Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([Si](C)(C)[O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[NH2:40])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:40][N:39]([CH2:38][CH2:37][CH2:36][OH:35])[CH3:41])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:4][CH:3]=1
Reactant: CN(N)CCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCO)NC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and N-[3-(t-butyl-dimethyl-silanyloxy)-propyl]-N-methyl-hydrazine trifluoroacetate (1:1) as starting materials; the silyl protecting group was lost during reaction and work-up; LC-MS (UV peak area/ESI) 91.5%, 418.1139 (M+H)+.
Reaction SMILES: ClCO[C:4](=[S:6])[CH3:5].[N+:7]([C:10]1[NH:11][CH:12]=[CH:13][N:14]=1)([O-:9])=[O:8].[Na+].[I-].[CH:17](N(C(C)C)CC)(C)C>CC#N>[C:4]([CH2:17][N:11]1[CH:12]=[CH:13][N:14]=[C:10]1[N+:7]([O-:9])=[O:8])(=[S:6])[CH3:5]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=S)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=S)Cn1ccnc1[N+](=O)[O-]

Procedure:
To a solution of the chloromethylthioacetate in MeCN (100 mL) was added 2-nitroimidazole (3 g), NaI (1 g) and diisopropylethyl amine (DIEA) and refluxed. A precipitate formed after 3 h. Additional DIEA (3 mL) was added to the reaction mixture and refluxed for 4 h. Volatiles were removed, EtOAc (300 mL) added to the residue, and the ensuing mixture filtered. The filtrate was washed with water, 1M aqueous citric acid, brine, and concentrated to yield a residue. The residue was separated by column chromatography using 0-90% EtOAc/Hexane as eluent to yield 1-thioacetylmethyl-2-nitroimidazole (vi, 3.15 g) that was chlorinated as described above in Example 1A to yield compound vii.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:7]=[CH:6][C:5]=12.[C:20]([O:24][C:25](=[O:38])[C@H:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:23])([CH3:22])[CH3:21].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:20]([O:24][C:25](=[O:38])[C@H:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:13]([C:12]2[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4=[N:1][O:2][N:3]=[C:4]4[CH:9]=3)=[N:19][CH:18]=[CH:17][CH:16]=2)=[O:15])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:21])([CH3:22])[CH3:23]
Reactant: C[C@@H](Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccnc1Oc1ccc2nonc2c1
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.30) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(benzo[2,1,3]oxadiazol-5-yloxy)-nicotinic acid and (R)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[Cl:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[Cl:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:17]1[N:28]=[N:29][C:2]2[CH:1]3[CH2:7][CH:4]([C:3]=2[CH:16]=1)[CH2:5][CH2:6]3
Reactant: COP(=O)(CC(=O)c1ccc(F)cc1Cl)OC
Reactant: O=C1C(=O)C2CCC1C2
Reactant: NN
Solvent: O
Product: Fc1ccc(-c2cc3c(nn2)C2CCC3C2)c(Cl)c1

Procedure:
yellow gum. MS (EI): 274.1 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(2-Chloro-4-fluoro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:29]=2[F:28])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4F)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 2,3-difluorobenzoyl chloride gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([C:18]1[S:19][C:20](Br)=[CH:21][C:22]=1[NH:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[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>[C:11]([O:15][C:16]([C:18]1[S:19][C:20]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:21][C:22]=1[NH:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
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: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(NS(=O)(=O)c3ccccc3C)c(C(=O)OC(C)(C)C)s2)cc1
Temperature: 70 °C
Yield: 87.7 %

Procedure:
To the mixture of 4-methylbenzeneboronic acid (38.0 mg, 0.279 mmol) and 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (40 mg, 0.0925 mmol) in 5:1 mixture of toluene/MeOH (2.0 mL) was added a solution of Pd(PPh3)4 (12.0 mg, 0.01 mmol, 10 mol %) in toluene (1.0 mL) followed by aqueous 2M Na2CO3 solution (0.1 mL, 0.2 mmol). The resultant reaction mixture was heated at 70° C. for 16 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC (1 mm, 60 A° using ethyl acetate/hexane (1:10) as an eluent furnished 3-(Toluene-2-sulfonylamino)-5-p-tolyl-thiophene-2-carboxylic acid tert-butyl ester (36.0 mg, 81% yield). 1H NMR (CDCl3, 300 MHz) 9.94 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.44-7.25 (m, 6H), 7.18 (d, J=8.1 Hz, 2H), 2.71 (s, 3H), 2.36 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:27][S+](C)C.[OH-].[K+].C(#N)C>O>[C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:27][O:21]3)=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[N:9]=1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[S+](C)C
Reactant: CC(C)Oc1cc(C=O)ccc1-c1cccc(NC(=O)C(C)(C)C)n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cc(C2CO2)ccc1-c1cccc(NC(=O)C(C)(C)C)n1
Temperature: 60 °C

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 2.99 g (8.79 mmol) N-t-butylcarbonyl-6-(2-isopropoxy-4-formylphenyl)-pyridin-2-ylamine, 1.79 g (8.79 mmol) trimethylsulfonium iodide, 0.98 9 (17.59 mmol) powdered potassium hydroxide, 44 mL acetonitrile, and 0.5 mL water. The reaction was heated to 60° C. for 2.5 hours, then cooled, filtered, and evaporated. The yellow oil was used directly, 3.3 g (˜100%).
Reaction SMILES: [CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@H:14]([O:16][C@:17]3([CH2:26][OH:27])[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@@H:18]3[OH:25])[C@H:13]([OH:28])[C@@H:12]([OH:29])[C@@H:11]2[OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@H:3]1[OH:33].[CH2:35](O)[C@H:36]1[O:41][C@H:40]([O:42][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:39](O)[C@@H:38](O)[C@@H:37]1O>>[CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@H:14]([O:16][C@:17]3([CH2:26][OH:27])[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@@H:18]3[OH:25])[C@H:13]([OH:28])[C@@H:12]([OH:29])[C@@H:11]2[OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@H:3]1[OH:33].[C:40]([O-:41])(=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:22][CH2:20][CH2:19][CH2:18][CH2:17][CH3:26]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@]3(CO)O[C@H](CO)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]

Procedure:
The procedure of Example 1 was repeated except that 10.08 g of raffinose was substituted for 3.4 g of sucrose. 6.65 g of raffinose oleate was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:21]([CH3:23])[CH3:22])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C=O)c1
Temperature: 60 °C
Yield: 98 %

Procedure:
To methyl 3-formyl-4-hydroxy-benzoate (10.0 g, 55.5 mmol), potassium carbonate (30.7 g, 222 mmol) and N,N-dimethylformamide (63 mL) was added 2-iodopropane (11.1 mL, 111 mmol). The mixture was heated at 60° C. for 18 hours. The mixture was filtered using ethyl acetate (200 mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and was washed with water (3×75 mL) and a saturated aqueous solution of sodium chloride (1×75 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield methyl 3-formyl-4-isopropoxy-benzoate (98%) as a yellow viscous liquid. ESI-MS m/z calc. 222.2, found 223.3 (M+1)+; Retention time: 1.51 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 8.17 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d, J=6.0 Hz, 6H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[CH2:15][NH2:16])([CH3:3])[CH3:2].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1.[NH2:29][C:30]1[C:35]2[O:36][CH2:37][C:38](=[O:40])[NH:39][C:34]=2[CH:33]=[CH:32][CH:31]=1>C1COCC1.CN(C=O)C>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=[CH:7][C:6]=1[CH2:15][NH:16][C:22]([NH:29][C:30]1[C:35]2[O:36][CH2:37][C:38](=[O:40])[NH:39][C:34]=2[CH:33]=[CH:32][CH:31]=1)=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)ccc1CN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc2c1OCC(=O)N2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2c1OCC(=O)N2
Temperature: 70 °C
Yield: 16 %

Procedure:
To a solution of 27a (0.85 g, 3.6 mmol) in THF (30 mL) was added CDI (2.1 mol eq, 1.24 g) and the mixture was heated at 70° C. overnight. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×20 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure (pale yellow oil, 1.25 g, quantitative yield). The oil obtained (0.6 g, 1.82 mmol) was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.29 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (1:1 EtOAc:petroleum ether) to obtain the product as a white solid (0.121 g, 0.29 mmol, 16% Yield). 1HNMR (DMSO, 400 MHz) δ 1.29 (s, 3H), 1.32 (s, 3H), 4.28 (d, 2H, J=6), 4.62 (s, 2H), 4.79 (m, 1H), 6.49 (dd, 1H, J=2), 6.80 (t, 1H, J=8), 7.25 (m, 4H), 7.71 (dd, 1H), 8.21 (s, 1H), 10.65 (s, 1H). [M+1] 423.97 (C20H20F3N3O4 requires 423.38).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]2[S:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.C(N(C(C)C)CC)(C)C.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[CH:15]=[N:16][S:17][C:18]=2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:32]
Reactant: O=C(O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (328 mg, 0.79 mmol) and diisopropylethylamine (0.41 mL, 2.37 mmol) in DMF (2 mL) were added O-(2-vinyloxy-ethyl)-hydroxylamine (163 mg, 1.58 mmol), EDCI (303 mg, 1.58 mmol) and HOBt (213 mg, 1.58 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, and washed with water then a saturated aqueous solution of sodium hydrogen carbonate, then brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, TBME in cyclohexane) to afford the title compound as a yellow foam (194 mg, 49%). LCMS (method B): RT=3.99 min, [M+H]+=500.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=1.[Cl:17][C:18]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:19]=1[CH2:20][NH:21][CH2:22][C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:21]([CH2:20][C:19]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[C:18]=2[Cl:17])[CH2:22][C@H:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24])[CH:6]=1
Reactant: C[C@H](CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)C[C@@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A solution of (3-{3-bromo-propoxyl}-phenyl)acetic acid methyl ester (0.55 g, 1.5 mmol) and (S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine (0.55 g, 1.6 mmol) in acetonitrile (10 ml) was treated with solid potassium carbonate(0.4 g, 2.4 mmol).The reaction was heated to reflux and stirred for 48 h. Upon cooling to RT, the reaction was filtered through a pad of celite, washed with ethyl acetate, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatograph (Ethyl acetate:Hexane/20:80) to give the title compound as an oil (0.6 g, 67%). MS (ESI) 534.6 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.Cl.[NH2:25][CH2:26][CH2:27][N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30].C[O-].[Na+]>CCO>[CH3:32][S:29]([N:28]([CH3:33])[CH2:27][CH2:26][NH:25][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:2])(=[O:31])=[O:30]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CN(CCN)S(C)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 63.1 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.081 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (61 mg, 0.32 mmol), and NaOMe (17 mg, 0.32 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 22 mg of the title compound as an off-white solid. MS: (+) m/z 431.28 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7](=[O:11])[CH2:8][C:9]#[N:10])=[O:5])[CH3:2].[CH2:12]([O:14][CH:15](OCC)OCC)[CH3:13]>C(OC(=O)C)(=O)C>[C:9]([C:8](=[CH:15][O:14][CH2:12][CH3:13])[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])#[N:10]
Reactant: CCOC(=O)NC(=O)CC#N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(=O)NC(=O)OCC

Procedure:
A mixture of N-ethoxycarbonylcyanoacetamide (42 g), triethylorthoformate (40 g) and acetic anhydride (100 ml) is heated at reflux for one hour. The reaction is allowed to stand until cool and then is filtered, washing with ether, to yield α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:29])[O:27][CH3:28])[CH:18]=[CH:19][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:14][C:15]1[CH:16]=[C:17]([N:21]([CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:27][CH3:28])=[O:29])[C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)NCCCNc1cccc(Cl)c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)NCCCN(C(=O)CN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl(methyl)amino)acetic acid in CH2Cl2 at 0° C. under argon atmosphere was added DMAP, methyl 3-(3-chlorophenylamino)propylcarbamate and DCC. The reaction mixture was allowed to stir at room temperature for 24 h. The resulting suspension was filtered, the filtrate concentrated under reduced pressure and the crude residue was subjected to silica gel chromatography to give tert-butyl 2-((3-chlorophenyl)(3-(methoxycarbonylamino)propyl)amino)-2-oxoethyl(methyl)carbamate. 1H NMR δ 0.7-0.9 (m, 4H), 1.0-1.15 (m, 1H), 1.3 (s, 3H), 1.4 (s, 9H), 1.65 (m, 2H), 2.85 (m, 3H), 3.7 (m, 4H), 3.75 (m, 2H), 5.65 (m, 1H), 7.0-7.2 (m, 1H), 7.25 (m, 2H), 7.4 (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([Br:16])=[CH:9][N:8]=1)C.Cl.[Sn](Cl)(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>C1COCC1>[Br:16][C:10]1[CH:9]=[N:8][C:7]2[O:6][CH2:5][C:4](=[O:3])[NH:13][C:12]=2[CH:11]=1
Reactant: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1COc2ncc(Br)cc2N1
Temperature: 65 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Ethyl[(5-bromo-3-nitropyridin-2-yl)oxy]acetate (intermediate 212) (4.3 g, 14.1 mmol) was dissolved in anhydrous THF (10 mL) and concentrated HCl (10 mL) was added at 0° C. Tin chloride (5.0 g, 26.4 mmol) was added in small portions. The reaction was stirred for 1 hr and heated at 65° C. overnight. The reaction mixture was concentrated under reduced pressure, extracted with chloroform, dried over magnesium sulfate and concentrated. Chromatography on silica gel with methanol/chloroform gave the product as a light pink solid (1.2 g, 37% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])=[N:4][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[OH-:35].[Na+]>O>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]([NH2:30])=[O:35])=[N:4][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc2CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC(N)=O)n3)cc2CC1
Yield: 20.1 %

Procedure:
(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-phenoxy)-acetonitrile (0.100 g, 0.2 mmol) and NaOH (1 mL, 0.05 mol) (50% solution) and water (1 mL) were heated at 100° C. for 16 h. The resulting ppt was filtered from the reaction mixture. Product was isolated as a white solid (20 mg, 19%), MP=123-125. LCMS 497.22 (M+H), HPLC purity 99+%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.66 (m, 1H), 9.38 (s 1H), 8.65 (s, 1H), 8.16 (s, 1H), 7.90 d, 1H), 7.50 (m, 2H), 7.46 (s, 1H), 7.31 (d, 1H), 7.16 (m, 1H), 7.02 (m, 3H), 4.55 (s, 2H), 3.73 (m, 2H), 3.64 (m, 2H), 3.38 (m, 2H), 3.34 (s, 3H), 3.15-2.88 (m, 5H), 2.68 (m, 1H).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:38][C@H:39]([C:43]([C:45]([C:48]([F:51])([F:50])[F:49])([F:47])[F:46])=[O:44])[CH:40]([CH3:42])[CH3:41].Cl>C(Cl)Cl>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:38][C@H:39]([C:43]([C:45]([C:48]([F:49])([F:50])[F:51])([F:46])[F:47])=[O:44])[CH:40]([CH3:41])[CH3:42])=[O:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](N)C(=O)C(F)(F)C(F)(F)F
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Temperature: -22 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Dissolve Boc-Val-Pro-OH (314 mg, 1.0 mmol) in methylene chloride (4 mL) and add N-methylmorpholine (252 mg, 2.5 mmol). Cool to -22° C. and add isobutylchloroformate (136 mg, 1.0 mmol). Stir for 20 minutes and add to H-Val-CF2CF3.hydrochloride (1.1 mmol). Stir for 1 hour at -22° C., allow to warm to room temperature and stir for 3 hours. Purify by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (405 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].N1C=CC=CC=1.[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21].Cl>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])=[O:21]
Reactant: NCc1ccc(F)cc1F
Reactant: CC(C)(CCl)C(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(CCl)C(=O)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
28.6 g (0.20 mol) of 2,4-difluorobenzylamine and 19.0 g (0.24 mol) of pyridine are dissolved in 100 ml of toluene. 34.1 g (0.22 mol) of chloropivaloyl chloride are added dropwise to this solution at 20°-25° C. over the course of 15 minutes with ice-bath cooling. A suspension forms and is stirred for a further 3 hours at room temperature until the reaction is complete (GC check). For work-up, the pH is adjusted to between 1 and 2 using 50 ml of 2N hydrochloric acid. The white emulsion produced is extracted three times with 100 ml of toluene. The extract is washed with 100 ml of water, dried using magnesium sulfate and evaporated on a vacuum rotary evaporator. 49.2 g (94% of theory) of a yellow oil are obtained.