Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]3[CH2:28][O:27][CH2:26][CH:25]3[C:29]([OH:31])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:32][OH:33]>>[OH:33][NH:32][C:29]([C@H:25]1[C@@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[CH2:28][O:27][CH2:26]1)=[O:31]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3COCC3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3COC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 11 %

Procedure:
According to the procedure of Example 24, Step 3, 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid (0.6 g, 1.35 mmol) and hydroxylamine afforded (3S,4R)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide as an amorphous white solid (0.07 g, 11%) after HPLC purification, eluting with acetonitrile:water. MS: 458 (M+H)+
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24]CC)=[O:23])[C@@H:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@@H:17]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+]>CO>[F:39][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[C@@H:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@@H:17]2[C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)O
Reaction time: 20 h
Yield: 94.5 %

Procedure:
Diethyl (1S,2S,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-dicarboxylate (3.0 g, 5.19 mmol, intermediate from Example 1, Step 1) was dissolved 50 mL methanol. NaOH (20 mL, 5 N) was added at room temperature. The mixture was stirred for 20 hr. Solvent methanol and water were removed under vacuum. The residue was dissolved in 100 mL 2N aq. HCl. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum to give the title compound (2.7 g). 1H-NMR (CDCl3) δ: 7.71 (1H, s), 7.21 (2H, s), 6.98 (2H, m), 6.85 (2H, m), 4.43 (1H, q, J=6.4 Hz), 3.75 (2H, q, J=7.1 Hz), 3.35 (1H, m), 2.92-2.72 (3H, m), 2.38 (1H, m), 2.30 (1H, m), 1.60 (2H, m), 1.33 (3H, d, J=6.4 Hz), 0.80 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[CH:18]1([N:22]2[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.ClCCl.CO.N>C1COCC1>[CH:18]1([N:22]2[CH2:27][CH2:26][CH:25]([O:17][C:14]3[CH:15]=[CH:16][C:11]([C:5]4([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]4)=[CH:12][CH:13]=3)[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: OC1CCN(C2CCC2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Yield: 10.6 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (0.75 g, 3.19 mmol), 1-cyclobutylpiperidin-4-ol (0.45 g, 2.90 mmol), PPh3 (0.84 g, 3.19 mmol), THF (10 ml) and DIAD (0.66 ml, 3.19 mmol) were reacted together similarly to general procedure C. The crude material was subjected to chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:0.2) to provide the title compound (114 mg, 11%) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 1.71-1.77 (m, 4H), 1.85-1.90 (m, 4H), 1.94 (s, 6H), 1.99-2.06 (m, 4H), 2.12-2.16 (m, 2H), 2.20-2.28 (m, 2H), 2.45 (s, 2H), 2.58-2.70 (m, 2H), 2.79 (m, 1H), 3.46-3.53 (m, 2H), 3.72-3.75 (m, 2H), 4.39 (m, 1H), 6.91 (d, 2H), 7.26 (d, 2H). HRMS ESI+ m/z 373.2846 [MH]+.
Reaction SMILES: [CH:1]1(Cl)[CH2:4][CH2:3][CH2:2]1.[Mg].II.[F:9][C:10]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20](F)[C:11]=1[C:12]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])=O.[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O>O1CCCC1.[OH-].[Na+]>[CH:1]1([C:20]2[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:10]([F:9])[C:11]=2[C:12]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[N:14]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(F)c(C(=O)NC(C)(C)CO)c(F)c1
Reactant: ClC1CCC1
Agent: II
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(F)c(C2=NC(C)(C)CO2)c(C2CCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclobutyl chloride (5.64 g, 62 mmol) in anhydrous tetrahydrofuran (60 mL) was added magnesium turnings (1.56 g, 65 mmol) followed by a crystal of iodine, at room temperature. The mixture was stirred at room temperature for 1 hour, followed by a further hour under reflux. A solution of the fluoro compound from preparation 2 (7.23 g, 30 mmol) in tetrahydrofuran (80 mL) was cooled in an ice-bath to 0° C., and the grignard solution (40 mL) was added dropwise over 15 minutes, the cooling bath was removed and reaction warmed to room temperature and stirred for 2 hours. Further grignard solution (10 mL) was added and the reaction stirred for a further 30 minutes. The reaction was poured into a solution of ethylenediaminetetraacetic acid disodium salt (12 g) in 1N sodium hydroxide (100 mL), and the mixture extracted with ethyl acetate (1×200 mL, 2×100 mL). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure, to afford the title compound as a pale yellow oil, 8.31 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[C:11](=[O:20])[NH:12][CH2:13][CH:14]=[C:15]([CH2:16][C:17]([OH:19])=O)[C:5]2=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:54][C:55]1[N:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1>CN(C=O)C>[Cl:54][C:55]1[N:60]=[CH:59][C:58]([NH:61][C:17](=[O:19])[CH2:16][C:15]2[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]=3[C:11](=[O:20])[NH:12][CH2:13][CH:14]=2)=[CH:57][CH:56]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(O)CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21)Nc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid, prepared as in reference 16, (25 mg, 0.091 mmol) in DMF (1 mL) is added DIEA (35.4 mg, 0.274 mmol), HATU (38.2 mg, 0.100 mmol) and 6-chloro-pyridin-3-ylamine (35.2 mg, 0.274 mmol). The mixture is stirred at room temperature for 2 hours and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.05% TFA) to give N-(6-Chloro-pyridin-3-yl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide; 1H NMR (DMSO-d6) δ 3.43 (t, 2H, J=5.6 Hz), 3.84 (s, 2H), 5.96 (t, 1H, J=7.2 Hz), 7.12 (dt, 1H, J1=2.4 Hz, J2=8.8 Hz), 7.43 (d, 1H, J=8.8 Hz), 7.46 (dd, 1H, J1=4.4 Hz, J2=8.8 Hz), 7.67 (dd, 1H, J1=2.4 Hz, J2=10.8 Hz), 8.01 (dd, 1H, J1=2.8 Hz, J2=8.0 Hz), 8.19 (t, 1H, J=5.2 Hz), 8.54 (d, 1H, J=3.2 Hz), 10.48 (s, 1H), 12.04 (s, 1H); m/z [M++1] 385.0.
Reaction SMILES: [I:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:6][C:5]([NH2:13])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.CC1(C)[O:23][C:22]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[CH:21][C:20](=O)[O:19]1>>[C:27]([C:26]1[CH:25]=[C:24]([C:22](=[O:23])[CH2:21][C:20]([NH:13][C:5]2[CH:6]=[C:7]([N:8]3[CH:12]=[CH:11][CH:10]=[CH:9]3)[C:2]([I:1])=[CH:3][C:4]=2[N+:14]([O-:16])=[O:15])=[O:19])[CH:31]=[CH:30][CH:29]=1)#[N:28]
Reactant: Nc1cc(-n2cccc2)c(I)cc1[N+](=O)[O-]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cccc3)c(I)cc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from 4-iodo-2-nitro-5-pyrrol-1-yl-phenylamine (Example F2) (329 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (252 mg, 1.1 mmol) according to the general procedure M. Obtained as a yellow solid (436 mg).
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Fe].C(O)(=O)C>[CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1ccc(N)cc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 5.6 g. of N-decyl-3-phenyl-3-(4-nitrophenyl)propenamide in 80 ml. of glacial acetic acid, at 85° C., was added, portionwise, during 20 minutes, 3.85 g. of iron powder. The reaction was exothermic and the temperature was between 85° and 90° C. during the addition. After the addition, the reaction mixture was filtered and the solids were washed with further hot acetic acid. The combined acetic acid solutions were evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was removed, washed with water, and dried. Evaporation in vacuo gave an oil which solidified. The solid was recrystallized from isopropyl ether, giving 2.3 g. of the title compound, m.p. 90°-100° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][C:2]1=[O:10].CO[CH2:13][Cl:14].Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[Cl:14][CH2:13][C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2](=[O:10])[CH2:3][C:4]=2[CH:9]=1
Reactant: O=C1Cc2ccccc2O1
Reactant: COCCl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1Cc2cc(CCl)ccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3H-benzofuran-2-one (7.45 mmol) and chlormethyl methyl ether (9.31 mmol) in 15 ml of CH2Cl2 at 0° C. was slowly added SnCl4 (15 mmol). The reaction was slowly allowed to warm to ambient temperature and was stirred for 2 hours. The reaction was cooled to 0° C. and carefully quenched with saturated sodium bicarbonate. The mixture was extracted (2×EtOAc) and the organics were washed with brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude residue was chromatographed on silica gel using 20% EtOAc in hexanes as the eluant to obtain the title compound (55).
Reaction SMILES: [C:1]([CH:3]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]1=2)#[N:2].[CH3:17]I.[H-].[Na+].O>CN(C)C=O>[C:1]([C:3]1([CH3:17])[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]1=2)#[N:2]
Reactant: CI
Reactant: N#CC1Sc2ccccc2-c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C#N)Sc2ccccc2-c2ccccc21
Yield: 75 %

Procedure:
To a stirred solution of 6-cyano-6H-dibenzo[b,d]thiopyran (4.5 g; 0.02 mol) and CH3I (28.4 g; 0.2 mol) in 100 ml of dimethylformamide, 50% NaH (1.5 g; 0.03 mol) was added in small portions. After 16 hours at room temperature the mixture was poured into water and extracted with diethyl ether. The organic phase was washed with water and dried over Na2SO4. Evaporation of the solvent gave 6-cyano-6-methyl-6H-dibenzo[b,d]thiopyran (3.58 g; 0.015 mol; yield 75%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([OH:15])=[O:14])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]([C:13]([OH:15])=[O:14])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1
Reactant: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c(cc1C(=O)O)OCO2

Procedure:
6-nitro-benzo[1,3]dioxole-5-carboxylic acid (19 g, 90 mmol) in 500 mL ethanol was hydrogenated at 50 psig over 5 g of 5% palladium on carbon for 2 hours. Catalyst was filtered off with Celite® and solvent was removed in vacuo to give 6-amino-benzo[1,3]dioxole-5-carboxylic acid; 4.5 g (27%) used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CO[C:12]1[C:21](=[O:22])[C:16]2[N:17]=[C:18]([CH3:20])[S:19][C:15]=2[C:14](=[O:23])[CH:13]=1>C(O)C>[CH3:20][C:18]1[S:19][C:15]2[C:14](=[O:23])[CH:13]=[C:12]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[C:21](=[O:22])[C:16]=2[N:17]=1
Reactant: NCCN1CCOCC1
Reactant: COC1=CC(=O)c2sc(C)nc2C1=O
Solvent: CCO
Product: Cc1nc2c(s1)C(=O)C=C(NCCN1CCOCC1)C2=O

Procedure:
51.2 μl (0.39 mmol; 3 equivalents) of 4-(2-aminoethyl)morpholine is added to 27 mg (0.129 mmol) of 5-methoxy-2-methyl-4,7-dioxobenzothiazole in solution in 2 ml of anhydrous ethanol. The reaction mixture is stirred under reflux for 18 hours then the solvent is evaporated off under reduced pressure. The residue is purified on a silica column (eluent: 5% methanol in dichloromethane). The expected compound is obtained in the form of a red powder.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C1(N)CC1.[Cl:18][C:19]1[CH:56]=[CH:55][C:22]([C:23]2[C:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:39]5N(CC)C6C=C[C:48](C(O)=O)=[CH:49][C:41]=6[N:40]=5)[CH:35]=4)[N:30]=3)=[CH:27][C:26]([O:53][CH3:54])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]2[C:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:39]5[N:40]([CH:41]6[CH2:49][CH2:48]6)[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:35]=4)[N:30]=3)=[CH:27][C:26]([O:53][CH3:54])=[CH:25][CH:24]=2)=[CH:55][CH:56]=1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: NC1CC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CC4)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and cyclopropylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[NH:23][C:22]5[CH:24]=[CH:25][C:26]([C:28](O)=[O:29])=[CH:27][C:21]=5[N:20]=4)=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.ClC1C=CC(C2(C3C=CC(C=O)=CC=3)OCCO2)=CC=1.[NH2:51]C1C=C(C=CC=1N)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[NH:23][C:22]5[CH:24]=[CH:25][C:26]([C:28]([NH2:51])=[O:29])=[CH:27][C:21]=5[N:20]=4)=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc3)nc2c1
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: O=Cc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc3)nc2c1

Procedure:
2-{4-[2-(4-Chloro-phenyl)-[1,3]dioxolan-2-yl]-phenyl}-1H-benzoimidazole-5-carboxylic acid. This compound was prepared as described in Example 1 Step C from 4-[2-(4-chloro-phenyl)-[1,3]dioxolan-2-yl]-benzaldehyde (100 mg, 0.34 mmol) and 3,4-diamino-benzoic acid (53 mg, 0.34 mmol). The title compound was obtained as a tan solid 135 mg (92%). MS (ESI): mass calculated for C23H17ClN2O4, 420.1; m/z found, 421.1 [M+H]+, 419.1 [M−H]−. HPLC (Method B): Rt=2.43.
Reaction SMILES: C(OC(N[C@@H](C(C)C)C(O)=O)=O)(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.NCCO.C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:69][C:70]([C:72]1([NH:77][C:78]([CH:80]2[CH2:84][CH:83]([O:85][C:86]3[C:95]4[C:90](=[CH:91][C:92]([O:96][CH3:97])=[CH:93][CH:94]=4)[N:89]=[C:88]([C:98]4[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=4)[CH:87]=3)[CH2:82][N:81]2[C:104](=[O:124])[NH:105][CH:106]([C:111](=[O:123])[NH:112][CH:113]2C3C(=CC=CC=3)C[CH:114]2[OH:122])[C:107](C)([CH3:109])[CH3:108])=[O:79])[CH2:74][CH:73]1[CH:75]=[CH2:76])=[O:71])C>>[OH:122][CH2:114][CH2:113][NH:112][C:111]([C@@H:106]([NH:105][C:104]([N:81]1[CH2:82][C@H:83]([O:85][C:86]2[C:95]3[C:90](=[CH:91][C:92]([O:96][CH3:97])=[CH:93][CH:94]=3)[N:89]=[C:88]([C:98]3[CH:99]=[CH:100][CH:101]=[CH:102][CH:103]=3)[CH:87]=2)[CH2:84][C@H:80]1[C:78]([NH:77][C@:72]1([C:70]([OH:71])=[O:69])[CH2:74][C@H:73]1[CH:75]=[CH2:76])=[O:79])=[O:124])[CH:107]([CH3:109])[CH3:108])=[O:123]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: NCCO
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)NCCO)C(C)C)C(=O)O
Yield: 8 %

Procedure:
(2S)-tert-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 16 followed by reaction with 2-aminoethanol as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (3 mg, 8% yield), Purity by HPLC>90% M+H+660.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][NH2:19]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:19][CH3:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CNc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
4-Bromo-1-fluoro-2-nitrobenzene (1.50 g, 6.82 mmol) and K2CO3 (1.88 g, 13.6 mmol) were suspended in DCM (7 mL). MeNH2 (40% in H2O, 7 mL) was added slowly and the mixture stirred at room temperature for 4 h. The mixture was diluted with H2O and extracted with DCM (3×40 mL). The combined DCM layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the product as a bright orange solid (1.47 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[N:26]1[CH2:29][CH:28]([C:30](O)=[O:31])[CH2:27]1.CCN=C=N[CH2:38][CH2:39][CH2:40][N:41](C)C.Cl.Cl.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[CH:40]1([NH:41][C:30]([CH:28]2[CH2:27][N:26]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH2:12][C:11]([C:17]5[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=5)([C:13]([F:14])([F:16])[F:15])[O:10][N:9]=4)=[CH:7][C:2]=3[Cl:1])[CH2:29]2)=[O:31])[CH2:38][CH2:39]1
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
To a stirred solution of 1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 14, 0.1 g, 0.190 mmol) in dry DMF (3 mL) was added EDCl.HCl (0.055 g, 0.280 mmol), DIPEA (0.049 g, 0.380 mmol) and cyclopropyl amine (0.011 g, 0.190 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (10 mL), extracted with EtOAc (10 mL). Organic layer was washed with saturated solution of lithium chloride (3×20 mL), water (2×20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.8% methanol in DCM to afford sticky mass, which was crystallized by chloroform:pentane (1:9) to afford off white solid (0.020 g, 20%). 1H-NMR (400 MHz, CDCl3) δ: 0.50-0.53 (m, 2H), 0.77-0.82 (m, 2H), 2.72-2.76 (m, 1H), 3.26-3.30 (m, 1H), 3.60 (d, 1H, J=17.12 Hz), 4.00 (d, 1H, J=17 Hz), 4.23-4.33 (m, 4H), 5.72 (bs, 1H), 6.47 (d, 1H, J=8.6 Hz), 7.40 (dd, 1H, J1=8.44 Hz, J2=1.88 Hz), 7.46 (d, 1H, J=1.8 Hz), 7.62 (s, 2H); LC-MS (m/z): [M−H] 563.50.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([Cl:24])=[C:18]([CH3:25])[C:17]=1[Br:26])C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([Cl:24])=[C:18]([CH3:25])[C:17]=1[Br:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(Cl)c(C)c(Br)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(Cl)c(C)c(Br)c1NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A suspension of N,N-di(tert-butyloxycarbonyl)-2-bromo-4-chloro-6-methoxy-3-methyl-phenylamine (4.1 g, 9.1 mmol) in methanol (90 ml) was heated to reflux with potassium carbonate (3.77 g, 27 mmol) for 2 days. The reaction was filtered, washed with methanol, and the solvent of the filtrate was evaporated. The residue was dissolved in diethyl ether, washed with cold 1N aqueous hydrogen chloride solution and with saturated sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was stirred for 15 minutes with heptane. The product (2.6 g, 82%) precipitated as an off-white solid and isolated by filtration.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][N:14]([CH3:18])[CH2:15]CO>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:13][N:14]([CH3:18])[CH3:15])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)CCO
Agent: [Na]
Product: CN(C)CCOC(=O)c1ccc(O)cc1
Temperature: 110 °C

Procedure:
In a first step, 1 g (43 mmol) of sodium was dissolved in 20 ml of 2-(dimethylamino)ethanol. An amount of 3.0 g (22 mmol) of methyl 4-hydroxybenzoate was added and heated to 110° C. for 24 hours and then cooled to room temperature. The solvent was removed under reduced pressure and using a column chromatography (silica gel, chloroform-methanol), a white solid of 2-(dimethylamino)-ethyl 4-hydroxybenzoate was obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26](I)=[N:27][N:28](C3CCCCO3)[C:22]=2[CH:21]=1.[CH3:36][N:37]([CH3:58])[C:38]([CH:40]1[CH2:44][C:43]2[CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=[CH:48][C:42]=2[O:41]1)=[O:39]>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26]([C:46]3[CH:47]=[CH:48][C:42]4[O:41][CH:40]([C:38]([N:37]([CH3:36])[CH3:58])=[O:39])[CH2:44][C:43]=4[CH:45]=3)=[N:27][NH:28][C:22]=2[CH:21]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)c3cn2)c1F

Procedure:
This compound was prepared as a TFA salt by using procedures analogous to those described for the synthesis of Example 83 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Example 52, Step 5) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (Peak II from chiral separation, Example 4, Step 1). LCMS (M+H)+=481.0.