ethyl acetate were stirred at 20°. A solution of 37 g (178 mmol) of dicyclohexylcarbodiimide in 110 ml of ethyl acetate was added within 10 minutes. The reaction had finished after stirring at 20° for 17 hours. The solid (dicyclohexylurea) was filtered off and the filtrate was treated while stirring firstly with 68 ml of deionized water and then with 1100 ml of hexane. After one hour at 0° the crystallizate was filtered off under suction and triturated in methanol at 20°. The suspension was cooled to -15° and the product was filtered off. 98.8 g (86%) of t-butyl 4-[(S)-2-[(S)-2-t-butanesulphonylmethyl-3-phenylpropionylamino]-2-[(1S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]ethyl]-1H-imidazole-1-carboxylate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[Br:15][CH2:16][C:17](Br)=[O:18]>C1(C)C=CC=CC=1>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:18]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(Br)CBr
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(CBr)Nc1ccc(Cl)cn1

Procedure:
To a solution of 5 g 5-Chloro-pyridin-2-ylamine and 1.5 mL pyridine in 30 mL toluene, 8 g bromo-acetyl bromide dissolved in 10 mL toluene were added dropwise under ice cooling. After 2 h the precipitate was isolated by filtration and recrystallized from toluene to yield a white solid.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([CH:22]4[CH2:24][CH2:23]4)[N:14]=[C:13]3[CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35]>CO.[OH-].[Na+].[Cl-].[Na+].O.O>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH:22]4[CH2:23][CH2:24]4)[N:14]=[C:13]3[CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:40])([F:38])[F:39])(=[O:36])=[O:35]
Reactant: CCOC(=O)c1c(C2CC2)nc(CC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc(C2CC2)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.6 %

Procedure:
A mixture of the product of Example 3 (1.72 g) and 2N aqueous sodium hydroxide (15 ml) in methanol (30 ml) was stirred at room temperature for 6 h. After standing overnight, the solution was diluted with further 2N aqueous sodium hydroxide (10 ml), stirred for a further 2 h at room temperature and then heated at 40° for 90 mins. After cooling, the solution was diluted with brine (80 ml) and water (50 ml) before being washed with ether (100 ml). The aqueous phase was then acidified with 2N hydrochloric acid to pH 1 and the cloudy solution was extracted with ethyl acetate (3×90 ml). The combined ethyl acetate extracts were dried and concentrated in vacuo to afford the title compound (1.72 g) as an off-white foam.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15]C)[CH2:6]1)[CH2:2][CH3:3].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:26][C:27](O)=O.B(Br)(Br)Br>C1(C)C(C)=CC=CC=1>[CH2:1]([N:4]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[CH2:6]1)[CH2:27][CH2:26][C:18]1[S:17][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=1)[CH2:2][CH3:3]
Reactant: CCCNC1CCc2c(cccc2OC)C1
Reactant: O=C(O)Cc1cc2ccccc2s1
Agent: BrB(Br)Br
Solvent: Cc1ccccc1C
Product: CCCN(CCc1cc2ccccc2s1)C1CCc2c(O)cccc2C1

Procedure:
A mixture of 2-(N-n-propylamino)-5-methoxytetralin, 2-benzothienyl acetic acid and trimethylaminoborohydride in dry xylene is refluxed under an atmosphere of nitrogen as described by Horn et al, Pharm. Weekbld. Sci. Ed. 7 208-211, 1985. The resulting methoxy intermediate is demethylated using boron tribromide as described in the above article to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39]>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([O:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[I:32])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccccc3I)n2)cc1Cl
Temperature: 80 °C
Yield: 94.7 %

Procedure:
A mixture of compound 133 (1.75 g, 4.57 mmol), potassium carbonate (3.15 g, 22.85 mmol) in dimethylformamide (8 mL) was added 2-iodophenol (1.20 g, 5.48 mmol). It is heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound as white solid (2.45 g, 95%). mp 206-208° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 5/60, 15/80, 30/80, 35/60, 40/60; 230 nm, Rt 26.65 min, 98.30% purity; MS (CI): m/z 566 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:13][CH3:14])=[N:4][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:13][CH3:14])=[N:4][C:5]([C:8]2[O:9][C:10]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: CSc1nc(-c2ccco2)ncc1Cl
Solvent: ClCCl
Product: CSc1nc(-c2ccc(S(=O)(=O)Cl)o2)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-2-(furan-2-yl)-4-(methylthio)pyrimidine (800 mg, 3.53 mmol, 1.0 equiv.) in CH2Cl2 (5 mL) was added ClSO3H (25 mL) dropwise at −20° C. The reaction mixture was stirred at 25° C. for 2 h, then, quenched with cracked ice at −20° C. The mixture was extracted with ethylacetate. The combined organic layers was dried with Na2SO4 to give a solution of 5-(5-chloro-4-(methylthio)pyrimidin-2-yl)furan-2-sulfonyl chloride in ethylacetate, to which t-butylamine (10 mL) was added. The mixture was stirred at 20° C. for 2 h, then, concentrated. The residue was purified by column chromatography to afford N-tert-butyl-5-(5-chloro-4-(methylthio)pyrimidin-2-yl)furan-2-sulfonamide (147 mg, 12% over 2 steps). LC-MS (m/z)=362.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[C:17]([O:23][C:24]([C:27]([O:29]C)=[O:28])([CH3:26])[CH3:25])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[C:17]([O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Cl)cnc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 102.9 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-pyridin-3-yl]-2′-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol), LiOH.H2O (280 mg, 6.6 mmol), H2O (5 mL) and methanol (15 mL) was heated at 80° C. for 40 min. After cooled to room temperature, the solution was acidified to “pH” 1 by addition of 1N HCl solution. The aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (200 mg).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([C@H:24]5[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]5[OH:30])[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH3:31][N:32]([CH3:37])[C:33](=[O:36])[CH2:34]Cl>>[OH:30][C@H:25]1[C@@H:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7][N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:29][CH2:28][N:27]([CH2:34][C:33]([N:32]([CH3:37])[CH3:31])=[O:36])[CH2:26]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCNC[C@H]3O)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCN(CC(=O)N(C)C)C[C@H]3O)cc1OCC2
Yield: 56 %

Procedure:
cis-racemic-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-ol hydrochloride (86 mg, 0.19 mmol) was reacted with N,N-dimethyl-2-chloroacetamide (26 mg, 0.21 mmol) to give 319 (51 mg, 57%). LCMS: RT=2.58 min, [M+H]+=480. 1H NMR 400 MHz (DMSO-d) δ: 8.29 (1H, d, J=8.29 Hz), 7.90-7.90 (2H, m), 7.08 (1H, dd, J=8.37, 1.72 Hz), 6.98 (1H, d, J=1.65 Hz), 5.89-5.88 (1H, m), 4.56-4.41 (4H, m), 4.08 (1H, br), 3.79 (1H, br), 3.17 (2 H, m), 3.06 (3H, s), 2.88 (2H, m), 2.82 (3H, s), 2.62 (1H, m), 2.39 (1H, m), 2.22 (2H, m), 1.53 (1H, m), 1.48 (6H, d, J=6.61 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: OCCCc1cc(Cl)cc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Cl)cc(CCCBr)c1
Reaction time: 12 h
Yield: 80.9 %

Procedure:
Compound 35-2 (1.23 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.75 g) and N-bromosuccinimide (1.17 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.30 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[N:3]1([CH:8]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[OH:21][C:22]([CH3:28])([CH3:27])[C:23](OC)=[O:24]>CS(C)=O>[OH:21][C:22]([CH3:28])([CH3:27])[C:23]([NH:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1[CH:18]=[CH:19][CH:20]=[C:10]([CH:8]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH3:9])[CH:11]=1)=[O:24]
Reactant: CC(c1cccc(OCCCN)c1)N1CCCC1
Reactant: COC(=O)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(c1cccc(OCCCNC(=O)C(C)(C)O)c1)N1CCCC1
Temperature: 0 °C
Yield: 26.4 %

Procedure:
43 mg of 50% sodium hydride was suspended in 0.5 ml of dry dimethylsulfoxide, and with stirring under ice cooling, a solution of 200 mg of 3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine in 0.5 ml of dimethylsulfoxide was added dropwise. The mixture was stirred at room temperature for 20 minutes. Then, 105 mg of methyl α-hydroxyisobutyrate was added dropwise, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude oil was separated and purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 71 mg of N-(2-hydroxy-2-methylpropionyl)-3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine as an oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1([C:20]([F:23])([F:22])[F:21])[O:7][CH:6]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][O:4]1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O.C1C=CC=CC=1>[F:1][C:2]([F:25])([F:24])[C:3]1([C:20]([F:23])([F:22])[F:21])[O:7][CH:6]([CH2:8][N:26]=[N+:27]=[N-:28])[CH2:5][O:4]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C(F)(F)F)(C(F)(F)F)O2)cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1COC(C(F)(F)F)(C(F)(F)F)O1
Reaction time: 3.5 h

Procedure:
A sample of 14.00 grams of 2,2-bis(trifluoromethyl)-4-tosyloxymethyl-1,3-dioxolane (m.p. 58°-60° C.) is dissolved in 40 ml of dimethylformamide and 4.85 grams NaN3 is added. The mixture is stirred magnetically at 140°-149° C. for 3.5 hours. The product is diluted with benzene and filtered. The filtrate is washed thoroughly with water, vacuum-stripped and distilled. The product, 2,2-bis(trifluoromethyl)-4-azidomethyl-1,3-dioxolane, has a boiling point of 78° C./20 mm Hg and a refractive index of 1.37447 at 20° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 59.1 %

Procedure:
5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.233 g, 0.571) and ethyl formate (0.140 mL, 1.71 mmol) were dissolved in anhydrous ethanol (1.10 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.10 mL, 2.85 mmol). This reaction mixture was heated at 78° C. for 1 h, turning the reaction mixture to a brownish red color. The reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale brown precipitate. The suspension was filtered yielding a tan solid as pure 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.147 g, 0.337 mmol, 59%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][CH:9]=O)=[N:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=CNCc1ncc(Br)s1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1cn2cncc2s1
Temperature: 90 °C
Yield: 60.3 %

Procedure:
Toluene (1.0 L) was added to 104 g of 5-bromo-2-formylaminomethylthiazole, and the mixture was heated to 90° C. and was stirred. A solution of 65.8 g of phosphorus oxychloride in 100 ml of toluene was added to the reaction mixture, and the mixture was stirred at that temperature for 1.5 hr. After standing to cool, 2 L of a 0.5 N aqueous hydrochloric acid solution was added, and the aqueous layer was separated. The aqueous layer was adjusted to pH 6.2 by the addition of a 5 N aqueous sodium hydroxide solution and was extracted with 1.5 L of ethyl acetate and then with 1.0 L of ethyl acetate. The organic layers were combined, were washed with a 5% aqueous sodium bicarbonate solution and a 20% aqueous sodium chloride solution in that order, and were dried over anhydrous magnesium sulfate. The solvent was removed to bring the volume to about 100 ml, 500 ml of ethyl acetate:hexane=1:4 solution was added thereto, and the mixture was stirred in an ice-water bath for crystallization to give 57.6 g of 2-bromimidazo[5,1-b]thiazole.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27]([OH:29])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:24])([F:26])[F:25])[CH:17]=3)[CH2:13][CH:12]([C:27]3[O:29][N:37]=[C:32]([CH2:33][CH2:34][O:35][CH3:36])[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C)c(C(F)(F)F)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.48 mmol) of the compound from Example 163A and 114 mg (0.72 mmol) of t-hydroxy -3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 2. Yield: 105 mg (44% of theory).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18].C(=O)([O-])O.[Na+]>CC(O)C.Cl>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([NH2:20])(=[O:18])=[O:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (300 mg, 1.32 mmol) and 2-amino-benzenesulfonamide (340 mg, 1.97 mmol) in 2-propanol (3 mL), concentrated hydrochloric acid (0.06 mL) is added and the mixture is stirred at 90° C. for 4.5 hours. The mixture is poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate three times. The organic layer is washed with water, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by column chromatography (hexane:ethyl acetate=2:1) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[C:15]12[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH:20]C(=O)O[C:16]2=[O:17].Cl>C(OCC)(=O)C>[NH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[C:16]([NH:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])=[CH:7][CH:8]=1)=[O:17]
Reactant: CN(C)CCOc1ccc(CN)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(CNC(=O)c2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 20 ml of ethyl acetate was added 1.04 g of isatoic anhydride. The mixture was stirred at room temperature for 15 minutes. Hydrochloric acid (10%) was added to the mixture. The aqueous layer was separated, made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. Recrystallization of the residue from ethyl acetate gave 1.85 g of colorless pillars, m.p. 104°-105° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:14]N1C(=O)CCC1=O>CO>[Cl:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=2)[NH:1][CH:2]=1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: COC(=O)c1ccc2[nH]cc(Cl)c2c1
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A solution of methyl 5-indolecarboxylate (501.1 mg, 2.65 mmol) in methanol (15 mL) was treated with N-chlorosuccinimide (425.4 mg, 3.18 mmol), stirred for 18 hours, and concentrated. The concentrate was dissolved into ethyl acetate, and this solution was washed with 1M NaHCO3 (2×), dried (MgSO4), filtered, and concentrated. The concentrate was purified on silica gel with 15% ethyl acetate/hexanes to provide 368.8 mg of the desired product.