Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C@H:25]1[CH2:28][C@H:27]([NH2:29])[CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C@H:25]1[CH2:26][C@H:27]([NH:29][C:10](=[O:12])[C:9]([C:8]2[C:3]([Cl:2])=[N:4][CH:5]=[CH:6][CH:7]=2)([CH3:14])[CH3:13])[CH2:28]1
Reactant: CC(C)(C(=O)O)c1cccnc1Cl
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Intermediate 25 (216 mg, 1.083 mmol), intermediate 11 (198 mg, 0.903 mmol), HBTU (376 mg, 0.993 mmol) and triethylamine (377 μl, 2.71 mmol) were dissolved in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with saturated ammonium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give the crude material as a tan solid. The crude material was absorbed onto a plug of silica gel and purified by silica chromatography (hexane to ethyl acetate gradient) to provide N-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-2-(2-chloropyridin-3-yl)-2-methylpropanamide (220 mg, 0.549 mmol, 60.8% yield) as white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(O)cc12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(Oc3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
1-(1′-Acetyl-5-hydroxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (40 mg, 0.122 mmol) was dissolved in methylene chloride (1.5 mL). Thereafter, 4-fluorophenylboronic acid (34 mg, 0.244 mmol), copper(II) acetate (22 mg, 0.122 mmol), triethylamine (62 mg, 0.610 mmol), and molecular sieves 4A (40 mg) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 18 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate) to obtain 1-(1′-acetyl-5-(4-fluorophenoxy)spiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (30 mg, 56%) in the form of a light yellow solid.
Reaction SMILES: [C:1]([S:9][CH2:10][C@@H:11]([CH3:46])[C:12]([N:14]1[CH2:34][CH:33]([O:35][C:36]2[CH:41]=[CH:40][C:39]([CH:42]=[CH:43]OC)=[CH:38][CH:37]=2)[CH2:32][C@H:15]1[C:16]([O:18]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:47][C:48]1[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[C:51]([S:58]([NH2:61])(=[O:60])=[O:59])=[CH:50][C:49]=1[S:62]([NH2:65])(=[O:64])=[O:63].C1(OC)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(#N)C>[NH2:61][S:58]([C:51]1[C:52]([C:54]([F:56])([F:57])[F:55])=[CH:53][C:48]2[NH:47][CH:43]([CH2:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH:33]4[CH2:34][N:14]([C:12](=[O:13])[C@H:11]([CH3:46])[CH2:10][S:9][C:1](=[O:8])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C@H:15]([C:16]([OH:18])=[O:17])[CH2:32]4)=[CH:41][CH:40]=3)[NH:65][S:62](=[O:63])(=[O:64])[C:49]=2[CH:50]=1)(=[O:59])=[O:60]
Reactant: Nc1cc(C(F)(F)F)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: COC=Cc1ccc(OC2C[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)[C@H](C)CSC(=O)c3ccccc3)C2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: COc1ccccc1
Solvent: CO
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CC(Oc2ccc(CC3Nc4cc(C(F)(F)F)c(S(N)(=O)=O)cc4S(=O)(=O)N3)cc2)C[C@H]1C(=O)O

Procedure:
To a mixture of (S)-1-[(S)-3-(benzoylthio)-2-methyl-1-oxopropyl]-4-[4-(2-methoxyethenyl)phenoxy]-L-proline, diphenylmethyl ester (3.6 g., 5.66 mmole), 4-amino-6-(trifluoromethyl)-1,3-benzenedisulfonamide (1.8 g., 5.7 mmole) and anisole (3.5 ml.) in 80 ml. of acetonitrile is added 120 mg. of p-toluenesulfonic acid. The reaction is essentially complete after refluxing for one hour. The solvent is removed under vacuum and the residue is triturated with diethyl ether to give a solid. The solid is purified by chromatography on an LPS-1 column eluted with ethyl acetate:pyridine:acetic acid:water (2400:50:15:27). After removal of the solvents on a rotary film evaporator using benzene to azeotrope off the acetic acid and pyridine, 3.8 g. of a homogeneous solid is obtained. Approximately half this material is passed through an LH-20 column (methanol) to give an analytically pure sample of (S)-4-[4-[[7-(aminosulfonyl)-3,4-dihydro-1,1-dioxo-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazin-3-yl]methyl]phenoxy]-1-[(S)-3-(benzoylthio)-2-methyl-1-oxopropyl]-L-proline; m.p. 170°-182° (foams); [α]D =-24.6° (c=1.0%, methanol). TLC (silica, methylene chloride:methanol:acetic acid; 8:1:1) Rf =0.47.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:15]=1)[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=[O:29].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][C:6]1[CH:15]=[C:2]([CH:28]([C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[OH:29])[CH:3]=[CH:4][C:5]=1[O:16][CH3:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COc1ccc(Br)cc1O[Si](C)(C)C(C)(C)C
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Yield: 69.5 %

Procedure:
(5-Bromo-2-methoxyphenoxy)-tert-butyldimethylsilane (0.98 g, 3.09 mmol), n-butyl lithium (1.24 ml, 3.09 mmol), and 3,5-dimethoxybenzaldehyde (0.47 g, 2.81 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give [3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-(3,5-dimethoxyphenyl)-methanol as an oil (0.79 g, 69%), HPLC purity was 98.3% at 2.55 min. (90/10 ACN/0.1% H3PO4): 1HNMR (CDCl3) δ 6.92-6.78 (m, 3H, Ar), 6.53 (d, J=2 Hz, 2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.66 (d, J=3 Hz, 1H, CH), 3.78 (s, 3H, single OCH3), 3.76 (s, 6H, 2OCH3), 2.15 (d, J=3 Hz, 1H, OH), 0.97 (s, 9H, 3OCH3), 0.13 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:32][CH:33]([F:35])[F:34])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Na+].C(O)(=O)C>CO.O>[F:35][CH:33]([F:34])[O:32][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:36])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(NS(=O)(=O)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(NS(=O)(=O)CC)cc1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A solution of [4-difluoromethoxy-3-(4-ethanesulfonylaminobenzyl)-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.051 g) in methanol (5.0 mL) and water (0.5 mL) was treated with 5.0 M aqueous sodium hydroxide solution (0.25 mL), and the resulting mixture was left to stand at room temperature for 1 hour. The mixture was acidified by the addition of glacial acetic acid, concentrated under reduced pressure, and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane, methanol and glacial acetic acid (100:1:0.5 to 25:1:0.125 by volume) gave title compound as a cream solid (0.032 g).
Reaction SMILES: C([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[C:31](O)=[O:32])C1C=CC=CC=1.S(Cl)(Cl)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)(Cl)Cl>[CH2:20]([C@@H:18]1[CH2:19][N:14]2[C:15]([C:16]3[NH:8][C:9]([C:31]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:32])=[N:10][C:11]=3[N:12]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:27])=[N:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C(=O)O)n2Cc1ccccc1
Reactant: C1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C(=O)N3CCCCC3)nc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Compound 47a (70 mg, 0.158 mmol) obtained in Example 47 was dissolved in chloroform (2 mL), to the solution was added thionyl chloride (40 μL, 0.548 mmol, 3.4 equivalents), and the mixture was stirred at 60° C. for 30 minutes. To the reaction solution was added piperidine (320 μL, 3.24 mmol, 20 equivalents) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and directly purified by silica gel column chromatography (chloroform:methanol=98:2). Thereafter, the title compound (17 mg, 26%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:27][CH:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:27][CH:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:8])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
1.00 g of 4-chlorobenzoic acid and 1.45 g of dicyclohexylcarbodiimide (DCC) were solved in 30 ml of tetrahydrofuran, and the resulting solution was stirred at the room temperature for 2 hours. Subsequently, 1.35 g of diethyl aminomalonate hydrochloride and 0.65 g of triethylamine were added to 20 ml of tetrahydrofuran, and after stirring for about 20 minutes, the previously prepared solution was added to the this resulting solution. The mixed solution was then stirred at the room temperature for 2 hours to complete the reaction. After filtration of the solution and concentration of the filtrate, the concentrated filtrate was diluted with 50 ml of chloroform, washed with 20 ml of water twice and subjected to dry filtration to yield 1.72 g (86%) of diethyl 4-chlorobenzamidomalonate.
Reaction SMILES: COCN[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].[C:20]1([O:28][CH3:29])[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:22][CH3:23].O1CCCC1>O1CCCC1>[CH3:23][O:22][C:21]1[C:20]([O:28][CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]1)=[O:6]
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccccc1OC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: -17 °C
Reaction time: 3 h

Procedure:
Into a 500-mL jacketed-bottom-drain resin pot fitted with a five-joint head equipped with a mechanical stirrer, a thermocouple, a reflux condenser topped with a nitrogen bubbler, a septum, and a stopper was placed 28.9 g (0.092 mol) of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) (28.9 g, 0.092 mol, 87% pure) and 80 g of tetrahydrofuran. The solution was cooled to −17° C. and the cold lithiated veratrole/tetrahydrofuran slurry was added via cannula while maintaining the internal reaction temperature below −10° C. (15 minutes addition). The reaction mixture was then warmed to 10° C. and stirred for 3 hours. The solution may be used directly in Scheme L, step a, Example 109.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH2:32]=[C:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:37]([CH:35]2[CH2:36][C:33](=[CH2:32])[CH2:34]2)=[O:38])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: C=C1CC(C(=O)O)C1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol, 1.4 eq.), 4-dimethylamino pyridine (DMAP) (0.141 g, 1.15 mmol, 0.25 eq.), and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) were dissolved in anhydrous CH2Cl2 (25 mL). To this solution, a solution of 3-methylenecyclobutanecarboxylic acid (0.622 g, 5.54 mmol, 1.2 eq.) in anhydrous CH2Cl2 (25 mL) was added under N2 and the reaction was allowed to stir overnight at rt. Reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with water (2×), NaHCO3 (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20% →40% →70%], affording the title compound as a pale yellow solid. Additionally, the title compound could be prepared by the following route: 1,1′-Carbonyldiimidazole (CDI) (0.824 g, 5.08 mmol, 1.1 eq.) and 3-methylenecyclobutanecarboxylic acid (0.570 g, 5.08 mmol, 1.1 eq.) were dissolved in anhydrous THF (12 mL) and allowed to stir at 60° C. for 2 h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol) and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) in anhydrous CH2Cl2 (13 mL) was added to the acid mixture and the reaction was allowed to stir at 60° C., under N2, overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with NaHCO3 (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.86-2.96 (m, 2H), 3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78 (s, —NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, 1H); MS (ES+): m/z 238.19 (90) [MH+]; HPLC: tR=2.67 min (OpenLynx, polar—7 min).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[F:32])[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(=O)OCC)=S)=[N:18][CH:19]=2)=[O:8])=[CH:5][C:4]([CH3:33])=[N:3]1.[Cl-].O[NH3+].C([N:40](CC)C(C)C)(C)C.C(O)C>O.CO>[NH2:23][C:21]1[N:20]=[C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:29]=[CH:30][C:31]([F:32])=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=4)=[O:8])[CH:11]=3)=[CH:19][N:18]2[N:40]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(F)c(NC(=O)c3cc(C)nn3C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)nn4c3)ccc2F)n(C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl) carbonyl]amino}-4-fluorophenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (1.15 g, 2.43 mmol), hydroxylammonium chloride (1.18 g, 17.0 mmol), N,N-diisopropylethylamine (2.12 mL, 12.2 mmol), ethanol (10 mL) and methanol (10 mL) was stirred at 80° C. for 8 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (650 mg, 70%) as a yellow solid.
Reaction SMILES: C[CH:2]([OH:14])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].[CH2:24]1COCC1>[Na]>[C:20]([O:19][C:15](=[O:18])[CH2:16][CH2:17][O:14][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(O)COCCOCCOCCO
Reactant: C1CCOC1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Na]
Product: COCCOCCOCCOCCOCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Methyl tetraethylene glycol (1.0 g, 4.80 mmol) and tert-butyl acrylate (0.308 g, 2.40 mmol) were dissolved in dry THF (10 mL). Sodium metal 0.6 mg, 0.024 mmol) was added to the solution. After stirring for 4 h at room temperature was quenched by the addition of 1 M HCl (15 mL). The quenched reaction mixture was then extracted with CH2Cl2 (1×50 mL, 1×25 mL). The organic layer was dried (MgSO4) and concentrated. After purification by silica gel chromatography (ethyl acetate as eluent), the product was obtained as an oil (1.28 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=O)=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[C:7]2[N:6]([CH:13]=[N:12][CH:11]=2)[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])=[O:24]
Reactant: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc(Br)cc1F
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)c2cncn2c1Nc1ccc(Br)cc1F
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 29.2 %

Procedure:
To a suspension of 2-(4-bromo-2-fluoro-phenylamino)-5-fluoro-6-formylaminomethyl-nicotinic acid methyl ester (2.49 g, 6.2 mmol) in toluene (60 mL) was added phosphorous oxychloride (0.65 mL, 7.0 mmol). The reaction mixture was heated to 90° C. and stirred for 1.5 hour before cooling to room temperature and concentrating in vacuo. The resultant residue was dissolved in ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and then brine. The organic phase was isolated, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ether in hexane) to afford the title compound as a yellow solid (692 mg, 29%). LCMS (method B): RT=3.97 min, [M+H]+=382/384.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[O:7]1[C:6]([C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=2)=[CH:23][N:22]=[CH:21]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1cccc(-c2cnco2)c1
Yield: 90.2 %

Procedure:
3-Hydroxymethyl-benzaldehyde (1.14 g, 8.35 mmol), tosylmethyl isocyanide (2.47 g, 12.5 mmol) and potassium carbonate (1.75 g, 12.5 mmol) in methanol (25 ml) were refluxed at 85° C. for 1 h. The reaction was concentrated, residue dissolved in DCM/water and separated using a hydrophobic filter tube. The organic phase was concentrated and purified by silica chromatography using DCM followed by DCM:MeOH (19:1) to yield (3-oxazol-5-yl-phenyl)methanol (1.32 g, 90%) as an orange oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([C:24]([OH:26])=O)[N:4]=[C:3]1[CH3:27].F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)[N:46]1[CH2:51][CH2:50]OC[CH2:47]1)C(OCC)=O)#N.C(N(CC)C(C)C)(C)C.N1CCC1>CN(C=O)C>[CH3:22][N:12]1[CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[C:3]([CH3:27])=[N:4][C:5]=1[C:24]([N:46]1[CH2:47][CH2:50][CH2:51]1)=[O:26])=[O:23]
Reactant: Cc1nc(C(=O)O)c(C(=O)NCCc2nc(-c3ccccc3)cn2C)n1C
Reactant: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: C1CNC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCC2)c(C(=O)NCCc2nc(-c3ccccc3)cn2C)n1C
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-dimethyl-5-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamoyl)-1H-imidazole-4-carboxylic acid (30 mg, 81.7 μmol) in DMF (1 mL) were added under nitrogen atmosphere at 0-5° C. (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU; 38.5 mg, 89.8 μmol) and N,N-diisopropylethylamine (14.3 μL, 81.7 μmol). After stirring for 5 min, azetidine (6.18 μL, 89.8 μmol) and N,N-diisopropylethylamine (14.3 μL, 81.7 μmol) were added, the ice bath was removed after additional 10 min and the reaction mixture was stirred at RT for 2 h. The product was obtained after purification by preparative HPLC using an acetonitrile/water (containing 0.1% formic acid) gradient as colorless waxy solid (1.9 mg, 4.67 μmol, 5.72%). MS: M=407.4 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]=[N:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:5]=[C:6](I)[C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:26]2[O:27][C:28]([CH3:31])=[CH:29][CH:30]=2)O1>>[Br:1][C:2]1[CH:3]=[C:4](/[N:11]=[N:12]/[N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:5]=[C:6]([C:26]2[O:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:7]=1[O:8][CH3:9]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Reactant: COc1c(Br)cc(N=NN2CCCC2)cc1I
Product: COc1c(Br)cc(/N=N/N2CCCC2)cc1-c1ccc(C)o1

Procedure:
1-((3-Bromo-5-iodo-4-methoxyphenyl)diazenyl)pyrrolidine (0.15 g, 0.366 mmol) and 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (0.076 g, 0.366 mmol), were reacted in the same manner as Example 1 Part B for 18 hours to give crude product which was purified on an Isco 12 g silica cartridge eluting with ethyl acetate/hexane (0% to 25%) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][C:25](=[NH:28])OC)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][N:12]([C:25](=[NH:28])[NH:24][C:22]([O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=N)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CN(C(=N)NC(=O)OCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
0.9 g (4.8 mmol) of 3-(N-tert-butyloxycarbonylaminomethyl) azetidine and 1.3 g (6.3 mmol) of N-benzyloxycarbonyl-O-methylisourea was mixed in 6.5 mL toluene and heated to 70° C. for 72 h and then left at roomtemperature for another 72 h. Evaporation followed by flash chromatography using EtOAc followed by MeOH (saturated with NH3 (g))/CH2Cl2, 1/9, as eluent gave 0.67 g (38%) of the title compound as a white powder.