Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=[O:2].[N:8]([CH2:11][C@H:12]1[O:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C(C)(C)C)=[O:24])=[C:19]([F:30])[CH:18]=2)[CH2:13]1)=[N+:9]=[N-:10]>C(Cl)Cl>[N:8]([CH2:11][C@H:12]1[O:16][C:15](=[O:2])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([F:30])[CH:18]=2)[CH2:13]1)=[N+:9]=[N-:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N2CO[C@H](CN=[N+]=[N-])C2)cc1F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
60% TFA in DCM (5 mL) was added to 5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine (0.336 g, 1 mmol), and the solution kept at r.t. for 1 h. Solvents were removed in vacuo to afford 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl-]oxazolidine-2-one dried (0.280 g, 99%). N-Trimethylsilyl-N,N-diethylamine (0.23 mL, 1.2 mmol) was added to above product in dry dichloromethane (3 mL) under nitrogen atmosphere, and the solution stirred for 15 min. Solvents and excess reagent were removed in vacuo, and residue dissolved in dichloromethane (4 mL). The solution was cooled to about 0° C., and oxalyl chloride (1.5 mmol, 0.13 mL) was added dropwise, followed by catalytic N,N-dimethylformamide (about 0.01 mL). The mixture was allowed to warm up to r.t. (room temperature), and stirred at r.t. for another 2 h. Solvents were removed in vacuo to afford the product as a white solid. Yield 0.292 g (98%).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:18]([NH2:31])[N:17]=1>COCCOC.O>[CH:1]1([CH2:7][O:8][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[C:18]([NH2:31])[N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCC1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1nc(OCC2CCCCC2)nc2c1ncn2C1CCCCO1
Temperature: 93 °C

Procedure:
Cyclohexylmethanol (4.5784 g) was diluted with 1,2-dimethoxyethane (99%+) (20 mL) before sodium tert-butoxide (3.853 g) was added gradually with stirring under nitrogen. An exotherm was observed on addition of sodium tert-butoxide. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.5428 g) was added and the resultant mixture was heated to reflux at 93° C. (internal). A further quantity of 1,2-dimethoxyethane (99%+) (20 mL) was added to help dissolution and refluxed overnight. The reaction mixture was dissolved in water (100 mL) and extracted with ethyl acetate (100 mL, twice). The combined organic extracts were washed with brine (100 mL) before the organic layer was separated and dried by passing through a hydrophobic frit. Evaporated volatiles under reduced pressure and then azeotroped with toluene (50 mL, twice) to give mobile amber oil. This material was purified by silica chromatography (ISCO) eluting with 0-100% ethyl acetate: cyclohexane). This gave the title compound after placing under vacuo as pale yellow foam (1.0364 g) (94% purity by LCMS, 6% 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine) and was used in next step without further purification.
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[N:2]([N:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4]2)[CH3:1])=[CH:17][CH:16]=1
Reactant: CNn1cnc2ccccc2c1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCCl
Product: CN(C(=O)Nc1ccc(Cl)cc1)n1cnc2ccccc2c1=O

Procedure:
A mixture of 3-methylamino-4(3H)quinazolinone (2.00 g, 11.4 mmol) and 4-chlorophenyl isocyanate 2.01 g, 13.1 mmol) in 1,2-dichloroethane is heated at reflux for 72 hours, concentrated in vacuo and diluted with ether. The organic mixture is heated to reflux and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 3.61 g (96%), mp 186°-188° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47](O)=[O:48])=[N:43][N:44]=1>ClCCl>[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47]([NH:6][CH:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])=[O:48])=[N:43][N:44]=1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)C(C)NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Alanine methyl ester hydrochloride (1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71 mmol) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture is stirred at room temperature for 18 hours and then purified by SGC (0-100% EtOAc/Hexanes).
Reaction SMILES: CC1(C)O[O:3]1.[C:6]([O:19][CH:20]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:23][CH:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21]1)(=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CC(C)=O>[C:6]([O:19][CH:20]1[CH2:21][CH:22]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:23]([OH:3])[CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25]1)(=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC1(C)OO1
Reactant: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)NC(c2ccccc2)C1
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)N(O)C(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
A solution of 590 mL (27.7 mmol) of dimethyldioxirane, 0.047M in acetone (prepared by the procedure of Eaton and Wicks, J. Org. Chem. 1988, 53, 5353) is added via a cannula to a 0° C. solution of 12.1 g (27.7 mmol) of 2,6-diphenyl-4-piperidyl laurate in 200 mL of acetone. After stirring for 10 minutes at 0° C., the reaction mixture is concentrated under reduced pressure and the residue is recrystallized from methanol to yield 9.7 g (78% yield) of the title compound as a white solid: mp 89°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@@H]2C3[CH:46]=[CH:47][S:48]C=3CC[C@H]2CCC)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:19]3[CH:46]=[CH:47][S:48][C:20]=3[CH2:22][CH2:21][C@H:26]2[CH2:25][CH2:24][CH3:23])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.50, 7.35–7.31, 7.11, 6.91, 5.21, 4.59, 2.82, 2.64, 2.48, 2.05, 1.82, 1.43–1.35, 1.25, 1.18, 0.94; HRMS (FAB) calcd for C25H29Cl2N3S+H 474.1537, found 474.1526.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:21][C:22]6[O:26][C:25]([C:27]([OH:29])=O)=[C:24]([C:30](=[O:33])[NH:31][CH3:32])[C:23]=6[CH:34]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.C1C=CC2N(O)N=[N:47][C:45]=2C=1.CCN=C=NCCCN(C)C.Cl.CN.CCN(CC)CC>CN(C=O)C>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:21][C:22]6[O:26][C:25]([C:27]([NH:47][CH3:45])=[O:29])=[C:24]([C:30]([NH:31][CH3:32])=[O:33])[C:23]=6[CH:34]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: On1nnc2ccccc21
Reactant: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc2c1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A mixture of compound 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (50 mg, 0.09 mmol), HOBT (24 mg, 0.17 mmol), EDCI (102 mg, 0.53 mmol), methanamine hydrochloride (42 mg, 0.62 mmol) and Et3N (72 mg, 0.71 mmol) in DMF (2 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue was purified by prep-TLC (DCM:MeOH=200:1) to give the product 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N2,N3-dimethyl-6-(N-methylmethylsulfonamido)benzofuran-2,3-dicarboxamide (20 mg, yield: 39%). 1H NMR (CDCl3, 400 MHz) δ 10.49 (br s, 1H), 8.81 (s, 1H), 7.68 (s, 1H), 7.49 (s, 2H), 7.24˜7.17 (m, 3H), 7.12 (d, J=8.2 Hz, 1H), 6.88˜6.81 (m, 1H), 6.01 (s, 2H), 3.39 (s, 3H), 3.12 (d, J=5.2 Hz, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.65 (s, 3H). MS (M+H)+: 578.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:35]=[C:34]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:32][N:31]=1>>[Cl:29][C:30]1[CH:35]=[C:34]([C:36]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:37]=2)[CH:33]=[CH:32][N:31]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccnc(Cl)c1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccnc(Cl)c3)no2)C1

Procedure:
600 mg (1.49 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 281 mg (1.64 mmol, 1.1 eq.) of 2-chloro-N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 315 mg (39% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]2[C:10]=1[O:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>O1CCCC1>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:22])[CH2:20][CH3:21])=[C:10]2[C:6]=1[CH:7]=[CH:8][O:9]2
Reactant: Cc1ccc(O)c2occc12
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1ccc(C)c2ccoc12

Procedure:
To a stirred mixture of 7-hydroxy-4-methylcoumarone (88.0 g, 0.5 mole), triethylamine (83.4 mL, 0.6 mole) and tetrahydrofuran (1 L) was added propanoyl chloride (46.27 g 0.5 mole) dropwise. The mixture was poured into cold 0.5 N hydrochloric acid (3 L) slowly with stirring. The solid was collected, washed with water, and dried. mp. 147° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCOCC>[C:18]1([NH:17][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc2ccc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1cccc2ccc(Nc3ccccc3)nc12
Temperature: 50 °C
Yield: 35 %

Procedure:
NaH (60% w/w in mineral oil; 0.549 g, 13.73 mmol) was added to a mixture of 2-chloroquinoline-8-carboxylic acid (181a, 0.95 g, 4.58 mmol) and aniline (0.834 ml, 9.15 mmol) in THF (11 ml) at 0° C.; the reaction was heated to 50° C. for 2 h. The mixture was diluted with 75 ml of Et2O and washed with 1 N NaOH. The organic layer was separated, and the aq. layer was acidified to ˜pH 1 with 5 N HCl and extracted 4 times with 75 ml of EtOAc. All organic extracts were then combined dried over Na2SO4, and concentrated to give 2-(phenylamino)quinoline-8-carboxylic acid (35% yield) as a light-brown solid. MS (ESI, pos. ion) m/z: 265.2 (M+1).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:18])=[C:8]([NH:10][C:11](=[O:17])[C:12](=O)[CH:13]([CH3:15])C)[CH:9]=1)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:24]1C=CC=C(Cl)C=1>>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:18])=[C:8]2[C:9]=1[C:13]([CH3:15])=[C:12]([CH3:24])[C:11](=[O:17])[NH:10]2
Reactant: Clc1cccc(Cl)c1
Reactant: CCOc1ccc(C)c(NC(=O)C(=O)C(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1c(C)c2c(O)ccc(C)c2[nH]c1=O
Reaction time: 1.5 h
Yield: 46.2 %

Procedure:
N-(5-ethoxy-2-methylphenyl)-2-oxo-3-methylbutanamide (8.8 g, 35.3 mmol) was dissolved in m-dichlorobenzene (100 ml). Aluminum chloride (20.6 g, 155 mmol) was added to the solution, and the mixture was placed in a bath of 100° C. and stirred for 1.5 hours. The reaction mixture was poured in ice--water, and the precipitate was collected by filtration. To the filtrate, a mixture of chloroform--methanol (5:1) was added. The organic phase was extracted, and dried. The solvent was distilled off under reduced pressure. The resultant residue was recrystallized from methanol--ether to obtain 3.3 g in total of the title compound as yellow powder (46.2%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:9]([CH3:15])=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[C:9]([CH3:15])=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1)[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1ncc(Br)cc1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(Br)cc1N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of (5-bromo-2-methyl-pyridin-3-yl)-carbamic acid tert-butyl ester (Stage 158.1.2, 4.53 mmol) in DMF (20 ml) was cooled with an ice-bath and 55% NaH in oil (5.89 mmol) was added. The RM was stirred for 25 min at 0° C. then was added iodomethane (5.22 mmol). The RM was stirred for 2 h at it then was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with water (3×), with brine (3×), dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a brown solid (HPLC: tR 3.20 min (Method A); M+H=301, 303 MS-ES).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[O:42][C:41]([C:43]3[CH:48]=[CH:47][C:46]([CH2:49]Cl)=[CH:45][CH:44]=3)=[N:40][C:39]=2[CH:51]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:49][C:46]1[CH:45]=[CH:44][C:43]([C:41]2[O:42][C:38]3[CH:37]=[CH:36][C:35]([Cl:34])=[CH:51][C:39]=3[N:40]=2)=[CH:48][CH:47]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1O)C(=O)OC(C)(C)C
Reactant: ClCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
4.17 g (9.09 mmol) of rac-ethyl 5-{(tert-butoxycarbonyl)[2-(5-fluoro-2-hydroxyphenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate, 3.04 g (10.91 mmol) of 5-chloro-2-[4-(chloromethyl)phenyl]-1,3-benzoxazole and 3.14 g (22.74 mmol) of potassium carbonate in 120 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). This gave 5.43 g (7.75 mmol, 85% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:15][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCCCN
Product: CCCCNCc1ccc(Cl)c(Cl)c1
Yield: 53.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, 3,4-dichlorobenzaldehyde (10.0 g, 57.1 mmol) and butan-1-amine (4.18 g, 57.1 mmol) were converted to the title compound (7.09 g, 53%). 1H NMR (CDCl3) δ 7.45 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.19 (dd, J=2.0, 8.1 Hz, 1H), 3.79 (s, 2H), 2.68-2.59 (m, 2H), 1.59-1.45 (m, 2H), 1.36 (qd, J=7.3, 15.0 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H); MS (ESI+) m/z 232.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[C:30](=[O:31])[CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl>[CH3:34][N:28]1[CH2:29][C:30](=[O:31])[N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[N:16]=[C:15]([C:4]4[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=5)[N:5]=4)[O:19][N:18]=3)=[CH:21][CH:22]=2)[CH2:27]1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CNCC5=O)cc4)no3)cc2C)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CN(C)CC5=O)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
A mixture of 3-(4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-phenyl)imidazolidin-4-one (Example 141, 50 mg, 0.12 mmol) and aqueous formaldehyde solution (37%, 0.09 mL, 1.21 mmol) in acetic acid (0.5 mL) was stirred at rt for 15 min and then cooled to 0° C. Sodium triacetoxyborohydride (384 mg, 1.81 mmol) was added, and the mixture was stirred for 1 h at 0° C. and then at rt over night. Dichloromethane was added, and the mixture was extracted twice with saturated aqueous sodium bicarbonate solution, whereupon it was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to preparative HPLC (RP-18 column; acetonitrile/water gradient containing 0.1% trifluoroacetic acid). The product-containing fractions were combined, and the solvent was partly removed which resulted in precipitation of a solid. A neutral pH was established by adding saturated aqueous sodium bicarbonate solution, and the mixture was stirred for 30 min whereupon the solid was filtered off and dried under reduced pressure to yield the title compound (30 mg, 59%): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, 2H), 7.69 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 6.80 (s, 1H), 5.41 (s, 2H), 4.61 (s, 2H), 3.48 (s, 2H), 2.58 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H); ES-MS m/z 429 (MH)+, HPLC RT (Method D) 2.31 min.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.B([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)=[CH:17][CH:16]=1)(O)O>>[O:29]=[S:25]1(=[O:28])[CH2:26][CH2:27][N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:2]3[N:7]4[N:8]=[C:9]([NH2:11])[N:10]=[C:6]4[CH:5]=[CH:4][CH:3]=3)=[CH:16][CH:17]=2)[CH2:23][CH2:24]1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: O=S1(=O)CCN(Cc2ccc(B(O)O)cc2)CC1
Product: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Yield: 79.2 %

Procedure:
5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (368 mg, 1.73 mmol) and 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide (0.512 mg, 1.90 mmol), in a manner analogous to Step 73c. The residue was purified on a 12 g Isco silica gel column using a gradient of 0-15% methanol in dichloromethane as an eluent. 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (490 mg, 79%) was isolated as a beige foam. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 7.93 (d, J=8.5 Hz, 2H), 7.50 (m, 3H), 7.37 (d, J=7.8 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.02 (s, 2H), 3.78 (s, 2H), 3.15 (s, 4H), 2.91 (s, 4H). MS=358 (MH)+. 95b) 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (50 mg, 0.140 mmol) and 1-bromo-4-methoxy benzene (29 mg, 0.154 mmol) were combined in a manner analogous to Example 77 to yield 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-N-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine (28 mg, 42%) as a beige solid. The material was purified via trituration with methanol. MP=241° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.03 (d, J=8.1 Hz, 2H), 7.51-7.67 (m, 6H), 7.17 (d, J=6.4 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 3.80 (s, 2H), 3.69 (s, 3H), 3.15 (br s, 4H), 2.92 (br s, 4H). MS=464 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][CH2:22][C:23](=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][C:23]1[N:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH3:11])[C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1)[CH3:30]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C(=O)O)cc1C
Temperature: 140 °C
Yield: 50.4 %

Procedure:
4-Amino-3-methylbenzoic acid (0.322 g) was mixed with ethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C, see scheme 25) (0.498 g) and p-toluensulfonic acid (49 mg) in dioxane (3 mL). The mixture was heated at 140° C. via microwave over 2 hours. The resultant solution was diluted with EtOAc (20 mL) and washed with 0.5 N HCl (8 mL), Brine (8 mL) and dried over anhydrous Na2SO4. After removal of solvents under reduced pressure, the residue was purified by flash silica gel column chromatography, eluted with 10% MeOH in DCM, to afford 4-(2-(3-ethoxy-3-oxopropyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid (0.35 g) as a light yellow solid.