Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([N:19]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:17])=[O:18])=[CH:14][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Product: O=S(=O)(N=Cc1cccnc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 3-pyridine-carboxaldehyde (2.6 g, 24.2 mmol) and 4-chlorobenzenesulfonamide (5.0 g, 26.0 mmol) in toluene was added powdered molecular sieve 4A (2.5 g) and AMBERLYST H+ (2.5 g). The reaction mixture was heated in a Dean-Stark apparatus for 16 h. After cooling to room temperature, the mixture was filtered through a pad of CELITE. The CELITE was washed with EtOAc, and the filtrate was concentrated to give 6.4 g (94%) of the title product as a white solid. 1H NMR (CDCl3 300 MHz) δ 9.12 (1H, s), 9.06 (1H, s), 8.83 (1H, m), 8.28 (1H, m), 7.95 (2H, d), 7.55 (2H, d), 7.47 (1H, m), MS (ES) m/e 280.5 (M)+.
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C@@H:16]12[C:25](=O)[O:24][C:22](=[O:23])[C@@H:17]1[CH2:18][CH:19]=[CH:20][CH2:21]2.[BH4-].[Na+].Cl>O.CC(O)C>[OH:24][CH2:25][CH:16]1[CH:17]([C:22]([NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:23])[CH2:18][CH:19]=[CH:20][CH2:21]1
Reactant: CCCCCCCCCCCCCCN
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCNC(=O)C1CC=CCC1CO
Temperature: 140 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
1-Tetradecylamine (3.51 g) was added to cis-4-cyclohexene-1,2-dicarboxylic anhydride (2.50 g) and stirred for 5 hours at 140° C. The reaction mixture was suspended into a mixed solution of 2-propanol (125 ml) and water (21 ml) and then sodium borohydride (3.11 g) was added thereto at room temperature. After being stirred for 67.5 hours at room temperature, the reaction mixture was acidified with dilute hydrochloric acid. The resulting solid was collected by filtration under a vacuum, washed with water, and dried, thereby yielding the entitled compound (5.38 g) as white solid.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:5]([OH:7])=O)[CH3:3].[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:21][CH2:20]1>>[CH2:12]([O:11][C:9]([NH:8][C@H:4]([C:5]([N:19]1[CH2:20][CH2:21][CH:22]([O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:24]1)=[O:7])[CH:2]([CH3:1])[CH3:3])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC(OCC(=O)OC(C)(C)C)CC1
Yield: 96 %

Procedure:
By coupling 2.5 g of Z-L-valine with 2 g of t-butyl 4-piperidinyloxyacetate as described in Example 2b) there are obtained 4 g of t-butyl [[1-[N-[(benzyloxy)carbonyl]-L-valyl]-4-piperidinyl]oxy]acetate, MS (EI): 449 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[C:17](=[O:18])[CH2:16][N:15]([CH3:19])[C:14]2=[O:20])=[CH:4][CH:3]=1.[BH4-].[K+].[Cl-].[NH4+].Cl>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[CH:17]([OH:18])[CH2:16][N:15]([CH3:19])[C:14]2=[O:20])=[CH:4][CH:3]=1
Reactant: CN1CC(=O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CC(O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 89.6 %

Procedure:
5 g (15.8 mmol) of 3-[2-(4-chlorophenoxy)phenyl]-1-methylpyrrolidine-2,4-dione (compound IVb) was dissolved in a mixture of 150 mL of tetrahydrofuran and 15 mL of water. The solution was cooled to 0° C., and 4.3 g of potassium borohydride were added slowly, keeping the temperature below 10° C. The resulting solution was stirred at 0° C. for 6 hours. Then, a saturated solution of ammonium chloride was added, and the pH was adjusted to 3 with HCl 2 M. 100 mL of ethyl acetate were added. The organic phase was extracted, washed with saturated sodium bicarbonate and with water, dried and concentrated under vacuum, to obtain 4.5 g of 3-[2-(4-chlorophenoxy)phenyl]-4-hydroxy-1-methylpyrrolidine-2-one (compound XIIIb) as a sticky solid. Yield: 89.6%.
Reaction SMILES: C(OC([N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38])[C:9]1[CH:21]=[CH:20][C:12]([C:13](N2C=CN=C2)=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+].[NH2:43][CH2:44][CH:45]([OH:48])[CH2:46][OH:47]>C(Cl)(Cl)Cl>[OH:48][CH:45]([CH2:46][OH:47])[CH2:44][NH:43][C:13](=[O:14])[C:12]1[CH:20]=[CH:21][C:9]([NH:8][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCCCCCCCC(F)(F)F)c1ccc(C(=O)n2ccnc2)cc1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(NCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-[N-tert-butyloxycarbonyl-15-(trifluoromethyl)pentadecylamino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield the product as a light yellow solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][N:8]=1)#[N:2]>CO.O>[C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1)#[N:2]
Reactant: COC(=O)c1ccc(OCCCC#N)nc1
Solvent: O
Solvent: CO
Product: N#CCCCOc1ccc(C(=O)O)cn1
Reaction time: 8 h
Yield: 84.9 %

Procedure:
6-(3-cyanopropyloxy)nicotinic acid, methyl ester (1.8 mmol) was dissolved in methanol/water (16 mL:4 mL) and treated with LiOH monohydrate (2.7 mmol). After stirring overnight, volatiles were removed and reaction neutralized with 1N sulfuric acid. The solid product was collected by filtration, washed with water and dried to give 6-(3-cyanopropyloxy)nicotinic acid (315 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([S:12][C:13]3[NH:14][C:15]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([S:12]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[O:32])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2nc(SC3CCCc4cc(C)cnc43)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2nc(S(=O)C3CCCc4cc(C)cnc43)[nH]c2c1
Reaction time: 0.25 h

Procedure:
4.00 Grams of 3-methyl-8-(5-methoxy-2-benzimidazolyl)thio-5,6,7,8-tetrahydroquinoline was dissolved in 80 ml of dichloromethane, to this solution was added dropwise slowly at -10° C. a solution which was prepared by dissolving 2.37 g of meta-chloroperbenzoic acid (85%) in 30 ml of dichloromethane. After the dropwise addition was finished, the reaction mixture was stirred at -10° C. to -4° C. for 15 minutes. Water was added to the reaction mixture, then was made alkaline by adding sodium carbonate, then extracted with diethyl ether. The diethyl ether layer was washed with an aqueous solution saturated with sodium chloride, then was dried with anhydrous magnesium sulfate. The solvent was removed from the extract by evaporation, and was recrystallized from dichlomethane-diethyl ether to obtain 2.30 g of 3-methyl-8-(5-methoxy-2-benzimidazolyl)sulfinyl-5,6,7,8-tetrahydroquinoline in the form of white powdery crystals. Melting point: 114°-114.5° C. (decomposed).
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH3:7])[C:4](=[O:6])[CH3:5].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CO>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:5][C:4](=[O:6])[C:3]([O:8][CH3:9])([O:2][CH3:1])[CH3:7]
Reactant: COC(OC)N(C)C
Reactant: COC(C)(OC)C(C)=O
Solvent: CO
Product: COC(C)(OC)C(=O)C=CN(C)C
Yield: 90.1 %

Procedure:
100 g (0.76 mol) of 3,3-dimethoxy-2-butanone were stirred, at 120° C. for 48 h, with 90.2 g of N,N-dimethylformamide dimethylacetal (0.76 mol). The methanol which was formed during the reaction was continuously removed from the reaction solution by distillation. When the solution was cooled, spontaneous crystallization occurred, with this crystallization being brought to completion by adding a little heptane. This resulted in 128.24 g of crude product 8 (yield 90%), which was subjected to reaction without any further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10].[H-].[Na+].[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[N:26][C:25]=1[CH2:36]I.O>CC(OC)(C)C>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][CH2:2][O:1][CH2:36][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[O:28][C:24]=2[CH3:23])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cc1cccc(-c2nc(CI)c(C)o2)c1
Reactant: Cc1cccc(COCCCO)c1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1cccc(-c2nc(COCCCOCc3cccc(C)c3C(=O)O)c(C)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of tert-butyl 2-(3-hydroxypropoxymethyl)-6-methylbenzoate are dissolved in 1.0 ml of MTBE, and 57 mg of sodium hydride (60% in mineral oil) are added. After gas evolution ceases, 446 mg of 5-methyl-2-m-tolyloxazol-4-ylmethyl iodide are added, and the suspension is stirred at RT overnight. Water is then added, and the solution is poured into a kieselguhr cartridge (VARIAN CHEM ELUT 1010). The product is eluted with MTBE and concentrated. The residue is dissolved without purification in DCM/TFA (3:1) and stirred at 40° C. for 5 h. The solution is concentrated and purified by prep. HPLC, resulting in 202 mg of 2-methyl-6-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)propoxymethyl]benzoic acid.
Reaction SMILES: [N:1]1([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[N:24]([CH2:25][CH3:26])[C:23]5[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=5[N:21]=4)=[CH:15][CH:14]=3)=O)[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B.O1CCCC1>O1CCCC1>[CH2:25]([N:24]1[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[N:21]=[C:20]1[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:11][N:8]2[CH2:9][CH2:10][C@H:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7]2)=[CH:18][CH:17]=1)[CH3:26]
Reactant: CCn1c(Cc2ccc(C(=O)N3CCC(N4CCCC4)C3)cc2)nc2ccccc21
Agent: B
Solvent: C1CCOC1
Product: CCn1c(Cc2ccc(CN3CC[C@H](N4CCCC4)C3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of 1,3′-bipyrrolidin-1′-yl(4-((1-ethyl-1H-benzo[d]imidazol-2-yl)methyl)phenyl)methanone (69 mg, 0.172 mmol, 1 eq) in anhydrous tetrahydrofuran (3 mL) was added borane-tetrahydrofuran complex (860 μL, 0.860 mmol, 1 M in tetrahydrofuran) and the reaction mixture has heated to reflux and allowed to stir for 3 h. The reaction mixture was cooled to room temperature, quenched by dropwise addition of methanol, and the solvent was evaporated under reduced pressure. The residue was treated with hydrogen chloride in methanol (5 mL) and heated at reflux for 1 h. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and 1.0 N aqueous sodium hydroxide. The organic layer was separated and dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography to afford the title product (65%). 1H NMR (300 MHz, DMSO-d6): 7.74-7.86 (m, 2 H), 7.43-7.56 (m, 6 H), 6.64 (s, 2 H), 4.62 (s, 2 H), 4.46 (q, 2 H), 4.22 (s, 2 H), 4.00-4.10 (m, 1 H), 3.44-3.55 (m, 1 H), 3.24-3.40 (m, 6 H), 3.09-3.18 (m, 1 H), 2.35-2.45 (m, 1 H), 2.12-2.24 (m, 1 H), 1.91-2.02 (m, 4 H), 1.27 (t, 3 H). 389.22 (M+H).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:36])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[O:22])[CH:15]=1.CC(O)=O.C(Cl)Cl>CCCCCCC.CCOC(C)=O.[Zn]>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][O:23][C:21]([CH2:20][C:16]2[CH:15]=[C:14]([S:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:36])=[O:4])[CH:19]=[CH:18][CH:17]=2)=[O:22])=[CH:31][CH:30]=1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCCc1ccc(C(F)(F)F)cc1
Agent: [Zn]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)O)c1)OCCc1ccc(C(F)(F)F)cc1
Yield: 69.5 %

Procedure:
The titled compound was prepared according to the method described for example 1 above from 2-{3-[2-(4-trifluoromethyl-phenyl)-ethoxycarbonylmethyl]phenylsulfanylmethyl}-benzoic acid 2,2,2-trichloro-ethyl ester (160 mg, 0.264 mmol), zinc (345 mg, 5.28 mmol), HOAc, 97% (1.51 mL, 26.4 mmol) and DCM (12 mL). The crude was submitted to flash chromatography using heptane and EtOAc (70/30-60/40) as eluent to give the titled compound (87 mg, 69%) as an oil; 1H NMR (400 MHz, CDCl3): δ 2.97 (dd, 2H), 3.54 (s, 2H), 4.34 (dd, 2H), 4.58 (s, 2H), 7.00-7.06 (m, 1H), 7.12-7.18 (m, 2H), 7.21-7.34 (m, 5H), 7.42 (dd, 1H), 7.52 (d, 2H), 7.98 (d, 1H); Mass spectrum: M−H+ 473.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[CH:11]2[CH:7]([CH2:8][NH:9][CH2:10]2)[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])([OH:12])[CH2:5][CH2:4]1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32](O)=[O:33])=[CH:23]1>>[CH3:2][C:3]1([CH3:21])[CH:11]2[CH:7]([CH2:8][N:9]([C:32](=[O:33])[CH2:31][C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][CH:23]=3)[CH2:10]2)[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])([OH:12])[CH2:5][CH2:4]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1C1(O)CCC(C)(C)C2CNCC21
Agent: Cl
Product: COc1ccccc1C1(O)CCC(C)(C)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Yield: 20.4 %

Procedure:
By working according to the experimental procedure of Example 6, from 0.6 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol hydrochloride and 0.4 g of 3-indoleacetic acid, and after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 2.4 cm, height 15 cm), 0.17 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-(3-indolylacetyl)-4-perhydroisoindolol is obtained, in the form of a white foam.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[C:8]([C:17]([F:20])([F:19])[F:18])=[N:9][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][C:15]=2[CH:16]=1)=[O:6])[CH3:3].[CH3:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:34][C@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH:33]=1)[C:30](O)=[O:31])(=[O:24])=[O:23]>>[CH2:2]([O:4][C:5]([C:7]1[C:8]([C:17]([F:19])([F:20])[F:18])=[N:9][C:10]2[CH2:11][CH2:12][N:13]([C:30](=[O:31])[C:29]3[CH:33]=[C:25]([S:22]([CH3:21])(=[O:23])=[O:24])[CH:26]=[CH:27][C:28]=3[O:34][C@H:35]([CH3:40])[C:36]([F:39])([F:37])[F:38])[CH2:14][C:15]=2[CH:16]=1)=[O:6])[CH3:3]
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCNC2
Agent: Cl
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCN(C(=O)c1cc(S(C)(=O)=O)ccc1O[C@H](C)C(F)(F)F)C2

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine-3-carboxylic acid ethyl ester hydrochloride (CA [741736-90-3]; WO2004069162) and 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.3). MS (m/e): 569.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:14]([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=4[CH:26]=3)=[O:15])[C@@H:7]([CH2:10][C:11]([OH:13])=O)[CH2:8][O:9][C:4]=2[CH:3]=1.C1C[N:32]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:14]([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=4[CH:26]=3)=[O:15])[C@@H:7]([CH2:10][C:11]([NH2:32])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C(O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Yield: 28.7 %

Procedure:
{(3S)-7-Bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 29a, 160 mg, 0.36 mmol) was dissolved in DCM (3 mL). PyBOP (223 mg, 0.43 mmol) and TEA (0.248 mL, 1.79 mmol) was added followed by NH4Cl (77 mg, 1.43 mmol). The mixture was stirred at rt over weekend. EtOAc (40 mL) was added. Washed with sat. aq. Na2CO3 (2×30 mL), HCl (0.5M, 20 mL) and brine (20 mL). Dried through a phase separator and evaporated under reduced pressure. The residue was purified using a SFC2-MS system and eluting with MeOH on a Waters Viridis 2-EP column 5μ30×250 mm. Pooling of homogenous fraction and removal of solvents in vacuo gave the title compound (46.1 mg, 28.9%).
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[S:28])=[C:15]([C:18]4[O:19][C:20]5[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=5[N:22]=4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>C(Cl)Cl.O>[NH2:10][CH:11]1[C:43](=[O:44])[N:13]2[C:14]([C:27]([O:29][CH:30]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[S:28])=[C:15]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4o3)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4o3)CS[C@H]12
Temperature: -15 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A 327 mg portion of diphenylmethyl 7-phenylacetamido-3-(benzoxazol-2-yl)thio-3-cephem-4-carboxylate was dissolved in 4 ml of methylene chloride and the resulting solution was cooled to -15° C. To this were added 96 μl of pyridine and 161 mg of phosphorous pentachloride, followed by 1 hour of stirring at -5° C. Next, the reaction solution was cooled down to -20° C., mixed with 1.3 ml of methanol, and then stirred for 3 hours at -5° C. The resulting solution was mixed with 4 ml of water, stirred for additional 1 hour at the same temperature, and then subjected to liquid phase separation. The organic layer was mixed with 4 ml of water, adjusted to pH 7 with saturated sodium bicarbonate aqueous solution and then subjected to liquid phase separation. After drying the resulting organic layer on anhydrous magnesium sulfate and distilling off the solvent under a reduced pressure, the residue was purified by a column chromatography (20 g silica gel, toluene:ethyl acetate =2:1) to obtain 207 mg of the title compound (yield, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:61]1[CH:62]=[C:63]([NH:69][C:70]2[CH:75]=[CH:74][C:73]([N:76]3[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]3)=[CH:72][CH:71]=2)[C:64]([C:67]#[N:68])=[N:65][CH:66]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:82][N:79]1[CH2:80][CH2:81][N:76]([C:73]2[CH:74]=[CH:75][C:70]([NH:69][C:63]3[C:64]([C:67]#[N:68])=[N:65][CH:66]=[C:61]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:62]=3)=[CH:71][CH:72]=2)[CH2:77][CH2:78]1
Reactant: CN1CCN(c2ccc(Nc3cc(Br)cnc3C#N)cc2)CC1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(Nc3cc(Nc4ccccc4)cnc3C#N)cc2)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Aniline (22.4 mg, 0.24 mmol), cesium carbonate (91 mg, 0.28 mmol), palladium (II) acetate (2.25 mg, 0.01 mmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (9.34 mg, 0.015 mmol) were added to a dry microwave vial. The vial was capped and purged with nitrogen. A degassed solution of EXAMPLE 70A (74.5 mg, 0.2 mmol) in toluene (1 mL) was added to the microwave vial and the reaction was stirred at 110° C. for 3 hours. The reaction mixture was concentrated and purified on silica gel with 2-25% methanol in dichloromethane to afford 3-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-phenylamino-pyridine-2-carbonitrile. A solution of this (20 mg, 0.052 mmol) in dimethylsulfoxide was treated with potassium carbonate (36 mg, 0.26 mmol) and 30% hydrogen peroxide (1 mL) while keeping temperature below 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 18 hours. The reaction was quenched by the addition water, filtered, washed with water and dried to provide the title compound. 1H NMR (DMSO-d6) δ ppm 10.15 (s, 1H), 8.64 (s, 1H), 7.83-7.78 (m, 1H), 7.65 (d, J=2.3, 1H), 7.26 (t, J=7.7, 2H), 7.21 (d, J=3.4, 1H), 7.11-7.04 (m, 4H), 6.96-6.88 (m, 4H), 3.12-3.04 (m, 4H), 2.42-2.32 (m, 4H), 2.20 (s, 3H); MS (ESI) m/z 402 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:40])([CH3:39])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O>[CH3:40][Si:14]([CH3:13])([CH3:39])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[O:35])=[CH:37][CH:38]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 30.7 g. of benzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, with stirring and cooling, to a suspension of 5.4 g. of sodium hydride in 100 ml. of dry dimethylacetamide during 30 minutes at room temperature. Stirring is continued for 30 minutes. In the meantime, a mixture of 36.2 g. of 4-[14-(trimethylsilyl)tetradecylamino] benzoic acid in 100 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated and to the resulting oil residue is added, in one portion, the previously prepared mixture of sodium benzenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes and then filtered. The filtrate is poured into 2 liters of water and 250 ml. of saturated sodium chloride solution. The product is collected by filtration and then dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added. The layers are separated, the organic phase is dried and evaporated. The residue is crystallized to yield the product as a white solid.