Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>O>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NCC(=O)Nc2ccccc2C(=O)O)cc1
Yield: 81.9 %

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol) , para-methoxyaniline (9.55 g, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature, and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. to yield 7.62 g (85%) of the title compound as a white solid; 1H NMR (DMSO-d6) δ 13.5 (broad s, 1H), 12.04 (s, 1H), 8.73 (dd, J=8.4, J=1.0, 1H), 7.93 (dd, J=7.8, J=1.8, 1H), 7.59 (td, J=8.0, J=1.8, 1H), 7.13 (td, J=7.6, J=1.2, 1H), 6.73 (dt, J=8.8, J=2.2, 2H), 6.54 (dt, J=9.2, J=2.4, 2H), 6.2 (broad s, 1H), 3.77 (s, 2H), 3.62 (s, 3H); 13C NMR (DMSO-d6) δ 171.18, 168.95, 151.53, 142.2, 140.58, 134.12, 131.12, 122.62, 119.42, 116.03, 114.57, 113.42, 55.20, 49.76; MS (EI, m/z) 300 (M+).
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:26])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[F:27][C:28]1[CH:29]=[C:30]([C:36]2[C:44]3[C:39](=[N:40][CH:41]=[N:42][C:43]=3[NH2:45])[NH:38][N:37]=2)[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1>>[NH2:45][C:43]1[N:42]=[CH:41][N:40]=[C:39]2[N:38]([CH:2]([C:4]3[O:5][C:6](=[O:26])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)=[CH:16][CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:37]=[C:36]([C:30]3[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:28]([F:27])[CH:29]=3)[C:44]=12
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCC2)cc1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCCC4)cc3)c3ncnc(N)c23)c1
Yield: 26.5 %

Procedure:
The title compound was made in a similar way as that of the example 134, step a, from 3-(1-hydroxyethyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-isochromen-1-one (Intermediate B47, 380 mg, 1.088 mmol) and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 310 mg, 1.197 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-isochromen-1-one (170 mg, 0.288 mmol, 26.5% yield) as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[OH:27])[N:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[F:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:27])[C:20]=1[C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:38](=[O:39])[O:40][CH2:41][CH3:42])[CH2:4]2)[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3c(O)cccc3F)nc2c1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)NC[C@@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Temperature: -60 °C
Yield: 38.9 %

Procedure:
To a stirred solution of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (200 mg, 0.54 mmol) in 12 mL THF was added diisopropyl ethylamine (188 μL, 1.08 mmol) at room temperature. The mixture was cooled to −60° C., and a solution of ethyl chloroformate (52 μL, 0.54 mmol) in 0.6 mL THF was added dropwise. After allowing the reaction to warm to room temperature, the mixture was partitioned between H2O and CH2Cl2. The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 hexanes:CH2Cl2 gave ethyl ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (92 mg, 38%). LC/MS: m/z 439.5 (M+H)+ at 2.40 min (10% -99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]1([S:7]([C:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=3)[N:14]=2)([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:33]1([C:38](N2C=CN=C2)=[S:39])C=CN=[CH:34]1.CN>C1COCC1.C(Cl)Cl>[C:1]1([S:7]([C:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:27]=[CH:28][C:29]([NH:30][C:38]([NH:33][CH3:34])=[S:39])=[CH:31][CH:32]=3)[N:14]=2)([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccc2)nc(-c2ccc(N)cc2)n1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=S)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)cc(C(C)(C)S(=O)(=O)c3ccccc3)n2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of 4-[4-[2-(benzenesulfonyl)propan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (0.091 g, 0.2 mmol) in THF (1.0 mL) was added to a solution of di(imidazol-1-yl)methanethione (0.050 g, 0.28 mmol) in DCM (1.0 mL) and the resulting solution was stirred at 40° C. for 30 minutes. A solution of methylamine (2.0M in THF, 0.5 mL, 1.0 mmol) was added and the reaction was stirred at 40° C. for 30 minutes and the solvent was evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (63 mg).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])[CH3:3].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:13]>>[F:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:12](=[O:13])[O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(F)c1cc(N)no1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Product: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)no1
Yield: 100 %

Procedure:
Prepared from 5-(2-fluoropropan-2-yl)isoxazol-3-amine (40 mg, 0.278 mmol) and 4-chlorophenyl chloroformate (54 mg, 0.28 mmol) according to the procedure described in Example 122A Step 3, to afford 4-chlorophenyl 5-(2-fluoropropan-2-yl)isoxazol-3-ylcarbamate as a colorless solid (83 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 8.11 (brs, 1H), 7.36-7.40 (m, 2H), 7.12-7.17 (m, 2H), 6.83 (s, 1H), 1.76 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 299 (M+H)+.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([C:27]1[O:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:25]([C:27]1[O:31][C:30]([C:32]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:13][N:14]=3)=[CH:23][CH:22]=2)=[O:33])=[CH:29][CH:28]=1)[CH3:26]
Reactant: CCc1ccc(C(=O)O)o1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(CC)o3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 1.4 g of 5-ethyl-2-furancarboxylic acid (prepared as described by Perry et al., Appl. Organomet. Chem. 10, 389–392 (1996) from furan-2-carboxylic acid; m.p. 90° C.) and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals having the phase sequence X 80 (N62) I.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[CH:5]1[CH:10]=[C:9]2[CH:11]=[CH:12][C:13]([OH:26])=[C:14]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][C:16]=3[OH:25])[C:8]2=[CH:7][CH:6]=1>>[P:1]1([Cl:4])[O:26][C:13]2[CH:12]=[CH:11][C:9]3[C:8]([C:14]=2[C:15]2[C:24]4[C:19]([CH:18]=[CH:17][C:16]=2[O:25]1)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:7][CH:6]=[CH:5][CH:10]=3
Reactant: ClP(Cl)Cl
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Product: Clp1oc2ccc3ccccc3c2c2c(ccc3ccccc32)o1

Procedure:
The phosphinite-phosphites are synthesized as follows. Phosphorus trichloride is reacted with 1,1'-bi-2-naphthol to give the 1,1'-binaphthyl-2,2'-diyl phosphorochloridite. The chloridite is then reacted with either 1,1'-bi-2-naphthol or 2,2'-biphenol, followed by diphenylchlorophosphine. These reactions are all conducted stepwise in toluene with excess triethylamine present. The product is isolated by filtering off the triethylamine hydrochloride, then removing the solvent under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([O:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][C:3]=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:19]2=[N:18]1.N1C=CC=CC=1.[C:34](Cl)(=[O:38])[C:35]([CH3:37])=[CH2:36]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:34](=[O:38])[C:35]([CH3:37])=[CH2:36])=[CH:4][C:3]=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:19]2=[N:18]1
Reactant: C=C(C)C(=O)Cl
Reactant: COc1ccc2nn(-c3cc(OCCCO)cc(C(C)(C)C)c3O)nc2c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCCOc1cc(-n2nc3ccc(OC)cc3n2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
In a 2 L flask equipped with a mechanical stirrer, a thermometer and an addition funnel which was protected from moisture with a drying tube were placed 37.16 g (0.1 mol) of the benzotriazole of Example 3, 800 mL of dry toluene and 17 mL (0.21 mol) of dry pyridine. A solution of 13 mL (0.128 mol) of methacryloyl chloride (freshly distilled) in 10 mL of toluene was added to the mixture over 30 minutes. The reaction mixture was stirred overnight at room temperature (<25° C.). A white precipitate (pyridinium chloride) was separated by filtration and washed with toluene. The filtrate and washings were combined, washed with 1N hydrochloric acid, water, aqueous sodium bicarbonate and water successively, then dried with anhydrous sodium sulfate and evaporated. The residue (ca. 41 g) was dissolved in a mixture of 1 L of methanol and 500 mL of methylene chloride by heating in a water bath at 45° C. The resulting solution was filtered to remove a small amount of insoluble materials and diluted with 250 mL of methanol. The solution was cooled slowly at room temperature, in a refrigerator and finally then placed in a freezer where the temperature was reduced to about -5° C. The resulting crystals were separated by filtration, washed with 250 mL of cold methanol/methylene chloride (90/10 v/v) and dried in vacuo to give 38.4 g of 99.7% pure product m.p. 114°-116° C.
Reaction SMILES: [Na+:1].N[C@H:3]1[C@@H:6]([CH2:7][O:8][C:9](=[O:11])[NH2:10])[N:5]([S:12]([O-:15])(=[O:14])=[O:13])[C:4]1=[O:16]>CC(C)=O.O>[Na+:1].[C:9]([O:8][CH2:7][CH:6]1[N:5]([S:12]([O-:15])(=[O:14])=[O:13])[C:4](=[O:16])[CH2:3]1)(=[O:11])[NH2:10]
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)OCC1CC(=O)N1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.62 g (6.20 mmol) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 180 ml of acetone/water (2:1) and treated with 3.27 g (6.83 mmol) of (Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetic acid 2-benzthiazolyl thioester. The mixture is stirred at room temperature for 12 hours. A further 60 mg (0.12 mmol) of the aforementioned thioester are added thereto and the stirring is continued for a further 3 hours. Acetone is removed under reduced pressure and 50 ml of water are added thereto. The crystals obtained are filtered off and washed with a small amount of water. The mother liquor is partially evaporated (37°, 15 mmHg) and the residue is chromatographed (MCI gel, H2O). After lyophilization, there are obtained 2.28 g (77%) of (3S,4S)-3-[2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butyoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:10]=2[CH:11]=1.O[CH2:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][CH2:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([NH2:19])=[O:18])[CH:3]=1
Reactant: NC(=O)c1cccnc1CO
Reactant: Oc1cc(Br)cc2ncccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1cccnc1COc1cc(Br)cc2ncccc12
Yield: 45 %

Procedure:
100 mg 7-Bromo-quinolin-5-ol, 77.5 mg of 2-(hydroxymethyl)nicotinamide 3.7, 233.5 mg of triphenylphosphine and 205 mg of Di-tertbutyl-azodicarboxylate (DBAD) were dissolved in 2.5 mL of DCM and 7.5 mL of THF under Argon at room temperature. After 14 h the precipitate was collected and dried. The mother liquor was concentrated and the formed precipitate again collected to yield 72 mg Example 22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([F:21])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-fluoro-3-trifluoromethyl-aniline (69 mg, 0.39 mmol). The title compound was obtained as a solid (95 mg, 57% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.82 (1H, s), 9.01 (2H, s), 8.68 (1H, s), 8.09 (1H, m), 7.97 (1H, m), 7.54 (1H, m). MS m/z: 510.03, 512.02 [M+H]+.
Reaction SMILES: [C:1]([N:5]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:6][CH2:7][N:8]([CH2:19][CH2:20][C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl.[F:46][C:47]1[CH:48]=[C:49]([CH:53]=[C:54]([F:56])[CH:55]=1)[CH2:50][CH2:51][NH2:52]>C(O)C>[CH:32]1([N:5]([C:1](=[O:4])[CH2:2][CH2:3][NH:52][CH2:51][CH2:50][C:49]2[CH:53]=[C:54]([F:56])[CH:55]=[C:47]([F:46])[CH:48]=2)[CH2:6][CH2:7][N:8]([CH2:19][CH2:20][C:21]2[C:29]3[S:28][C:27](=[O:30])[NH:26][C:25]=3[C:24]([OH:31])=[CH:23][CH:22]=2)[C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: C=CC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cc(F)cc(F)c1)C1CCCCC1
Temperature: 25 °C

Procedure:
Benzyl {2-[acryloyl(cyclohexyl)amino]ethyl}[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]carbamate prepared as in Example 12 step i) (0.33 g), triethylamine (0.176 mL) and 3,5-difluorophenethylamine hydrochloride (0.244 g) were stirred in ethanol (3 mL) at 60° C. for 44 h. The mixture was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (50 mL), the organic extracts washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash silica chromatography with 10% methanol/dichloromethane as eluent. The pure fractions were evaporated to dryness to afford the sub-title product (0.35 g) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]=[CH2:25])[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]3[O:35][CH2:25]3)[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 72 h

Procedure:
To a solution of methyl 2-[(4′-chloro[1,1′-biphenyl]-4-yl)-sulfonylamino]-pent-4-eneoate 12c (9.2 g, 24.1 mmol) in CH2Cl2 (175 mL), NaHCO3 (4.2 g, 50 mmol) and water (100 mL) at 0 C., is slowly added m-chloroperbenzoic acid (57-86%) (19.4 g, ˜80 mmol). The reaction is stirred for 72 hours. The mixture is diluted with aqueous NaHCO3 and this mixture is extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layer is washed with brine, dried over MgSO4, filtered and concentrated to an oil. Purification of this compound is accomplished by column chromatography with 40% ethyl acetate in hexanes as the eluent to give the desired product.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:10][C:11]=1[NH2:12])(=O)C.[OH-].[K+].O>C(O)C>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)=[CH:7][C:6]=1[CH2:5][NH2:4]
Reactant: CC(=O)NCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(CN)c2)CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
To a solution of compound 16 (0.70 g, 2 mmol) in ethanol (20 mL) was added 4M solution of KOH in H2O (4 mL, 16 mmol) and the mixture was stirred at 90° C. for 12 h. The mixture was concentrated under reduced pressure to get a brown oil material, which was resolved over silica column eluting with CH2Cl2:MeOH (95:5) and then changing to (90:10) to get compound 17 as light brown thick oil (0.51 g, 84%). IR (KBr) νmax. cm−1: 3421, 3411 (NH), 3053 (Ar—H), 2936 (Alph-H), 1697 (C═O), 1606, 1578 (C═C), 1244 (C—N), 1166 (C—O). 1H NMR (500 MHz, CDCl3) δ=1.47 (s, 9H, (C(CH3)3), 3.10 (br. s, 4H, 2CH2), 3.22 (br. s, 4H, 2CH2), 4.08 (s, 2H, CH2), 4.58 (br. s, 2H, NH2), 5.18 (br. s, 2H, NH2), 6.68 (dd, 1H, J=2.3, 9.3 Hz, H-6), 6.73 (br. s, 1H, H-2), 6.81 (d, 1H, J=9.2 Hz, H-5). 13C NMR (125.7 MHz, CDCl3) δ=28.05 (C(CH3)3), 42.43 (CH2), 45.26 (CH2), 50.54 (CH2), 79.75 (C(CH3)3), 112.01 (aromatic-C), 112.08 (aromatic-C), 117.00 (aromatic-C), 130.28 (aromatic-C), 134.08 (aromatic-C), 143.08 (aromatic-C), 154.70 (CO). Calculated (%) for C16H26N4O2 (306.21); C, 62.72; H, 8.55; N, 18.29. found (%); C, 62.66; H, 8.62; N, 18.20.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([OH:11])=[CH:9][C:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[N:6]=1.Cl[CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN(C)C=O.C(OCC)C>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[CH2:16][O:11][C:10]1[C:5]([O:4][CH3:3])=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[CH:9]=1
Reactant: CCc1cc(O)c(OC)nc1C
Reactant: ClCc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1cc(OCc2nc3ccccc3o2)c(OC)nc1C
Temperature: 60 °C
Yield: 33.5 %

Procedure:
A quantity of 60% sodium hydride in mineral oil (24 mg, 0.6 mmol) was added to a solution of 2-methoxy-3-hydroxy-5-ethyl-6-methylpyridine (77 mg, 0.46 mmol) in dry dimethylformamide (2 mL). After gas evolution ceased, 2-(chloromethyl) benzoxazole (100 mg, 0.6 mmol) was added and the reaction mixture warmed at 60° C. for one hour. The reaction was then cooled, diluted with diethyl ether, the ether extract washed with water, dried (Na2SO4), filtered and evaporated to give 151 mg of crude mixture. This mixture was flash chromatographed on silica gel, eluting with 0.5% methanol/chloroform. Combined appropriate fractions gave 46 mg (32%) of oily product.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(OC)[C:11]([C@@H:13]1[CH2:17][C:16](=[O:18])[N:15]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH2:14]1)=[O:12].Cl>O1CCCC1>[C:1]1([C:11]([C@H:13]2[CH2:14][N:15]([C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:18])[CH2:17]2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON(C)C(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Under a nitrogen atmosphere, phenylmagnesium bromide (3N diethyl ether solution, 15 ml) was added dropwise to a tetrahydrofuran solution (50 ml) of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxamide (2.49 g, 9.0 mmol), followed by stirring at room temperature for 30 minutes. To the reaction solution was added 1 mol/l hydrochloric acid (50 ml) under ice cooling and the mixture was extracted with ethyl acetate (8 ml×2). The organic layer was washed with saturated saline (100 ml) and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. Elution with n-hexane/ethyl acetate (1/1) afforded the title compound (2.36 g, 89%) as a pale yellow oil.
Reaction SMILES: Cl.[C:2](=[NH:7])([O:4][CH2:5][CH3:6])[CH3:3].Cl.[F:9][C:10]([F:14])([F:13])[CH2:11]N.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:5]([O:4][C:2](=[N:7][CH2:11][C:10]([F:14])([F:13])[F:9])[CH3:3])[CH3:6]
Reactant: CCOC(C)=N
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(C)=NCC(F)(F)F
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
Ethyl acetimidate hydrochloride (1.23 g, 9.95 mmol) and 2,2,2-trifluoroethylamine hydrochloride (1.35 g, 9.95 mmol) were dissolved in CH2Cl2 (32 mL)/H2O (3.2 mL). K2CO3 (0.69 g, 4.98 mmol) was added and stirred for 30 minutes. The two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layer was dried with Na2SO4 and concentrated to give 1.48 g of N-(2,2,2-Trifluoro-ethyl)-acetimidic acid ethyl ester as a light yellow liquid in 87% yield.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.Cl>ClCCl.O>[CH3:1][NH:2][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNCCc1ccc([N+](=O)[O-])cc1
Reaction time: 15 h

Procedure:
2.7 g (86 mmol) of methylamine are dissolved in 120 ml of dichloromethane while cooling with ice. 4.9 g (21 mmol) of 4-(2-bromoethyl)-nitrobenzene are added and the mixture is allowed to come up slowly to ambient temperature. After 15 hours stirring the solvent is eliminated in vacuo and the residue taken up in water. An acid pH is created using 2 N hydrochloric acid and the mixture is washed with dichloromethane. The aqueous phase is then adjusted to a basic pH using 4 N sodium hydroxide solution and the product is extracted with dichloromethane.