Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:13]2[C:22]3[N:23]=[C:24]([CH2:30][CH2:31][CH2:32]O)[N:25]([CH2:26][O:27][CH2:28][CH3:29])[C:21]=3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:5]1([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:13]2[C:22]3[N:23]=[C:24]([CH2:30][CH2:31][CH2:32][Cl:3])[N:25]([CH2:26][O:27][CH2:28][CH3:29])[C:21]=3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOCn1c(CCCO)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCn1c(CCCCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Yield: 95.4 %

Procedure:
Thionyl chloride (5 mL, 68 mmole) was added to N,N-bis(phenylmethyl)-2-(3-hydroxypropyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (1 g, 2.1 mmole) and the reaction mixture was stirred rapidly until thin layer chromatography (silica gel, 10% ethyl acetate in methylene chloride v/v) indicated that the reaction was complete. The reaction mixture was diluted with methylene chloride then neutralized with 10% sodium hydroxide and sodium bicarbonate. The methylene chloride layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with 10-30% ethyl acetate in hexanes v/v) to provide 1 g of N,N-bis(phenylmethyl)-2-(3-chloropropyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7](Cl)=[O:8])=[O:4].[NH2:15][CH2:16][C:17](=[O:19])[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[O:19]=[C:17]([CH3:18])[CH2:16][NH:15][C:7]([CH:6]1[CH2:10][CH2:11][CH2:12][N:5]1[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])=[O:8]
Reactant: CC(=O)CN
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)CNC(=O)C1CCCN1C(=O)C(F)(F)F

Procedure:
A solution of (S)-N-(trifluoroacetyl)prolyl chloride (Aldrich) 1 equiv. in DCM is treated with 1-amino-propan-2-one (1.5 equiv.) in pyridine at rt for 5 hours. After usual work up, it provides 1-trifluoroacetyl-pyrrolidine-2-carboxylic acid (2-oxo-propyl)-amide.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:28][C@@:27]4([CH3:29])[C@@H:14]([CH2:15][CH2:16][C@@H:17]5[C@@H:26]4[CH2:25][CH2:24][C@@:22]4([CH3:23])[C@H:18]5[CH2:19][C@H:20]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C@@H:21]4[OH:30])[CH2:13][C@@H:12]3[OH:36])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:37](Cl)(=[O:39])[CH3:38].O>C(Cl)Cl.C(N(CC)CC)C>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([C@H:11]3[CH2:28][C@@:27]4([CH3:29])[C@@H:14]([CH2:15][CH2:16][C@@H:17]5[C@@H:26]4[CH2:25][CH2:24][C@@:22]4([CH3:23])[C@H:18]5[CH2:19][C@H:20]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)[C@@H:21]4[OH:30])[CH2:13][C@@H:12]3[OH:36])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1.[CH3:38][C:37]([CH2:6][C:5]([OH:4])=[O:1])=[O:39]
Reactant: CC(=O)Cl
Agent: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)CC(=O)O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution containing 10 g of 2β-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-16β-(1-pyrrolidinyl)-5α-androstane-3α,17β-diol in 50 ml of methylene chloride, 7 ml of triethylamine are added and the solution is cooled to 0° C. To this solution 4.4 ml of acetyl chloride are dropwise added while cooling and stirring at such a rate that the temperature remains below 10° C. After termination of the addition the cooling is stopped and the mixture is allowed to warm to room temperature. The complete reaction requires about 16 hours. Thereafter, the excess of acetyl chloride is decomposed by adding water and the methylene chloride solution is washed with aqueous sodium hydroxide solution and then with water until neutral. The methylene chloride phase is dried, evaporated and the residue is purified on a silica gel column to yield 9 g (77.1%) of the title product as a foam.
Reaction SMILES: [Li+].CCC[CH2-].[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CCCCCC.O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20]([N:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: O=C1CCCN1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(S(=O)(=O)N2CCCC2=O)c1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
15.75 cm3 of a 1.6M solution of N-butyllithium in hexane is added to 2.22 g of 2-pyrrolidinone in solution in 80 cm3 of tetrahydrofuran and cooled to -25° C., the temperature being maintained between -25° C. and -20° C. After agitation for 30 minutes at -25° C., a solution of 5.40 g of 3-methoxybenzenesulphonyl chloride [J. Chem. Soc. P.T.2., 579 (1982)] in 40 cm3 of tetrahydrofuran is poured drop by drop into the mixture, operating between -25° C. and -20° C. After agitation for 30 minutes at -25° C., the whole is allowed to return to ambient temperature. The solvent is evaporated under reduced pressure; the residue is taken up in water, filtered and crystallized from isopropanol. 3.5 g of expected product is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:15][C:16]1[C:21]([C:22]([N:24]([O:26][CH3:27])[CH3:25])=[O:23])=[CH:20][N:19]=[C:18]2[N:28](CC3C=CC(OC)=CC=3)[N:29]=[CH:30][C:17]=12)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C.C(OCC)(=O)C>[CH2:8]([NH:15][C:16]1[C:21]([C:22]([N:24]([O:26][CH3:27])[CH3:25])=[O:23])=[CH:20][N:19]=[C:18]2[NH:28][N:29]=[CH:30][C:17]=12)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2ncc3c(NCc4ccccc4)c(C(=O)N(C)OC)cnc32)cc1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cnc2[nH]ncc2c1NCc1ccccc1

Procedure:
Trifluoroacetic acid (5.35 ml, 69.6 mmol) was added to the solution of 4-(benzylamino)-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (3 gm, 6.96 mmol) (example 6) in dichloroethane (20 ml) and the reaction mixture was refluxed for about 2 hours under inert atmosphere. It was cooled, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:29])([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:29])([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([OH:15])=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Yield: 52.8 %

Procedure:
The nonpolar isomer tert-butyl 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-prolinate (0.087 g, 0.21 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 4 hours. Then the mixture was evaporated in vacuo and vacuum dried to yield the nonpolar isomer of 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-proline (0.04 g, HPLC RT=2.51 min, Method A; LCMS m/z=361).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3I)=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH3:38][NH2:39]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3[NH:39][CH3:38])=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Product: CNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Yield: 85.5 %

Procedure:
A methanolic solution of methylamine (10 mL) was added to 1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [4-(2-acetylamino-pyridin-4-yloxy)-2,5-difluoro-phenyl]-amide (90 mg, 0.145 mmol) and the resultant mixture was stirred at 80° C. for 3 h. The mixture was concentrated to dryness and the crude product was recrystallized from MeOH to afford N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamide (65 mg, 85.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1 H), 10.57 (s, 1 H), 10.34 (m, 1 H), 8.47 (dd, J=13.0, 7.2 Hz, 1 H), 8.17 (d, J=5.8 Hz, 1 H), 7.72 (d, J=7.8 Hz, 1 H), 7.65 (s, 1 H), 7.55-7.42 (m, 3 H), 7.33 (m, 2 H), 6.69 (d, J=5.9 Hz, 1 H), 6.24 (d, J=7.9 Hz, 1 H), 3.01 (d, J=5.0 Hz, 3 H), 2.02 (s, 3 H); MS (ESI) m/z: 524.01 (M+H+).
Reaction SMILES: C[Mg]Br.[CH2:4]1COCC1.[NH2:9][C:10]1[C:11]2[C:37]([CH3:44])([C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])[C:36](=[O:45])[NH:35][C:12]=2[N:13]=[C:14]([C:16]2[C:24]3[C:19](=[N:20][C:21](Cl)=[CH:22][CH:23]=3)[N:18]([CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[N:17]=2)[N:15]=1.Cl>CN1C(=O)CCC1>[NH2:9][C:10]1[C:11]2[C:37]([CH3:44])([C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])[C:36](=[O:45])[NH:35][C:12]=2[N:13]=[C:14]([C:16]2[C:24]3[C:19](=[N:20][C:21]([CH3:4])=[CH:22][CH:23]=3)[N:18]([CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[N:17]=2)[N:15]=1
Reactant: CC1(C(=O)NC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4nc(Cl)ccc34)nc(N)c21
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C(=O)NC3CC3)nn(CCC(F)(F)C(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (0.42 ml, 0.584 mmol, 1.4 M in THF) was added to a THF (1.2 ml) and NMP (0.3 ml) solution containing 4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N-cyclopropyl-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, as described in Example 176, (53 mg, 0.097 mmol) and iron(111) acetylacetonate (34.4 mg, 0.097 mmol). After stirring at rt for 30 min. the reaction mixture was adjusted to pH 7 with 1N HCl at 0° C. The reaction mixture was filtered through a plug of Celite™ (diatomaceous earth) and the filtrate was washed with ethyl acetate (30 mL). The combined organic fractions were evaporated under reduced pressure. The residue was purified by reverse phase HPLC to afford the indicated product. Chiral separation using SFC on a Chiralcel OJ column provided both enantiomers of the title compound. 1H NMR (500 MHz, CD3COCD3): δ 0.58 (m, 2H); 0.73 (M, 2H); 1.78 (s, 3H); 2.68 (s, 3H), 2.80 (m, 1H); 3.10 (m, 2H); 4.94 (t, J=7.1 Hz, 2H); 7.26 (d, J=8.2 Hz, 2H); 7.52 (br, 1H); 7.79 (br, 1H); 8.74 (d, J=8.2 Hz, 1H). m/z=525.17 (M+H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C([O-])(=O)C.[Na+].C(O)(=O)C.[C:45]1([CH:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.N>C(Cl)Cl.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[CH2:52][CH:51]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: CC(=O)[O-]
Agent: N
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(CC(c2ccccc2)c2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 11 with 88 mg (1.4 mmol) of sodium cyanoborohydride, 115 mg (1.4 mmol) of sodium acetate, 134 μl (2.34 mmol) of acetic acid and 335 μl (1.87 mmol) of diphenylacetaldehyde with the product. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.50, FD-MS: M+ =607.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13].C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCCC1>[CH3:10][O:11][C:12]([C:14]1[CH:19]=[C:18]([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: O=C(O)c1ccc(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccc(C(=O)O)o2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To 5-bromofuran-2-carboxylic acid (0.50 g, 2.6 mmol), 3-methoxycarbonylphenylboronic acid (0.52 g, 2.9 mmol), tetrakis(triphenylphosphine)palladium (45 mg, 0.039 mmol), and sodium hydrogen carbonate (0.49 g, 5.9 mmol) were added toluene (3.5 mL), tetrahydrofuran (3.0 mL) and water (3.5 mL), and the mixture was stirred at 90° C. for 2 hours. Water was added to the reaction mixture, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a pale-yellow powder (0.58 g, 2.3 mmol, 91%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH:9]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:19])=O>C(#N)C.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH:9]=1)[C:5]([Cl:19])=[O:6]
Reactant: CON=C(C(=O)O)c1cc2sccc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CON=C(C(=O)Cl)c1cc2sccc2s1

Procedure:
A solution of 400 mg of α-methoxyimino-α-(thieno[3,2-b]thien-2-yl)acetic acid in 50 ml of acetonitrile containing 15 ml of oxalyl chloride and two drops of N,N-dimethylformamide was stirred at 0° C. for two hours. The reaction mixture was concentrated to dryness by evaporation under reduced pressure to provide α-methoxyimino-α-(thieno[3,2-b]thien-2-yl)acetyl chloride as an oil. The oil was dissolved in 10 ml of fresh acetonitrile and added to a stirred acetonitrile solution of 707 mg of 7-amino-3-methyl-3-cephem-4-carboxylic acid silylated with 2.56 g of bis(trimethylsilyl)trifluoroacetamide (BSTFA). The reaction mixture was stirred at 25° C. for sixteen hours. The reaction mixture was concentrated to dryness to provide an oil which was sonicated for fifteen minutes with 300 ml of saturated aqueous sodium bicarbonate. The mixture was acidified to pH 2.3 by addition of 1N hydrochloric acid. The acid layer was extracted several times with ethyl acetate, and the combined extracts were dried and the solvent was removed by evaporation to provide 970 mg of 7-α-methoxyimino-α-(thieno[3,2-b]thien-2-yl)acetamido-3-methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH:19]2[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]3[CH:11]=[CH:10][C:5]4[NH:6][C:7](=[O:9])[NH:8][C:4]=4[CH:3]=3)[CH2:21][CH2:20]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C(CCl)N1CCC(Oc2ccc(Cl)cc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)[nH]c2c1)N1CCC(Oc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from 5-amino-1,3-dihydro-benzimidazol-2-one and 2-chloro-1-[4-(4-chloro-phenoxy)-piperidin-1-yl]-ethanone (Example 233a) according to the method described in Example 206. Melting Point: 201-205° C. (diethylether)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:13]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1)C(C1C=CC2C(=CC=CC=2)C=1)=O)=[O:12]>C(O)C.O.NN>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([NH:13][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])=[N:27][CH:28]=1
Reactant: Cc1ccc(N(C(=O)c2ccc3ccccc3c2)C(=O)c2ccc3ccccc3c2)nc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc3ccccc3c2)nc1
Yield: 98.2 %

Procedure:
N-(2-naphthylformyl)-N-(5-methylpyridin-2-yl)-2-naphthamide (2.91 g, 6.99 mmol) was dissolved in ethanol (50 mL) and 85% hydrazine hydrate (5 mL), and stirred at room temperature for 8 hours. It was concentrated under reduce pressure, chromatographed on a silica gel column (petroleum ether:ethyl acetate=3:1) to obtain a white solid 1.8 g, at a yield of 98.1%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[N:9](COCC[Si](C)(C)C)[N:8]=2)=[N:3]1.Cl>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[NH:9][N:8]=2)=[N:3]1
Reactant: Cn1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Yield: 80.7 %

Procedure:
A solution of 3-(1-methyl-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (43.22 mg, 0.1063 mmol) in Dioxane (5 mL) was treated with 4.0 M of Hydrogen chloride in 1,4-Dioxane (5 mL) overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC to afford 232 as an off-white solid (23.7 mg, 81%). 1H NMR (400 MHz, DMSO) δ 13.74 (s, 1H), 9.33 (s, 1H), 9.19 (s, 1H), 8.67 (d, J=11.2 Hz, 2H), 8.56 (d, J=7.9 Hz, 1H), 7.85 (s, 1H), 7.63 (s, 1H), 6.82 (s, 1H), 4.01 (s, 3H). ESI MS m/z=277.0 (M+1)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:16]([F:19])([F:18])[F:17])([OH:15])/[CH:4]=[CH:5]\[CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[K+].[Br-].C([O-])(O)=O.[Na+].[O-]Cl.[Na+]>ClCCl.O.CC1(C)N([O])C(C)(C)CCC1>[F:1][C:2]([F:20])([F:21])[C:3]([OH:15])([C:16]([F:18])([F:19])[F:17])/[CH:4]=[CH:5]\[CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][CH:11]=[O:12]
Reactant: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCCCO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCCC=O

Procedure:
To a solution of 3.39 g of (Z)-10,10,10-trifluoro-5,5-dimethyl-9-trifluormethyl-dec-7-ene-1,9-diol in 15 ml of dichloromethane was added a solution of 90 mg of KBr and 336 mg of NaHCO3 in 14 ml of water and 8.5 mg of 2,2,6,6-tetramethylpiperidin-1-oxyl, radical, and the mixture was treated at 0° under vigorous stirring with 8.00 g of aqueous NaOCl (10.8%) over 1 h. The organic layer was washed with sat. aqueous NaCl, dried over MgSO4 and evaporated to give 2.92 g of the pure (t.l.c.) title compound as a pale yellow oil. IR (neat): 1718s (C═O).
Reaction SMILES: C[O:2][C:3]1[CH:27]=[CH:26][C:6]2[CH2:7][CH:8]([CH2:10][N:11]3[CH2:16][CH2:15][C:14]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)([OH:17])[CH2:13][CH2:12]3)[O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.C(Cl)[Cl:33].C([O-])(O)=O.[Na+].Cl.Cl.OC1C=CC2CC(CN3CCC(C(C)C4C=CC=CC=4)(O)CC3)OC=2C=1>C(Cl)Cl.CO>[ClH:33].[OH:2][C:3]1[CH:27]=[CH:26][C:6]2[CH2:7][CH:8]([CH2:10][N:11]3[CH2:12][CH2:13][C:14]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)([OH:17])[CH2:15][CH2:16]3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)C2
Reactant: ClCCl
Agent: BrB(Br)Br
Agent: CC(c1ccccc1)C1(O)CCN(CC2Cc3ccc(O)cc3O2)CC1
Agent: Cl
Solvent: CO
Product: Cc1ccc(CC2(O)CCN(CC3Cc4ccc(O)cc4O3)CC2)cc1
Temperature: -8 °C
Reaction time: 0.5 h

Procedure:
(RS)-1-(6-methoxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (1.24g, 3.37 mmol) dissolved in 35 ml of CH2Cl2 was cooled to −8° C. and 1M BBr3—CH2Cl2 solution (6.8 ml, 2 eq.) was added dropwise under argon. The violet suspension was allowed to warm to room temperature and then stirred for 30 minutes. The reaction was then cooled to 0° C. and MeOH (9 ml) was added to quench the reaction, followed by satd. NaHCO3 (50 ml). The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2×50 ml). The combined organic extracts were dried with Na2SO4 then filtered and evaporated. The resulting yellow foam was chromatographed over SiO2 (Merck 230-400 mesh) eluting with MeOH—CH2Cl2 (1:19) followed by MeOH—CH2Cl2 (1:9) to provide a yellow foam which was dissolved in MeOH (5 ml) and treated with 1N HCl (3.4 ml) to provide (RS)-1-(6-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(methyl-benzyl)-piperidin-4-ol hydrochloride (0.92g, 70%) as a white solid and mixture of E/Z isomers. Mp. 203-205° C. MS: m/e=354.3(M+H+)
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:19][C:14]=3[CH2:13][N:12]([S:26]([CH3:29])(=[O:28])=[O:27])[C@H:11]([CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:10]2)[N:5]=[CH:4]1.[S:37]1C=[CH:40][CH:39]=[C:38]1S([Cl:45])(=O)=O.Cl.BrC1C=CC2N(CC3N=CNC=3)C[C@@H](CC3C=CC=CC=3)N(S(C)(=O)=O)CC=2C=1>>[ClH:45].[ClH:1].[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:19][C:14]=3[CH2:13][N:12]([S:26]([C:29]3[S:37][CH:38]=[CH:39][CH:40]=3)(=[O:28])=[O:27])[C@H:11]([CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:10]2)[N:5]=[CH:4]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CS(=O)(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1cccnc1
Agent: CS(=O)(=O)N1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Product: O=S(=O)(c1cccs1)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1cccnc1

Procedure:
Example 329 was prepared as an off white solid from (R)-2,3,4,5-tetrahydro-7-phenyl-3-(3-pyridinylmethyl)-1H-1,4-benzodiazepine (prepared as described in Example 273) and 2-thiophenesulfonyl chloride by the following sequence: Compound C of Example 224; Compound D of Example 224. MS (M+H)+ 542.
Reaction SMILES: [N:1]([C@H:4]1[CH2:28][C@@:27]2([CH3:29])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][CH:5]1[OH:31])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O>[NH2:1][C@H:4]1[CH2:28][C@@:27]2([CH3:29])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][CH:5]1[OH:31]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(O)[C@@H](N=[N+]=[N-])C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(O)[C@@H](N)C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
4 g 2β-azido-cholestane-3-ol and 0.2 g lithium aluminium hydride are stirred in 50 ml abs. ether for one day at room temperature. After careful decomposition with water and repeated ether extraction, the combined ethereal solutions are washed with water, dried over sodium sulfate and the solvent is reduced to 50 ml. Upon introduction of hydrogen chloride, the corresponding hydrochloride crystallizes out in the form of colorless needles which, after recrystallization from acidified methanol, melt at 254-256° C.