Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([NH:40][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([N:11]2[C:10](=[S:28])[N:9]([C:6]3[CH:7]=[N:8][C:3]([C:1]#[N:2])=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:5]=3)[C:16](=[O:17])[C:12]32[CH2:15][CH2:14][CH2:13]3)=[CH:19][C:20]=1[F:27])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)NCc4ccccc4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid (Compound 224, 68 mg, 0.14 mmol), benzylamine (22 mg, 0.21 mmol), HATU (70 mg, 0.18 mmol), and DIEA (40 μL, 0.21 mmol) in DMF (3 mL) was stirred at room temperature for 3 h. The crude reaction mixture was purified by reverse phase HPLC (acetonitrile/water:TFA) to afford 51 mg of N-benzyl-4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (d, 1H), 9.12 (t, 1H), 8.75 (d, 1H), 7.87 (t, 1H), 7.49 (dd, 1H), 7.40 (dd, 1H), 7.37-7.31 (m, 4H), 7.29-7.24 (m, 1H), 4.51 (d, 1H), 2.69-2.63 (m, 2H), 2.55-2.44 (m, 2H), 2.03-1.94 (m, 1H), 1.62-1.56 (m, 1H). LCMS [M+1]+ 554.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[O:30]1[CH2:33][CH:32]([NH2:34])[CH2:31]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:34][CH:32]2[CH2:33][O:30][CH2:31]2)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NC1COC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3COC3)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with oxetan-3-amine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=469.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([OH:18])(=[O:17])[CH2:13]C(O)=O.C([O-])(=O)C.[NH4+:23]>C(O)C>[NH2:23][CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:13][C:12]([OH:18])=[O:17]
Reactant: O=C(O)CC(=O)O
Reactant: [NH4+]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.06 mol of 2-nitrobenzaldehyde, 5.72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol are boiled under reflux for 8 hours and stirred at room temperature overnight. The cooled reaction mixture is then filtered with suction, washed with ethanol and ether and dried in air. 3-Amino-3-(2-nitrophenyl)propionic acid is obtained, melting point 222°. Subsequent esterification by activation with thionyl chloride and reaction with methanol under standard conditions produces methyl 3-amino-3-(2-nitrophenyl)propionate.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[O:4][N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[O:32])[CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:37]([C:36]4[CH:35]=[CH:34][C:33]([C:31]([NH:30][C:27]5[CH:28]=[C:29]6[C:24]([CH:23]=[CH:22][NH:21]6)=[CH:25][CH:26]=5)=[O:32])=[CH:40][CH:39]=4)[NH:18][C:11]=3[CH:10]=2)[O:4][N:3]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Reactant: Cc1noc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)n1
Product: Cc1noc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc6cc[nH]c6c5)cc4)[nH]c3c2)n1

Procedure:
Compound 660 was prepared according to the procedure similar to that described in Scheme III from 1-(3-methyl-1,2,4-oxadiazol-5-yl)methoxy-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C26H20N6O3: 465.16; found: 465.04.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH2:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(N(CC)CC)C.ClC1C=C(C=CC=1OC)CN>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH:20][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
To a solution of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at. room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and extracted with ethyl acetate. The extract is washed successively with a 10% aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue is washed with n-hexane to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (38.34 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:12][C:13]2[N:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Nc2cc(Cl)nn3ccnc23)nc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
A mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (272 mg, 1.17 mmol, Eq: 1.00) and (6-aminopyridin-3-yl)(morpholino)methanone (255 mg, 1.23 mmol, Eq: 1.05) in DMF (10.0 ml) was cooled to 0° C. To this reaction mixture was added sodium hydride (150 mg, (60% in mineral oil), 3.74 mmol, Eq: 3.2). The reaction was allowed to stir at 0° C. for 10 minutes and then allowed to warm to room temperature and stir 18 h. The reaction mixture was quenched with sat. NaHCO3 (aq) and diluted with water and EtOAc. An insoluble solid was collected by filtration to give [6-(6-chloro-imidazo[1,2-b]pyridazin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone (420 mg, 99%). LC/MS-ESI observed [M+H]+ 358.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([C:17]([O:19][CH3:20])=[O:18])[C:13]([O:15][CH3:16])=[O:14])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1.C([N:23]1CCOCC1)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[Br:51][C:52]1[CH:64]=[CH:63][C:55]([O:56][C:57]([CH3:62])([CH3:61])[C:58](O)=[O:59])=[C:54]([Cl:65])[CH:53]=1>CN(C=O)C>[Br:51][C:52]1[CH:64]=[CH:63][C:55]([O:56][C:57]([CH3:62])([CH3:61])[C:58]([NH:23][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[CH:8]([CH:12]([C:17]([O:19][CH3:20])=[O:18])[C:13]([O:15][CH3:16])=[O:14])[C:9]#[C:10][CH3:11])=[O:59])=[C:54]([Cl:65])[CH:53]=1
Reactant: CC#CC(c1ccc(N)cc1)C(C(=O)OC)C(=O)OC
Reactant: CCN1CCOCC1
Reactant: CC(C)(Oc1ccc(Br)cc1Cl)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(c1ccccc1NC(=O)C(C)(C)Oc1ccc(Br)cc1Cl)C(C(=O)OC)C(=O)OC
Reaction time: 18 h
Yield: 44.8 %

Procedure:
To a solution of 200 mg (0.73 mmol) of dimethyl 2-[1-(4-aminophenyl)but-2-ynyl]-malonate, 251 mg (2.18 mmol) of N-ethylmorpholine, 122 mg (0.8 mmol) of HOBt hydrate and 124 mg (0.80 mmol) of EDAC in 5 ml of DMF was added a solution of 213 mg (0.73 mmol) of 2-(4-bromo-2-chlorophenoxy)-2-methylpropionic acid in 3 ml of DMF. After 18 h at room temperature, another 1.1 equivalents each of N-ethylmorpholine and HOBt hydrate were added. After 72 h, the reaction mixture was concentrated completely and separated by means of preparative HPLC (Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm; A: H2O+0.05% TFA; B: ACN+0.05% TFA; flow rate: 50 ml/min; in 10 minutes 10% B→80% B; in 5 minutes 80% B→90% B). The product fractions were freeze-dried to obtain 180 mg (45%) of dimethyl 2-(1-{-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)malonate.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@:38]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:95]=[C:96]1[CH:100]=[CH:99][C:98](=[O:101])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH2:110])=[O:108]>CN(C=O)C>[O:101]=[C:98]1[CH:99]=[CH:100][C:96](=[O:95])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH:110][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@:38]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:108]
Reactant: CCOC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C)C[C@@H]1c1ccccc1
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN2C(=O)C=CC2=O)C(C)C)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mg (12 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S,2R)-1-(ethoxycarbonyl)-2-phenylcyclopropyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 3 ml of DMF and then admixed with 8.9 mg (23 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 10 μl of N,N-diisopropylethylamine and with 12 mg (47 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT for 1 h. This was followed by concentration under high vacuum and purification of the remaining residue by means of preparative HPLC. Thus, 5.8 mg (37% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:23]2[CH2:27][S:26]C(=S)[S:24]2)[CH:17]=[C:18]([O:21][CH3:22])[C:19]=1[OH:20]>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:23]([SH:24])[CH2:27][SH:26])[CH:17]=[C:18]([O:21][CH3:22])[C:19]=1[OH:20]
Reactant: COc1cc(C2CSC(=S)S2)cc(OC)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(S)CS)cc(OC)c1O
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (0.553 g, 14.58 mmole) is added to 10 ml dry diethyl ether and 10 ml dry THF. To this slurry is added dropwise 4-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-dithiolane-2-thione (34) (2.00 g, 6.94 mmole) predissolved in 40 ml dry THF. The reaction is stirred under a nitrogen (N2) atmosphere until the solution becomes colorless (1 hour). The reaction is cooled to 0° C. and the excess hydride destroyed with H2O. The reaction mixture is acidified with 10% HCl and immediately extracted with diethyl ether. The organic layer was washed with H2O, dried over MgSO4, filtered and evaporated to a white solid (1.64 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=1)=[O:10].C1([O:26][C:27](=O)[NH:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)C=CC=CC=1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][N:15]([C:27]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:14][C:13]=2[CH:12]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CCNC2
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1cc2c(s1)CCN(C(=O)Nc1cccnc1)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (1.0 eq) obtained in step VIII in DMF was treated with Pyridin-3-yl-carbamic acid phenyl ester (1.0 eq) in presence of base like Et3N and stirred at 50° C. for 8 h Reaction was then quenched with water and extracted with ethyl acetate and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C)C=O>[Si:9]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
Pyridin-4-ylmethanol (2.2 g, 20 mmol) was dissolved in N,N-dimethylformamide, and tert-butyldimethylsilyl chloride (3.3 g, 22 mmol) and imidazole (2.0 g, 30 mmol were added thereto. The mixture was stirred at a room temperature overnight. After the completion of the reaction was confirmed by HPLC, water was added to the mixture, and the extraction with diethyl ether was performed 3 times. The combined organic layer was washed with a saturated saline solution and dried over magnesium sulfate, and the solvent was distilled off. Thus the title compound (4.5 g, 100%) was obtained as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([CH:30]=1)[CH2:7][C:8]1[CH:13]([C:14]([OH:16])=[O:15])[N:12]2[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:11]2[S:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([CH:30]=1)[CH2:7][C:8]1[CH2:9][S:10](=[O:40])[C@@H:11]2[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:17](=[O:29])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cc(F)ccc3O)=CS[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(Cc3cc(F)ccc3O)CS(=O)[C@H]12
Reaction time: 2 h

Procedure:
A solution of 2.0 g of 3-(5-fluor-2-hydroxy-benzyl)7β-phenylacetylamino-ceph-2-em-4ξ-carboxylic acid in 10 ml of isopropanol is treated at 0°-5° in small amounts with 1.2 g of 3-chloro-perbenzoic acid and stirred for 2 hours. The reaction mixture is concentrated to half-volume and diluted with 10 ml of diethyl ether. The crystalline precipitate that forms is filtered off and recrystallised from methyl acetate to yield the 3-(5-fluoro-2-hydroxy-benzyl)-7-phenylacetylamino-ceph-3-em-4-carboxylic acid 1-oxide, which melts at 183°-185°; thin-layer chromatogram (silica gel) Rf = 0.48 (system: n-butanol/acetic acid/water 75:7.5:21), Rf = 0.64 (system: n-butanol/ethanol/water 40:10:50) and Rf = 0.77 (system: chloroform/methanol 1:1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=O)[N:3]=[CH:2]1.[CH3:25][NH2:26]>CO>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:26][CH3:25])=[O:15])[N:3]=[CH:2]1
Reactant: COC(=O)c1ccccc1CCOc1ccccc1-c1c[nH]cn1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1ccccc1CCOc1ccccc1-c1c[nH]cn1
Temperature: 70 °C
Yield: 36.6 %

Procedure:
A mixture of methyl 2-(2-(2-(1H-imidazol-4-yl)phenoxy)ethyl)benzoate (30 mg, 0.093 mmol) and methylamine (2M, 3.3 mL, 6.51 mmol) in methanol was heated at 70° C. for 7 days. Methanol was removed under reduced pressure the crude product was purified by flash column chromatography to afford the desired product as a yellow solid (11 mg, 0.034 mmol, 37%). 1H NMR (CD3OD): 2.69 (s, 3H), 3.29 (t, 2H, J=6.4 Hz), 4.36 (t, 2H, J=6.4 Hz), 6.96 (dt, 1H, J=7.6 Hz, 1.2 Hz), 7.04 (d, 1H, J=8 Hz), 7.17-7.41 (m, 6H), 7.63 (s, 1H), 7.76 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([S@:27]([NH2:29])=[O:28])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=[N:29][S@@:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=Cc1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To a solution of 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carbaldehyde (5.2 g, 16.49 mmol) in THF (55.0 mL) was added (R)-(+)-t-butylsulfinamide (2.2 g, 18.14 mmol), and Ti(OEt)4 (7.52 mL, 36.3 mmol). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with brine (50 mL) and EtOAc (70 mL) followed by addition of Celite®. Then, the mixture was vigorously stirred for 1 h, and filtered. The filtrate was extracted by EtOAc. The organic layers was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by automatic column chromatography to yield (R)—N-((5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (6.5 g, 94%) as pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.91 (1H, s), 8.04 (1H, m), 7.38-7.22 (5H, m), 7.16-7.05 (2H, m), 4.62 (2H, s), 1.25 (9H, s). LC/MS (uplc): MH+ 419.1, 1.31 min.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Br:7][C:8]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[OH2:19]>N1C=CC=CC=1>[Br:7][C:8]1[CH:17]=[CH:16][C:15]([C:18]([OH:2])=[O:19])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: Cc1ccc(Br)c2cccnc12
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(Br)c2cccnc12
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A solution of potassium permanganate (18.2 g, 115.5 mmol, 2 equiv) in H2O (200 mL) was added to a hot (110° C.) solution of 5-bromo-8-methyl-quinoline (Step 159.4) (12.8 g, 57.7 mmol) in pyridine (120 mL). The reaction mixture was stirred for 10 min at 110° C. and filtered while hot. The residue in the filter was washed with H2O and pyridine. The filtrate was concentrated to remove pyridine, diluted with Et2O and basified by addition of a 2 N aqueous solution of NaOH (20 mL). The aqueous layer was separated and made acidic (pH 3) by addition of a 2 N aqueous solution of HCl. The resulting precipitate was collected by vacuum filtration to provide 1.45 g of the title compound as a green solid: ESI-MS: 251.9/253.9 [M+H]+; tR=3.56 min (System 1).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:15]([O:28][CH3:29])=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[C:7]([NH2:13])=[CH:8][C:9]([I:12])=[CH:10][CH:11]=1.[CH:30](OCC)(OCC)OCC>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:15]([O:28][CH3:29])=[CH:14][C:3]=1[CH2:4][N:5]1[C:6]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=2[N:13]=[CH:30]1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(COc2cc(F)c(CNc3ccc(I)cc3N)cc2OC)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COc1ccc(COc2cc(F)c(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a stirred solution of N1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodobenzene-1,2-diamine (0.36 g, 0.70 mmol) in ethanol (10 mL) was added triethyl orthoformate (0.31 g, 2.11 mmol) and p-toluenesulfonic acid (0.007 g, 0.035 mmol). The reaction mixture was heated to reflux. After 30 min, the brown solution was allowed to cool to room temperature and was concentrated. The residue was partitioned between water and dichloromethane. The phases were separated, and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 12 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 0.25 g (68%) of 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-1H-benzo[d]imidazole as a tan solid.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:14])([F:13])[C:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[NH2:15][C:16]1[S:17][C:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1.O>CN(C)C(=O)C>[C:24]1([S:21]([C:18]2[S:17][C:16]([NH:15][C:8](=[O:9])[C:7]([OH:12])([CH3:11])[C:6]([F:14])([F:13])[F:5])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)s1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)s1)C(F)(F)F
Reaction time: 1 h

Procedure:
Thionyl chloride (80 μl, 1.1 mmol) is added to 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (170 mg, 1.08 mmol) in 5 ml of N,N-dimethylacetamide at -15°/-10° C. and the mixture is stirred at this temperature for one hour. After adding 2-amino-5-(phenylsulfonyl)thiophene (170 mg, 0.710 mmol) and equilibration to room temperature and after the reaction has ended, the reaction mixture is poured into 200 ml of water and subjected to extraction with 3×100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and filtered and the solvent is distilled off. The orange-colored oil which remains is purified by flash chromatography (eluent: 50% v/v ethyl acetate in petroleum ether (40/60)).