Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:7]=1[Cl:17])=[O:4].[NH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.C1COCC1>[Cl:17][C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:18][CH2:19][CH2:20][OH:21]
Reactant: NCCO
Reactant: N#Cc1cc(NC(=O)CBr)c(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1cc(NC(=O)CNCCO)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution of 2-bromo-N-(2-chloro-5-cyano-3-nitrophenyl)acetamide (30 mg, 0.094 mmol) in DCM (2 mL) was added a solution of 2-aminoethanol (5.75 mg, 0.094 mmol) in THF (2 mL) then CESIUM CARBONATE (30.7 mg, 0.094 mmol) was added. After stirring at room temperature for 1.5 h, LC-MS indicated completion. After concentration purification via flash chromatography (0-100% EtOAc in Hexane, 12 g) gave N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)amino)acetamide as a yellow solid (15 mg).
Reaction SMILES: C([N:4]1[C:17]2[C:16]([C:18](=[O:20])[NH2:19])=[CH:15][C:14]([CH2:21][CH3:22])=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([CH2:23][CH3:24])[CH:9]=2)(=O)C.Cl>CO.CC(C)=O>[CH2:21]([C:14]1[CH:15]=[C:16]([C:18](=[O:20])[NH2:19])[C:17]2[NH:4][C:5]3[C:10]([O:11][C:12]=2[CH:13]=1)=[CH:9][C:8]([CH2:23][CH3:24])=[CH:7][CH:6]=3)[CH3:22]
Reactant: CCc1ccc2c(c1)Oc1cc(CC)cc(C(N)=O)c1N2C(C)=O
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: CCc1ccc2c(c1)Oc1cc(CC)cc(C(N)=O)c1N2
Temperature: 0 °C

Procedure:
A solution containing 1.4 g of the just-mentioned phenoxazine compound in 10 ml of methanol and 8 ml of acetone was treated with 10 ml of concentrated hydrochloric acid and heated to reflux for 30 minutes. The mixture was cooled to 0° C. and the solids filtered. The solid was slurried in 10 percent sodium carbonate. To this was then added 50 ml of 1:1 acetone:ethylacetate. The mixture was filtered and the layers split. The organic phase was dried over sodium sulfate and the solvent removed to give crude 3,7-diethylcarbamoyl(10H)phenoxazine.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[CH:10]=[CH2:9]
Reactant: Oc1cccc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(O)c1

Procedure:
A solution of resorcinol (40 g, 0.4 mol) and allyl bromide (32 g, 0.26 mol) in acetone (500 ml) containing potassium carbonate (55 g, 0.4 mol) was heated, with stirring, under reflux for 10 hours. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by means of PrepPak 500/silica on a Waters Associates Prep LC/System 500 at 250 ml/min using hexane-ethyl acetate (8:1, v/v) as a liquid phase. 3-Allyloxyphenol was isolated as a colorless oil (20 g, 51% based on ally bromide); NMR (chloroform-d): δ4.78 (s, OH), 4.55 (d, J=5.5 Hz, CH2CH=CH2), 5.29-5.50 (m, CH2CH=CH2), 6.07 (m, CH2CH=CH2), 7.18 (t, J=8.5 Hz, H-5), 6.46-6.58 (m, remaining Ar--H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C([Li])CCC.[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Li]C1C=CC2C(=CC=C(OC)C=2)C=1>>[O:25]=[C:19]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Agent: [Li]c1ccc2cc(OC)ccc2c1
Product: CCOC(=O)C(=O)c1ccc2cc(OC)ccc2c1

Procedure:
2-Bromo-6-methoxynaphthalene was converted to the 2-lithio derivative by reaction with n-butyllithium. Diethyl oxalate was then reacted with the 2-lithio-6-methoxynaphthalene to afford ethyl α-keto-6-methoxy-naphth-2-ylacetate. The latter compound was reacted with hydroxylamine hydrochloride and sodium acetate to provide ethyl α-hydroxyimino-6-methoxynaphth-2-ylacetate. A solution of 17.55 g of the oxime in 600 ml of methanol containing 5.3 g of zinc metal dust and 135 ml of 50% (v/v) aqueous formic acid was stirred at 0° C. for three hours. After filtering the reaction mixture, the solvent was removed by evaporation to give 10.3 g of ethyl α-amino-α-(6-methoxynaphth-2-yl)acetate.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9][CH:8]2[CH2:24][C:25]([OH:27])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:48]([CH3:50])[CH3:49])C2C=CC=CC=2N=N1.CNC>C1COCC1.ClCCl>[CH3:49][N:48]([CH3:50])[C:25](=[O:27])[CH2:24][CH:8]1[CH2:9][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:11][C:12](=[O:13])[N:7]1[CH2:6][C:5]1[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of [1-(4-fluorobenzyl)-4-(benzyloxycarbonyl)-6-oxo-piperazin-2-yl]acetic acid (0.8 g, 2.0 mmol) in THF (30 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.07 g, 4.68 mmol) and dimethylamine (2.0 M in THF, 2.34 mL, 4.68 mmol). The reaction was stirred overnight. The reaction mixture was then diluted with dichloromethane, washed with aqueous hydrochloric acid, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography with silica gel using hexanes and ethyl acetate as eluents to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.23-7.38 (m, 7H), 7.01 (t, J=8.6 Hz, 2H), 5.0-5.24 (m, 3H), 4.45-4.60 (m, 1H), 3.88-4.26 (m, 4H), 3.02-3.20 (m, 1H), 2.62-2.95 (m, 6H), 2.42-2.62 (m, 1H), 2.24 (d, J=15.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][O:60][C:61](=[O:68])[CH2:62][CH2:63][NH:64][CH:65]([CH3:67])[CH3:66]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:59][O:60][C:61](=[O:68])[CH2:62][CH2:63][N:64]([CH:65]([CH3:67])[CH3:66])[C:12](=[O:14])[C:11]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=[C:9]([CH3:8])[CH:10]=1
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)O)c1
Reactant: COC(=O)CCNC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCN(C(=O)c1cc(C)cc(OCCNc2ccncc2)c1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
To a stirred solution of 3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate (0.025 g) and TBTU (0.021 g) in DMF (1 ml) was added DIPEA (0.022 ml) followed by 3-isopropylamino-propionic acid methyl ester (0.01 g) after 3 min. The reaction was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.031 g) as a colourless oil, by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][CH2:53][C@H:54]2[NH:58][CH2:57][C@H:56]([OH:59])[CH2:55]2)[CH2:51][CH2:50]1>CN(C=O)C.C(Cl)Cl>[CH:49]1([NH:52][CH2:53][C@@H:54]2[CH2:55][C@@H:56]([OH:59])[CH2:57][N:58]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:51][CH2:50]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: O[C@H]1CN[C@H](CNC2CC2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1C[C@H](O)C[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
To a mixture of {5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (238 mg, 0.46 mmol), HOBt (69 mg, 1.2 eq.) and EDC (105 mg, 1.2 eq.) in DMF (8 mL) was added TEA (69 mg, 2.5 eq.) and (3R,5S)-5-cyclopropylaminomethyl-pyrrolidin-3-ol (312 mg, 4 eq.). After stirring at rt for 1 day, the reaction was diluted with DCM (200 mL), washed with ammonium chloride solution, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 52 mg of the titled compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11](Br)[CH:12]=[CH2:13].O1CCOCC1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:13]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Br:1])[CH:12]=[CH2:11]
Reactant: Brc1nc2ccccc2[nH]1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCn1c(Br)nc2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 2-bromo-1H-benzo[d]imidazole (0.400 g, 2.04 mmol), allyl bromide (0.35 mL, 4.08 mmol), 1,4-dioxane (15 mL), and 2 M aqueous sodium hydroxide solution (15 mL, 3.00 mmol) stirred for 2 h at 100° C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic phase was separated and washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 20% ethyl acetate/petroleum ether) to afford 1-allyl-2-bromo-1H-benzo[d]imidazole (0.251 g, 52%) as a yellow oil. MS (ESI, pos. ion) m/z 237, 239 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C=[CH:9][CH:10]=1)C(O)=O.[Cl:11][C:12]1[CH:13]=[C:14](I)[CH:15]=[C:16]([Cl:18])[CH:17]=1.[C:20]([OH:23])(=[O:22])[CH3:21].C(CC(C)(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC([O-])=O.[Ag+].C(OCC)(=O)C.ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:4]2[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:21]=2[C:20]([OH:23])=[O:22])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: CC(=O)O
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Clc1cc(Cl)cc(I)c1
Agent: [Ag+]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)CC(C)(C)C
Solvent: ClCCl
Product: O=C(O)c1ccc(Br)cc1-c1cc(Cl)cc(Cl)c1
Temperature: 120 °C

Procedure:
Palladium acetate (11.4 mg 0.05 mmol), AgOAc (217 mg 1.3 mmol), 3-bromobenzoic acid (201 mg, 1.0 mmol), 3,5-dichloroiodobenzene (819 mg, 3.0 mmol) and acetic acid (200 μL) were combined and heated at 120° C. for 5.5 h. After purification light tan solid was obtained, 183 mg (53%), mp 182-186° C. (isooctane). Rf-0.38 (1/9 ethyl acetate-dichloromethane). 1H NMR (300 MHz, acetone-d6) δ 7.32 (br s, 2H), 7.36 (d, J-8.4 Hz, 1H), 7.44 (br s, 1H), 7.79 (d, J-8.4 Hz, 1H), 8.05 (br s, 1H). Carboxylate proton signal was not observed. 13C NMR (75 MHz, acetone-d6) δ 122.2, 127.6, 127.7, 133.2, 133.3, 134.6, 135.0, 139.4, 144.5, 166.7. A signal for one aromatic carbon could not be located. FT-IR (neat, cm1) υ 1699, 1299, 857. Anal. calcd for C13H7BrCl2O2 (346.00 g/mol): C, 45.13; H, 2.04. Found: C, 45.17; H, 2.04. The 1H NMR and 13C NMR spectra are shown in FIGS. 27A&B, respectively.
Reaction SMILES: [N:1]1([NH2:15])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[NH2:14].[N:16]1([NH2:30])[C:28]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=[C:17]1[NH2:29]>>[CH:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13]1[N:1]3[NH:15][CH:17]=[N:14][C:2]3=[N:3][C:4]=1[CH:5]=[N:6]2.[N:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:28]1[N:16]3[NH:30][CH:2]=[N:29][C:17]3=[N:18][C:19]=1[CH:20]=[N:21]2
Reactant: Nc1nc2cnc3cccnc3c2n1N
Reactant: Nc1nc2cnc3ccccc3c2n1N
Product: c1ccc2c(c1)ncc1nc3nc[nH]n3c12
Product: c1cnc2c(c1)ncc1nc3nc[nH]n3c12

Procedure:
In step (2) of Reaction Scheme VIII, a 1H-imidazo[4,5-c]quinoline-1,2-diamine or 1H-imidazo[4,5-c][1,5]naphthyridine-1,2-diamine of Formula LXVI is treated with an ortho ester of Formula R2aC(O-alkyl)3 to provide a [1,2,4]triazolo[1′,5′:1,2]imidazo[4,5-c]quinoline or [1,2,4]triazolo[1′,5′:1,2]imidazo[4,5-c][1,5]naphthyridine of Formula LXVII. The reaction can be carried out by adding the ortho ester to a compound of Formula LXVI in a suitable solvent such as toluene. The reaction is carried out at a temperature high enough to drive off alcohol formed during the reaction; a Dean-Stark trap can be used to collect the volatiles.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[CH:16]/[CH2:17]O)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CS([Cl:24])(=O)=O.N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[CH:16]/[CH2:17][Cl:24])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](/C=C/CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](/C=C/CCl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4.37 g (16.35 mmol) of trans-(1E)-[4-(3-Hydroxy-propenyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 120 ml CH2Cl2 was treated at 0° C. with 1.4 ml (17.98 mmol) of methanesulfonylchloride, 1.97 ml (24.52 mmol) pyridine and 2 g (16.35 mmol) of DMAP. The reaction mixture was stirred at RT for 3 h, water (5 ml) was added and the reaction was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×), the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 3.51 g (75%) of trans-(1E)-[4-(3-Chloro-propenyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, mp: 42.5-43.9° C.; MS: 387 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([NH:24][C@@H:25]([CH2:30]O)[C:26]([O:28][CH3:29])=[O:27])=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1.CC(C)C(NC(C1ON=C(C2C=CC(NC(NC3C=CC(C(F)(F)F)=CC=3)=O)=CC=2)C=1)=O)C(OC)=O.S(Cl)(C)(=O)=O.CCN(CC)CC>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([NH:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27])=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Agent: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)cc2)no1)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1)C(=O)OC
Temperature: 25 °C
Yield: 29.2 %

Procedure:
(S)-methyl 2-(3-(4-(3-(2-fluorophenyl)ureido)phenyl)isoxazole-5-carboxamido)-3-hydroxypropanoate (compound of Example 275, 500 mg, 1.13 mmol) was taken in DCM and mesyl chloride (0.13 ml, 1.69 mmol) and Et3N (0.24, 1.69 mmol) were added and the reaction mixture was stirred at RT for half an hour. Water was added to quench the reaction and the organic layer was extracted with DCM. Organic layer was dried over Na2SO4 and concentrated under vacuum. Crude compound was purified by precipitation using DCM and petroleum ether to yield 140 mg (30%) of the required compound as white solid. MS: ES (+) m/z 425(M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 10.241 (s, 1H), 8.367 (s, 1H), 8.656 (d, 1H), 8.180 (t, 1H), 7.907 (d, 2H), 7.769 (s, 1H), 7.645 (d, 2H), 7.290 (m, 1H), 7.189 (t, 1H), 7.067 (m, 1H), 6.046 (s, 1H), 5.918 (s, 1H), 3.782 (s, 3H).
Reaction SMILES: O1C=CC=C1C(Cl)=O.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:16]=[C:17]=[S:18])=[O:15].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([F:41])[CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:16]=[C:17]=[S:18])=[O:15].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:17]([NH:16][C:14]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[O:15])=[S:18])=[C:36]([F:41])[CH:35]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccco1
Agent: O=C(N=C=S)c1ccco1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccco4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
2-Furancarbonyl isothiocyanate was prepared using commercially available 2-furancarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Furancarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 68%). Mass spectrometry value (ESI-MS, m/z): 468 (M++1)
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[NH2:5][C:6]1[N:14]=[C:13](Cl)[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[C@H:16]1[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]2[O:27][N:26]=[C:25]([CH3:28])[N:24]=2)[O:17]1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>CS(C)=O>[CH:1]([OH:4])=[O:3].[NH2:5][C:6]1[N:14]=[C:13]([NH:34][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[C@H:16]1[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]2[O:27][N:26]=[C:25]([CH3:28])[N:24]=2)[O:17]1
Reactant: Cc1noc([C@H]2O[C@@H](n3cnc4c(N)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CC(=O)O
Reactant: NC1CCCC1
Solvent: CS(C)=O
Product: Cc1noc([C@H]2O[C@@H](n3cnc4c(N)nc(NC5CCCC5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO

Procedure:
Intermediate 17 (0.048 g), cyclopentylamine (0.06 ml) in DMSO (0.05 ml) were heated in a sealed vial (eg Reacti vial™) at 90° C. for 20 hrs. The crude material was purified by Autoprep HPLC, solvent was removed in vacuo and the residue freeze-dried to give the title compound as a pale yellow solid (0.006 g) LC/MS system A Rt=2.2 min, m/z=403(MH+)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:26]1CCOCC1)[CH3:25].ClC(OCC(C)C)=O.[Cl-].C([NH3+])C>O1CCCC1.CN(C)C=O>[CH2:24]([NH:26][C:18](=[O:20])[C@@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:25]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CC[NH3+]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
32 g (0.1 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 250 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 12.7 ml (0.1 mol) of N-ethylmorpholine and 13.1 ml (0.1 mol) of isobutyl chloroformate were then added and the solution was stirred at -10° C. for 20 minutes. To this mixture was then added a further 12.7 ml of N-ethylmorpholine followed by a solution of 8.15 g (0.1 mol) of ethylammonium chloride in 50 ml of dimethylformamide. The solution was stirred for 1 hour at 0° C. then left for 16 hours at room temperature. The solvents were removed by evaporation and the residue was triturated with 450 ml of ethyl acetate and washed successively with 200 ml of 1-N hydrochloric acid, 200 ml of water and 200 ml of 5% sodium bicarbonate solution. After drying over sodium sulphate and filtration, the solvent was removed by evaporation. The resulting oil crystallised slowly from ethyl acetate ether to yield 20.7 g of N-benzyloxycarbonyl-L-alanyl-L-proline ethylamide of melting point 110°-113° C. Evaporation of the mother liquors followed by treatment with ethyl acetate/ether gave a further crop of 1.2 g of melting point 107°-110° C.; total yield 68% [α]D20 =-96.0° (c=1.04% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[O:17])[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22].[CH3:23][Mg]Br>C1COCC1.CCOCC>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]([OH:17])[CH3:23])[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: C[Mg]Br
Reactant: COc1cc(CNC(=O)c2cc(C=O)nc(C)n2)ccc1F
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(CNC(=O)c2cc(C(C)O)nc(C)n2)ccc1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
A solution of N-(4-fluoro-3-methoxybenzyl)-6-formyl-2-methylpyrimidine-4-carboxamide (2 g, 6.59 mmol, Preparation #8) in THF (200 mL) was cooled to about −78° C. and methyl magnesium bromide was added drop wise (8.79 mL, 26.4 mmol, 3M in ether). Upon completion of addition, the reaction mixture stirred for about 4 h at −78° C. The reaction mixture was quenched with aqueous ammoniumchloride (20 mL) and the product extracted with EtOAc (2×100 mL). The organic layer was washed successively with water (1×50 mL), brine (1×50 mL), dried over sodium sulphate and concentrated under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-6-(1-hydroxyethyl)-2-methylpyrimidine-4-carboxamide (1 g, 47.6% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO): δ 9.40 (bs, 1H) 7.95 (s, 1H) 7.17-7.11 (m, 2H) 6.89-6.88 (m, 1H) 5.75-5.71 (m, 1H) 4.49-4.47 (m, 2H) 3.81 (s, 3H) 2.68 (s, 3H) MS m/z=320 (m+H)+.
Reaction SMILES: CN1CCOCC1.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]1)=[O:14])(C)(C)C.ClC(O[CH2:28][CH:29]([CH3:31])[CH3:30])=O.Cl.[NH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:46])[F:45])[CH:38]=1)=[O:36]>O1CCCC1>[C:29]([O:23][C:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:13](=[O:14])[NH:33][CH2:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:45])[F:46])[CH:38]=2)=[O:36])[CH2:20][CH2:19]1)=[O:22])([CH3:31])([CH3:30])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C1CCN(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
Add N-methylmorpholine (3 equiv; 631.52 mmoles; 69.66 mL) to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.20 equiv; 252.61 mmoles; 57.92 g) in tetrahydrofuran (THF) (400 mL). Cool the mixture to −10° C. with a dry ice-acetone bath. Add isobutyl chloroformate (1.1 equiv; 231.56 mmoles; 30.26 mL) dropwise while maintaining the temperature below −5° C. After 30 min at −5°-10° C., add 2-amino-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethanone hydrochloride (54.23 g; 1.00 equiv; 210.51 mmoles) suspended in THF (300 mL) and stir the mixture in the bath at −5° C. for 20 min. Stir for 1 hour at RT. Add water and EtOAc, then wash the organic layer with water and saturated aqueous sodium chloride. Dry over MgSO4, filter and remove solvent in vacuo. Suspend the crude in MTBE and stir for 2 hours. Filter the solid and dry in vacuo to give 1-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-4-carboxylic acid tert-butyl ester (64.44 g; 70.79% yield).