Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2C[N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C([C:57](NC)=[O:58])=C(OC)C(C2C=NN(CCCO)C=2)=CC=1>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]([C:15](=[O:20])[NH:16][CH3:19])[C:18]=2[O:58][CH3:57])[CH:7]=[N:6]1
Reactant: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1OC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(OC)c3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 6-amino-3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methoxy-N-methyl benzamide (Compound 30C). 1H NMR (CD3OD, 400 MHz): δ 8.31 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 6.96 (t, J=2.0 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 4.33 (t, J=6.8 Hz, 2H), 3.99 (m, 4H), 3.90 (s, 3H), 3.66 (s, 3H), 3.58 (t, J=6.3 Hz, 2H), 3.19 (d, J=21.5 Hz, 2H), 2.92 (s, 3H), 2.11 (m, 2H), 1.22 (t, J=7.1 Hz, 6H). MS (ESI): m/z=722.53 [M+H]+. HPLC: tR=3.63 min (ZQ3: polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F:22][C:23]([F:43])([F:42])[C:24]([C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1)([CH3:26])[CH3:25]>CN(C=O)C>[OH:18][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:29]4[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:23]([F:43])([F:42])[F:22])[O:31][N:30]=4)=[O:34])[CH:21]=[CH:20][CH:19]=3)=[N:7][CH:8]=[N:9]2)=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1O
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)ncnc2cc1O
Temperature: 60 °C
Reaction time: 72 h
Yield: 23 %

Procedure:
To a stirred solution of 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol (100 mg, 0.35 mmol) prepared as described in example 95A in anhydrous DMF (3 mL), was added phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (111 mg, 0.35 mmol) and the mixture was heated to 60° C. for 2 h. Additional phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (50 mg, 0.16 mmol) was added and heating was continued for a further 72 h. Concentration in vacuo followed by purification via preparative reverse phase HPLC (eluted with a gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O), afforded 1-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (40 mg, 23%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.93 (brs, 1H), 9.83 (s, 1H), 9.11 (s, 1H), 8.47 (s, 1H), 7.56 (dd, J=2.1, 2.1 Hz, 1H), 7.53 (s, 1H), 7.40 (dd, J=8.1, 8.1 Hz, 1H), 7.26 (dd, J=8.1, 8.1 Hz, 1H), 7.21 (s, 1H), 6.96 (m, 1H), 6.88 (s, 1H), 3.98 (s, 3H), 1.54 (s, 6H); LC-MS (ESI) m/z 504 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH:12]=[CH2:13])[CH:3]=1.Br[CH2:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:23])=[C:20]([F:22])[CH:21]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH:12]=[CH:13][C:17]2[N:18]=[C:19]([Cl:23])[C:20]([F:22])=[CH:21][C:16]=2[CH2:15]1)(=[O:11])[CH3:10]
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2cc(Cl)ccc21

Procedure:
Compound 9C was prepared from 9B and 1B by a route analogous to that used for the preparation of 1D. HPLC Rt=3.146 min; LCMS Found: (M+H)+=337.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:15][C:16]([OH:18])=[O:17])=[CH:9][NH:10]2.[C:19](=O)([O-])O.[Na+]>CO>[CH3:19][CH:15]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[Br:5])[NH:10][CH:9]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1c[nH]c2cccc(Br)c12
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CC(C(=O)O)c1c[nH]c2cccc(Br)c12
Reaction time: 0.5 h

Procedure:
To methanol (10 mL), thionyl chloride (0.76 mL) was added dropwise at −15 to −10° C., followed by stirring for 30 minutes. To the mixture, (4-bromo-1H-indol-3-yl)acetic acid (Chemical and Pharmaceutical Bulletin, 33(9), 3696-3708 (1985), 1.32 g) was added, followed by stifling at room temperature for 2 hours. To the reaction mixture, an aqueous saturated sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried and then concentrated. The residue was washed with diisopropyl ether/n-hexane (1:2) to obtain the titled compound having the following physical properties (1.26 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:11][NH2:12])[CH2:9][NH2:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-])=O.[N:23]#[C:24][Br:25]>>[BrH:25].[C:1]([O:5][C:6]([CH:8]([CH2:9][NH2:10])[CH2:11][N:12]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:24]1[NH2:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(CN)CN
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N#CBr
Product: Br
Product: CC(C)(C)OC(=O)C(CN)Cn1c(N)nc2ccccc21

Procedure:
1-(2-tert-Butoxy carbonyl aminopropyl)-2-aminobenzimidazole hydrobromide was prepared by the method of Example 1 using 2-tert-butoxycarbonyl aminopropylamine and 2-fluoro-nitrobenzene as starting materials. The cyclization reaction using cyanogen bromide gave the desired material as a solid which was collected by filtration MS 290 (M+1). 1H NMR (DMSO): δ 0.74 (s, 9H,) 0.96 (d, 3H), 3.67 (m, 3H), 6.57 (d, 1H), 7.03(m, 3H), 8.44 (s, 2H, NH2), 12.35 (broad s, NH).
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH2:9][OH:10])=[O:6]>C1C=CC=CC=1.CS(C)=O.C(N(CC)CC)C>[O:1]=[C:2]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=[O:10])=[O:6]
Reactant: O=C(CCC(=O)N1CCC[C@H]1CO)NCCCN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: O=C[C@@H]1CCCN1C(=O)CCC(=O)NCCCN1CCCC1=O
Reaction time: 1 h
Yield: 65.1 %

Procedure:
N-{4-Oxo-4-[3-(2-oxo-1-pyrrolidinyl)propylamino]butanoyl}-L-prolinol (85 mg) was dissolved in a mixed solvent of benzene (0.18 ml), DMSO (0.5 ml) and triethylamine (0.18 ml), and sulfur trioxide pyridine complex (200 mg) was added thereto under ice-cooling. After 1 hour's stirring at a temperature of 10°-15° C., the reaction mixture was treated in the same manner as in Example 10-C) to give 55 mg of N-{4-oxo-4-[3-(2-oxo-1-pyrrolidinyl)propylamino]butanoyl}-L-prolinal.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][CH2:18][C:19]1[O:24][C:23](=[O:25])[C:22]([CH3:26])=[C:21]([OH:27])[C:20]=1[CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:29][O:30][CH2:31]Cl>C1COCC1>[CH2:10]([O:17][CH2:18][C:19]1[O:24][C:23](=[O:25])[C:22]([CH3:26])=[C:21]([O:27][CH2:29][O:30][CH3:31])[C:20]=1[CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCCl
Reactant: Cc1c(COCc2ccccc2)oc(=O)c(C)c1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(C)c(COCc2ccccc2)oc(=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylethylamine (2.1 ml) was added to a solution of 6-(benzyloxy)methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (2.60 g) in THF (50 ml), and after stirring the mixture at room temperature for one hour, chloromethyl methyl ether (921 μl) was added at 0° C. and the mixture was stirred at room temperature for one hour. After concentrating the reaction solution under reduced pressure, water was added to the residue, extraction was performed with AcOEt, and the organic layer was dried with Na2SO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→1/1) to obtain 6-(benzyloxy)methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:5][C:4]=1[F:20].[CH3:23][C:24]([O:27][C:28]([N:30]1[CH2:35][CH:34]=[C:33](OS(C(F)(F)F)(=O)=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])[CH3:25].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][C:24]([O:27][C:28]([N:30]1[CH2:31][CH:32]=[C:33]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]3=[O:19])=[CH:5][C:4]=2[F:20])[CH2:34][CH2:35]1)=[O:29])([CH3:23])[CH3:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 108 h

Procedure:
A mixture of (S)-(−)-N-[[3-[4-trimethylstannyl-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (690 mg), 3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (step 2 of EXAMPLE 20, 500 mg), tris(dibenzylideneacetone)dipalladium(0) (14 mg) and triphenylarsine (37 mg) in N-methyl-2-pyrrolidinone (7.5 mL) is degassed, stirred under N2 at ambient temperature for 4.5 days, diluted with ethyl acetate, washed with water (3×40 mL) and saline (20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 120 g), eluting with a gradient of methanol/methylene chloride (1/99-2/98), and those fraction having an Rf=0.27 by TLC (methanol/chloroform, 2×5/95) are pooled and concentrated to give the title compound, 1H NMR (CDCl3, 400 MHz) 7.39, 7.22, 7.13, 7.01, 5.92, 4.82, 4.06, 3.80, 3.67, 3.61, 2.47, 2.03, 1.49δ.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:27](O)=[O:28])[CH3:26])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:56])[CH:39]([CH2:52][CH:53]([CH3:55])[CH3:54])[NH:40][C:41](=[O:51])[CH:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(N[C@H](C(NCC(N[C@H](C(O)=O)C)=O)=O)CC1C=CC(O)=CC=1)=O)(C)(C)C.C(OC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1C=CC=CC=1)N)C1C=CC=CC=1>>[CH2:30]([O:37][C:38](=[O:56])[CH:39]([CH2:52][CH:53]([CH3:54])[CH3:55])[NH:40][C:41](=[O:51])[CH:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH:43][C:27](=[O:28])[CH:25]([CH3:26])[NH:24][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(NC(=O)CNC(=O)C(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CC(NC(=O)C(N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)CC(NC(=O)C(Cc1ccccc1)NC(=O)C(C)NC(=O)CNC(=O)C(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When equivalent quantities of N-t-butoxycarbonyl-DL-tyrosylglycyl-DL-alanine and DL-phenylalanyl-DL-leucine benzyl ester are substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine and L-phenylalanyl-L-leucine benzyl ester, respectively in Example 12 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-DL-tyrosylglycyl-DL-alanyl-DL-phenylalanyl-DL-leucine benzyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([C:2]3[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)[N:3]=3)[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccc(-c2nc(C)cc(Cl)n2)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C)cc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)n2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
1.17 g of 4-chloro-2-(4-methoxyphenyl)-6-methylpyrimidine and 1.38 g of 1-diphenylmethylpiperazine were dissolved in 20 ml of N,N-dimethylformamide. After the addition of 1 g of potassium carbonate, the mixture was stirred for 6 hours at 80° to 85° C. The reaction mixture was poured into ice-water, then the resulting crystals were filtered off, washed with water and dried. Whereby 2.2 g of crystals were obtained. 1.85 g of the crystals were obtained by recrystallizing with ethanol. Melting point is 147° to 149° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([O:12][CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3C(OC(C)(C)C)=O)=[CH:6][CH:5]=[CH:4][C:3]1=2.FC(F)(F)C(O)=O>ClC(Cl)C>[NH:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:8]=1[CH2:9][CH2:10][CH2:11][C:2]2=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc2c1CCCC2=O
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCc2c(OC[C@H]3CCCN3)cccc21

Procedure:
13.2 6.5 g of tert-butyl (R)-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yloxy-methyl)pyrrolidine-1-carboxylate are reacted with trifluoroacetic acid in dichloroethane and worked up as described, giving 4.1 g of 5-((R)-1-pyrrolidin-2-ylmethoxy)-3,4-dihydro-2H-naphthalen-1-one; Rt.: 1.325 min; [M-1-H]+246.2.
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg:5].[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([Mg:5][Br:6])[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]([CH:1]2[CH2:3][CH2:2]2)[OH:12])=[CH:9][CH:8]=1
Reactant: [Mg]
Reactant: O=Cc1ccc(Br)cc1
Reactant: BrC1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Br[Mg]C1CC1
Product: OC(c1ccc(Br)cc1)C1CC1
Temperature: 5 °C

Procedure:
Solution of cyclopropyl magnesium bromide is prepared from cyclopropyl bromide (12 g, 0.099 mol) and magnesium turnings (3.0 g, 0.123 mol) in tetrahydrofuran (60 mL) by using standard Grignard reaction procedure. This reagent solution is cooled to 5° C. and a solution of 4-bromobenzaldehyde (15.0 g, 0.081 mol) in tetrahydrofuran (30 mL) is added to it over a period of 15 minute at 10-15° C. The reaction mixture is treated with aqueous ammonium chloride solution and extracted with ethyl acetate (50 mL). The organic layer is concentrated under reduced pressure and the residue is purified by column chromatography (silica gel 230-400 mesh) to give (4-bromophenyl)-cyclopropylmethanol.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6].[CH3:12][S-:13].[Na+]>CS(C)=O.O>[CH:10]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[S:13][CH3:12])=[O:11]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(C#N)ccc1C=O
Reaction time: 0.75 h

Procedure:
3-Fluoro-4-formylbenzonitrile (2.00 g, 13.4 mmol; Example 8A) was dissolved in DMSO (27 ml), and sodium methanethiolate (1.50 g, 21.5 mmol) was added with ice-bath cooling. The mixture was stirred for 45 min and then diluted with water (100 ml). The resulting precipitated product was filtered off with suction, washed with water and dried under reduced pressure. This gave 1.36 g (51% of theory) of the target compound as a yellow crystalline solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].C[O:22][C:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:23](=[O:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)CCCCCCc1ccc2c(n1)NCCC2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCCCCCc1ccc2c(n1)NCCC2
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of diisopropylamine (5.17 mL, 36.9 mmol) in anhydrous tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium in hexanes (16.2 mL of a 2.5 M solution). After 5 minutes, t-butyl acetate (4.97 mL, 36.9 mmol) was added. After an additional 5 minutes, 7-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-heptanoic acid methyl ester 29-4 (3.4 g, 12.3 mmol) in tetrahydrofuran (30 mL) was added and the solution was warmed to −40° C. for one hour. The reaction mixture was then poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with ethyl acetate to give 29-5 as a yellowish oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[O-:14][Mn](=O)(=O)=O.[K+].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>C1COCC1>[CH2:20]([N:22]1[C:23](=[O:24])[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:11](=[O:14])[S:12]1)[CH3:21]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCN=C=O
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1sc(=O)n(-c2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
Reagents: 4-nitrophenyl isothiocyanate (1.17 g, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), ethyl isocyanate (0.51 ml, 6.5 mmol) in THF.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[F:11].O.[S-2].[Na+].[Na+].CI>C(O)C.O>[F:11][C:3]1[CH:4]=[C:5]([S:8][CH3:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#CSc1ccc(N)c(F)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CI
Solvent: CCO
Solvent: O
Product: CSc1ccc(N)c(F)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
A solution of the product of Example 26, Step A, 4-amino-3-fluorophenyl thiocyanate (500 mg, 2.97 mmol), in ethanol (7.5 mL) was added to a solution of sodium sulfide monohydrate (714 mg, 2.97 mmol) in water (1.5 mL) and the mixture heated at 50° C. for 2 hours. Methyl iodide (464 mg, 3.27 mmol) in ethanol (0.5 mL) was added and heating continued for a further 4 hours. The reaction mixture was then diluted with water (15 mL) and extracted with Et2O (4×5 mL). The combined Et2O extracts were washed with water (3×10 mL), saturated NaCl (10 mL), and dried (Na2SO4), followed by removal of the solvent under reduced pressure to afford a pale yellow oil. This material was purified by dry flash column chromatography on silica (5% Et2O/hexanes as eluant) to give 2-fluoro-4-methylthioaniline as a pale yellow oil (407 mg, 87%); 1H NMR (400 MHz, CDCl3) δ 7.01 (dd, J=11.3, 2.1 Hz, 1 H), 6.94 (ddd, J=8.2, 2.1, 0.9 Hz, 1 H), 6.71 (dd, J=9.3, 8.2 Hz, 1 H), 3.67 (br s, 2 H), 2.42 (s, 3 H). Step C: Preparation of 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]-benzoic acid
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[H][H].C(N(CC)CC)C>O1CCCC1.[Pd]>[O:12]=[S:9]1(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]2[CH:14]=[CH:2][CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[C:5]=2[O:10]1
Reactant: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 0 °C
Yield: 75.1 %

Procedure:
120 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide are dissolved in 2.4 liters of tetrahydrofuran and the solution is hydrogenated with hydrogen for 40 minutes, in the presence of 41.3 g of triethylamine and 12.0 g of 5% palladium on carbon catalyst, under normal pressure and in the temperature range from 20° to 25° C. The mixture is filtered, the filtrate is concentrated, and the residue is taken up in 1300 ml of hot 90% aqueous ethanol. The insoluble constituents are separated and the solution is cooled to 0° C. The precipitate is separated and dried, affording 70 g of 2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 204°-205° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.Cl>>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Product: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CN)c1
Reaction time: 3 h
Yield: 93.8 %

Procedure:
Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-(3,4-dichloro-benzamido)phenoxy)phenyl)acetate (130 mg, 0.232 mmol) was treated with HCl (0.581 mL, 2.32 mmol), After stirring for 3 hours, the material was concentrated to yield 100 mg of methyl 2-(3-(aminomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3]([F:20])([F:19])[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[N:8]=1.C[Si](C)(C)[Si](C)(C)C.II.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:25][C:2]([F:1])([C:21]([F:22])([F:23])[F:24])[C:3]([F:19])([F:20])[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:18])[C:14]([OH:16])=[O:15])=[CH:9][C:7]=2[N:8]=1
Reactant: COC(=O)C(C)c1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: II
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C(=O)O)c1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A mixture of methyl 2-(2-heptafluoropropylbenzoxazol-5-yl)propionate (11.6 g, 0.0311 mol), hexamethyldisilane (6.81 g, 0.047 mol) and iodine (11.85 g, 0.047 mol) was stirred in refluxing toluene (110 ml) for 6 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed sequentially with water, saturated aqueous sodium thiosulfate solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting initially with dichloromethane and then with ethyl acetate:dichloromethane 1:4, to give 2-(2-heptafluoropropylbenzoxazol-5-yl)propionic acid (6.3 g).