Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]3[NH:40][C:39]([C@@H:41]5[CH2:45][C@H:44]([CH3:46])[CH2:43][N:42]5C(OC(C)(C)C)=O)=[N:38][CH:37]=3)[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:46][C@@H:44]1[CH2:43][NH:42][C@H:41]([C:39]2[NH:40][C:36]([C:31]3[CH:30]=[CH:29][C:28]4[C:33](=[CH:34][CH:35]=[C:26]([C:23]5[CH:22]=[CH:21][C:20]([C:17]6[NH:16][C:15]([C@@H:10]7[CH2:11][C@H:12]([CH3:14])[CH2:13][NH:9]7)=[N:19][CH:18]=6)=[CH:25][CH:24]=5)[CH:27]=4)[N:32]=3)=[CH:37][N:38]=2)[CH2:45]1
Reactant: C[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc5nc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)OC(C)(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CN[C@H](c2ncc(-c3ccc(-c4ccc5nc(-c6cnc([C@@H]7C[C@H](C)CN7)[nH]6)ccc5c4)cc3)[nH]2)C1
Yield: 158 %

Procedure:
4M HCl (0.2 mL, 0.800 mmol) in dioxane was added to a solution of (2S,4S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinolin-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (16.6 mg, 0.024 mmol) in dioxane (1 mL) and the reaction mixture was stirred at rt for 3d. The reaction mixture was concentrated to yield a crude HCl salt of 2-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-6-(4-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline (19.1 mg) as yellow solid. LC-MS retention time 2.765 min; m/z 504.47 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: Cl.[N:2]1([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:7][CH2:6][C:5]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][CH2:8]2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].Cl>C(Cl)Cl>[CH3:40][S:41]([N:9]1[CH2:8][C:5]2([CH2:6][CH2:7][N:2]([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:27])[F:29])[CH2:3][CH2:4]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:43])=[O:42]
Reactant: O=C(/C=C/c1ccccc1C(F)(F)F)N1CCC2(CC1)CNCc1ccccc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1Cc2ccccc2C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A solution of (E)-1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one HCl salt (40 mg, 0.09 mmol) in CH2Cl2 (4 mL) was treated with i-Pr2NEt (0.05 mL, 0.28 mmol) and MeSO2Cl (0.014 mL, 0.18 mmol). The mixture was stirred overnight at rt and applied to a 10-mL Chem-Elut cartridge that had been wetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was concentrated and the residue was purified by prep HPLC to afford (E)-1-(2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (20 mg, 45%). 1H NMR (CDCl3) 1.77 (m, 1H), 1.88 (m, 1H), 2.04 (m, 1H), 2.13 (m, 1H), 2.92 (s, 3H), 3.00 (m, 1H), 3.23 (m, 1H), 3.47 (m, 1H), 3.90 (m, 1H), 4.02 (m, 1H), 4.37 (m, 1H), 4.59 (m, 1H), 4.78 (d, 1H), 6.82 (d, 1H), 7.05-7.75 (8H), 7.99 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl.N1C=CC=CC=1>[CH3:16][S:17]([O:15][CH2:14][CH2:13][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11])(=[O:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 2-(3-nitrobenzenesulfonyl)ethanol (101) (5.0 g, 21.6 mmol) in dichloromethane (31.5 mL) and pyridine (7 mL) was added methanesulfonyl chloride (4.9 g, 43 mmol). The mixture was stirred at room temperature overnight before it was partitioned between dichloromethane (200 mL) and 0.5 N HCl (200 mL). The organic layer was dried over MgSO4 and concentrated on a rotavap to give 102 (4.78 g, 71%).
Reaction SMILES: [CH3:1][CH:2]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].C([BH3-])#N.[CH:23](=O)[CH2:24][CH3:25]>CO.C(Cl)CCl>[CH2:23]([NH:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][CH:2]([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:10]=[CH:11][CH:12]=2)[N:17]=1)[CH2:24][CH3:25]
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(N)nc12
Reactant: CCC=O
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCCl
Product: CCCNc1ccc2cccc(OC(C)CC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 4 mL scintillation vial was added a stir bar and the title compound from Example 16 (15.0 mg, 0.058 mmol). To this was added 0.42 mL of a 1:1 MeOH/ClCH2CH2Cl mixture followed by MP-cyanoborohydride resin (84 mg, 3.7 equiv Argonaut Technologies, Inc.) and 40 μL (10 equiv) of propionaldehyde. The reaction vessel was placed in an oil bath that had been preheated to 80° C. and the contents were allowed to stir overnight. Upon cooling to room temperature, the suspension was filtered and the filtrate was evaporated in vacuo. The crude material was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.06 (d, 1H), 7.30 (m, 1H), 7.17 (m, 2H), 6.90 (d, 1H), 4.54–4.81 (m, 1H), 3.38 (m, 2H), 2.38 (m, 1H), 1.80 (m, 1H), 1.50 (m, 2H), 1.39 (d, 3H), 1.03 (t, 3H), 0.96 (s, 9H); MS (DCI/NH3) m/z 301 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([CH3:25])([O-:24])=[O:23]>C(O)C>[CH2:1]([N:8]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[S:9]([CH2:12][CH2:13][CH2:25][N+:22]([O-:24])=[O:23])(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1ccccc1)S(=O)(=O)CC)OCC
Reactant: C[N+](=O)[O-]
Solvent: CCO
Product: CCOC(CN(Cc1ccccc1)S(=O)(=O)CCC[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of crude ethanesulfonic acid benzyl-(2,2-diethoxy-ethyl)-amide (10 g, 32 mmol) in ethanol (150 ml) under argon was added nitromethane (100 ml) followed by Na-tert-pentoxide (1.8 g, 16 mmol) at rt. After stirring for overnight at ambient temperature, the mixture was concentrated in vacuo, diluted with chloroform (300 ml), washed with cold 1N HCl (200 ml), dried over MgSO4, filtered, and purified on silica gel column (dichloromethane) to give the title compound (5 g, 42% for 2 steps); 1H NMR (CDCl3): 1.25 (t, 6H), 2.55 (m, 2H), 3.20 (m, 2H), 3.55 (m, 2H), 3.75 (m, 21), 4.60 (m, 5H), 7.40 (m, 5H); LCMS: 393 (MH+).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]21[CH2:12][C:11](=[O:13])[O:10][C:8](=O)[CH2:7]2.[NH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C1(C)C(C)=CC=CC=1>O>[N:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:8](=[O:10])[CH2:7][C:2]3([CH2:1][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:12][C:11]2=[O:13])=[CH:16][CH:17]=1
Reactant: Nc1ccncc1
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CC2(CCCCC2)CC(=O)N1c1ccncc1

Procedure:
The starting material is prepared as follows: The mixture of 25 g of 2,2-cyclohexane diacetic anhydride, 12.92 g of 4-aminopyridine, and 400 ml of xylene is refluxed for 25 hours using a water separator. The hot, supernatant xylene solution is decanted from an oily precipitate (which is discarded), cooled, filtered and the residue recrystallized from ethanol, to yield the 3-(4-pyridyl)-3-azaspiro[5,5]undecan-2,4-dione melting at 213°-215°.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31](Cl)(=[O:33])=[O:32]>>[C:1]1([CH2:7][O:8][C:9]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:31]([C:22]3[CH:23]=[CH:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=3)(=[O:33])=[O:32])=[CH:17][CH:18]=2)=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1ccc(CCNC(=O)OCc2ccccc2)cc1
Product: O=C(NCCc1ccc(NS(=O)(=O)c2ccc3ccccc3c2)cc1)OCc1ccccc1

Procedure:
In a manner analogous to that of Example 5, the title compound was prepared from the Cbz amine from Example 3 and 2-naphthalenesulfonyl chloride: 1H NMR (400 MHz, CDCl3) δ8.32 (s, 1H), 7.85 (m, 3H), 7.71 (dd, 1H, J=1.8, 8.7 Hz), 7.61-7.52 (m, 2H), 7.34-7.28 (m, 5H), 6.99 (s, 4H), 6.77 (br s, 1H), 5.04 (s, 2H), 4.65 (br s, 1H), 3.33 (br q, 2H, J=5.9 Hz), 2.68 (t, 2H, J=7.0 Hz); FAB MS m/z 461 (M+1), 270.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OS(C(F)(F)F)(=O)=O)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][C:26]=3[Cl:28])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2ccc(Br)cc2o1
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: C1CCOC1
Product: O=c1cc(-c2ccc(Cl)cc2Cl)c2ccc(Br)cc2o1
Temperature: 70 °C
Yield: 67.9 %

Procedure:
To a solution of the triflate from Step 1 (712 mg, 1.91 mmol) in 15 ml THF was added 2,4-dichlorophenyl boronic acid (400 mg, 2.10 mmol), (Ph3P)4Pd (110 mg, 0.095 mmol) and aqueous Na2CO3 (1.91 mL, 3.82 mmol). The mixture was heated at 70° C. for 2 h, cooled and partitioned between aqueous NH4Cl and EtOAc (50 mL each). The layers were separated and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was evaporated and the residue chromatographed on silica gel (hexane: EtOAc 9:1) to give 480 mg (68%) of the title compound.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:25])[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20](=O)N(C)C)=[CH:15][CH:14]=1)([CH3:11])[CH3:10])[CH3:6].[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][C:35](C3C=CC=CC=3)=[CH:34][CH:33]=2)=[N:29][C:28]=1[CH2:44]COS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH3:10])([O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19][CH2:20][CH2:44][C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:31][C:27]=2[CH3:26])=[CH:17][CH:18]=1)[CH3:11])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(=O)N(C)C)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(SCCc2nc(-c3ccccc3)oc2C)cc1
Yield: 87 %

Procedure:
Freshly prepared sodium ethoxide (from 50 mg (2.2 mmol) Na) was charged with 2-(4-dimethylcarbamoylsulfanyl-phenoxy)-2-methyl-propionic acid ethyl ester (420 mg, 1.35 mmol) and refluxed for 3 h. Toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)-ethyl ester (2.2 mmol) was added and the mixture was refluxed for another 3 h. The reaction was cooled and concentrated. The residue was shaken with ethyl acetate/water. After a second water wash, the organic layer was dried (MgSO4) and concentrated to give 500 mg crude product.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])(O)=[O:2].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])=[O:2]
Reactant: CC(Oc1ncn(-c2ccccc2)n1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Oc1ncn(-c2ccccc2)n1)C(=O)Cl

Procedure:
A 22.8 g portion of the compound of Example 22 was suspended in 150 ml of toluene, and 49 ml of thionyl chloride was added. The mixture was heated under reflux for 2 hours, and was then cooled and evaporated under vacuum. One hundred ml of additional toluene was added and was removed under vacuum, and the residue was recrystallized from toluene.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH:15]=2)[C:10]([CH2:36][CH2:37][CH3:38])=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:35][C:21]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[S:24][C:20]=1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH2:36][CH2:37][CH3:38])=[CH:9][N:8]2[CH2:7][C:6]([OH:39])=[O:5])=[CH:12][CH:13]=1
Reactant: CCCc1cn(CC(=O)OC(C)(C)C)c2cc(OCCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12
Agent: [Li+]
Agent: [OH-]
Product: CCCc1cn(CC(=O)O)c2cc(OCCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12

Procedure:
In analogy to the procedure described in example 2 c], (6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-3-propyl-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy]-3-propyl-indol-1-yl)-acetic acid as brown solid.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[NH2:15][C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([NH2:19])=[O:18]>>[C:17]([C@@H:16]([NH:15][C:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([S:5][CH2:1][CH:2]([CH3:3])[CH3:4])[N:11]=1)=[O:14])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])[NH2:19]
Reactant: CC(C)CSc1cccc(C(=O)O)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)CSc1cccc(C(=O)N[C@@H](CC(C)C)C(N)=O)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(isobutylthio)picolinic acid (CAN 1247607-03-9) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=324.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:4]([N:5]=[C:15]=[S:16])[CH:6]=[CH:7][CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cccc(N)c1N1CCOCC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(N=C=S)c1N1CCOCC1

Procedure:
Reaction of 3-methyl-2-morpholinoaniline (9.4 g) with thiophosgene (6 ml) in dioxane (50 ml) and water (200 ml) at 0° C. for 30 minutes and at room temperature for 2 hours gave a product which was extracted with dichloromethane to give 3-methyl-2-morpholinophenyl isothiocyanate as a red oil.
Reaction SMILES: [CH2:1]([CH2:4][C:5](Cl)=[S:6])[CH:2]=[CH2:3].[CH3:8][CH:9]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])[N:12]2[C:23](=[O:26])[CH:24]([NH2:25])[C@H:11]2[S:10]1>ClCCl>[CH3:8][CH:9]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:20])[Cl:21])=[O:16])[N:12]2[C:23](=[O:26])[CH:24]([NH:25][C:5](=[S:6])[CH2:4][CH2:1][CH:2]=[CH2:3])[C@H:11]2[S:10]1
Reactant: C=CCCC(=S)Cl
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Solvent: ClCCl
Product: C=CCCC(=S)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (0.764 g) in dried dichloromethane (8 ml) were added at -30° C. a solution of triethylamine (0.18 g) in dichloromethane (2 ml) and then a solution of dimethylaniline (0.27 g) in dichloromethane (2 ml). While, allylthioacetic acid (0.528 g) was added to thionyl chloride (5 ml) and the mixture was allowed to stand for 20 minutes at room temperature and 5 minutes at 50° C., after which thionyl chloride was removed under reduced pressure, and the residue was added a small amount of benzene, and then removed under reduced pressure to give allylthioacetyl chloride (0.527 g). A solution of thus obtained allylthioacetyl chloride (0.452 g) in dichloromethane (3 ml) was dropwise added to -30° C. over 5 minutes to the above-mentioned solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate, and the mixture was stirred for 1 hour at -20° C. After the reaction, the reaction mixture was in turn washed twice with 5% hydrochloric acid, once with water, twice with a saturated sodium bicarbonate aqueous solution and once with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After the solvent was distilled off, the residue (0.82 g) was recrystallized from a mixture of ether and isopropyl ether to give 2,2,2-trichloroethyl 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylate (0.71 g), mp 96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][C:12]([C:18]([O:20]C)=[O:19])=[CH:11][C:10]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[CH:22]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccccc3Cl)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OCc3ccccc3Cl)ccc2S(=O)(=O)CC1
Temperature: 65 °C
Reaction time: 20 h
Yield: 89.8 %

Procedure:
Into a solution of methyl 7-[(2-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (350 mg) in THF-methanol (7-3.5 ml) was added at room temperature a 2 M aqueous solution of potassium carbonate (0.9 mg), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, the reaction mixture was mixed with 1 N hydrochloric acid (10 ml) and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[(2-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (303 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C1C=CC=CC=1.[OH-].[Na+]>[C:14]([O:13][C:11](=[O:12])[C@H:10]([CH3:18])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(Cl)C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C[C@H](NCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To 65.0 g of benzylamine in 100 ml of benzene was added with stirring 25.0 g of tert-butyl 2-chloropropionate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C. for an additional one hour. At the end of this period, the reaction mixture was taken up in 70 ml of 2N NaOH solution and 80 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 33.2 g (90.0 percent) of N-benzylalanine tert-butyl ester, B.P. 164° C./14 mmHg.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:22]1([C:25]([NH2:33])([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH3:26])[CH2:24][CH2:23]1>>[CH:22]1([C:25]([NH:33][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:5][O:4][CH2:3]3)=[CH:11][N:10]=2)=[O:14])([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH3:26])[CH2:24][CH2:23]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)COC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (Example 142b) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (32.6 mg, 37%); MS (ESI, m/z): 459.5 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH2:10][C:11]1[C:12]([CH3:23])=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:19]3[CH:20]=[CH:21][C:16]([C:15]4[O:14][N:13]=[C:12]([CH3:23])[C:11]=4[CH2:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:24])=[CH:17][CH:18]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)OCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)OCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid benzyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6](/[C:19](/[C:27]2[NH:32][C:31](=[O:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].O>CO.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:5]=[C:6](/[C:19](/[C:27]2[NH:32][C:31](=[O:33])[C:30]([C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18]
Reactant: CCN(CC)CCCOc1ccc(/C(=C\[C@H]2CCC(=O)C2)c2ccc(C(F)(F)F)c(=O)[nH]2)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CC)CCCOc1ccc(/C(=C\[C@H]2CCC(O)C2)c2ccc(C(F)(F)F)c(=O)[nH]2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
Sodium borohydride (4.4 mg) was added to a solution of 6-{(E)-1-{3-chloro-4-[3-(diethylamino)propoxy]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-one obtained in Example 1-83 (30 mg) in methanol (0.15 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water and brine were added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether to give the title compound (10 mg, 34%) as a pale yellow solid.