Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:13][CH:12]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:27])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCCc2ccccc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(OCCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-Butyl 4-(4-(2-(2-Fluorophenyl)ethoxy)phenyl)-4-oxobutyrate (Step 2, 1.2 g, 3.2 mmol) in dichloromethane (25 ml) was treated with trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 4 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].O>CN(C)C=O>[N:1]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: c1cc[nH]c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the mixture of pyrrole (2.3 ml) and 60% sodium hydride (1.3 g) in N,N-dimethylformamide (50 ml) was added methyl 3-(bromomethyl)benzoate (5.0 g) under ice-cooling and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with water, dried over magnesium sulfate and evaporated to give methyl 3-(pyrrol-1-yl)methylbenzoate (4.14 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from [4-chloro-5-(methyl-propyl-amino)-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C6) (3.15 g, 9.16 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a pale brown solid (2.58 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18]1COCC1>C[Mg+].[Br-].CCOCC>[OH:1][C:2]1[C:11]2[CH2:10][C:9]([OH:12])([CH3:18])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cnc2c(c1O)CC(=O)CC2
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CCOC(=O)c1cnc2c(c1O)CC(C)(O)CC2
Reaction time: 1 h

Procedure:
To a stirred suspension of ethyl 4-hydroxy-6-oxo-5,6,7,8-tetrahydroquinoline 3-carboxylate (12 g) in 250 mL of THF, 35 mL of 3N MeMgBr in Et2O is added dropwise under cooling maintaining the temperature at 0° to 5°. The mixture is stirred for another 1 hour at the same temperature, then quenched and evaporated. The dried residue is taken up in CHCl3, washed with aqueous NaCl, dried (MgSO4) and evaporated to obtain ethyl 4,6-dihydroxy-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCC[CH2:15]2.CI>C1C=CC=CC=1>[CH3:15][O:12][C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Solvent: CI
Product: COC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution was added 74.84 g (0. 528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, saturated sodium bicarbonate solution, and brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4 %) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[C:48]([C:49]([NH2:51])=[O:50])=[C:43]3[CH2:44][NH:45][CH2:46][CH2:47][N:42]3[N:41]=2)[CH:36]=[CH:37][C:38]=1[F:39].C[N:53]([CH:55]=[O:56])C>C1(C)C=CC=CC=1>[C:49]([C:48]1[C:40]([C:35]2[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=2)=[N:41][N:42]2[CH2:47][CH2:46][N:45]([C:55]([NH:53][CH:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]3)=[O:56])[CH2:44][C:43]=12)(=[O:50])[NH2:51]
Reactant: CN(C)C=O
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNCC2
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)N2CCn3nc(-c4ccc(F)c(Cl)c4)c(C(N)=O)c3C2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred solution of Intermediate 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (273 mg, 1.47 mmol) in toluene (6 mL) was added TEA (0.472 ml, 3.39 mmol) followed by DPPA (0.22 ml, 1.0 mmol) and the mixture was stirred at 90° C. for 1 h. The reaction mixture was cooled to RT and a solution of Intermediate 185B (200 mg, 0.679 mmol) in DMF (2 mL) was added and stirring continued at RT for 16 h. The reaction was quenched with a 10% aq. solution of NaHCO3, the organic layer was separated, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography (4 g REDISEP® column, eluting with 5% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 339A as a buff colored solid (250 mg, 75% yield) MS(ES): m/z=493.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].C(Cl)(Cl)Cl.C[Si]([N:17]=[N+]=[N-])(C)C>C(O)C>[CH3:3][C:2]1[NH:17][C:1](=[O:8])[O:7][C:5](=[O:6])[CH:4]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)oc(=O)[nH]1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
At room temperature, to a mixture of 44.8 g of citraconic anhydride and 60 ml of chloroform was added 50.0 g of trimethylsilylazide. The mixture was stirred at 50 to 60° C. for 5 hours. After the reaction mixture was cooled with an ice, 25.0 g of ethanol was added, followed by further stirring for 30 minutes. The resulting solid was collected by filtration, and washed with a mixed solvent of chloroform and ethanol to obtain crude 4-methyl-2H-1,3-oxazine-2,6-(3H)-dione represented by the formula:
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.F[C:26]1[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(C(F)(F)F)cc2F)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2,3-difluoro-5-trifluoromethyl-pyridine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.56 min; Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 94 %

Procedure:
As described for example 61b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (95 mg, 94%) which was obtained as a white foam. MS: m/e=400.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([NH:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:5].[C:18](Cl)(Cl)=[O:19]>Cl>[Cl:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][C:18](=[O:19])[N:6]([N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)[C:4]2=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)NN1CCOCC1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)n1N1CCOCC1

Procedure:
23.5 g 2-Amino-5-chloro-N-morpholinobenzamide are dissolved in 500 cc 2N hydrochloric acid. A phosgene stream is passed through the solution for 1 hour. When the reaction is complete, the equipment is purged, after which the resulting material is suction filtered and washed with water. It is purified by crystallization from ethanol, M.P.=335° C.
Reaction SMILES: CC(C)(OC([O:7][N:8]([CH:16]([CH3:35])[CH2:17][CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20])C(=O)OC(C)(C)C)=O)C>ClCCl>[OH:7][NH:8][CH:16]([CH3:35])[CH2:17][CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)(=[O:20])=[O:21]
Reactant: CC(CCS(=O)(=O)c1ccc(Oc2ccccc2)cc1)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(CCS(=O)(=O)c1ccc(Oc2ccccc2)cc1)NO
Temperature: 23 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
A solution of Example 120B (1.59 g, 3.05 mmol) in 20 mL of dichloromethane at 0° C. was treated with trfluoroacetic acid (5 mL), stirred at 23° C. for 1 hour, concentrated, dissolved in ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. Purification on silica gel with 5% methanol/dichloromethane provided 820 mg (84%) of the desired product.
Reaction SMILES: [N:1]1([C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([C@H:30]3[CH2:32][C@H:31]3[CH2:33][CH2:34]O)[CH2:26][CH2:25]2)=[N:22][CH:23]=1)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[N:1]1([C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C@@H:31]3[CH2:32][C@@H:30]3[CH:27]3[CH2:26][CH2:25][N:24]([C:21]4[N:20]=[CH:19][C:18]([CH2:16][CH3:17])=[CH:23][N:22]=4)[CH2:29][CH2:28]3)=[C:9]([F:14])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cc1ccc(O)c(F)c1)N1CCC1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(azetidin-1-yl)-2-(3-fluoro-4-hydroxyphenyl)ethanone (65.0 mg, 0.236 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (59.0 mg, 0.283 mmol), triphenylphosphine (polymer-bound, 186 mg, 0.534 mmol), and di-tert-butyl azodicarboxylate (109 mg, 0.472 mmol). The reaction mixture as stirred at RT for 3 hours. The mixture was filtered by Celite and concentrated. The residue was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-100% acetonitrile in 0.1% formic acid in water gradient), to give the title compound. LC/MS (m/z) 467.3 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[C:3]1([CH3:9])C=CC=C[CH:4]=1.[OH:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13]([CH3:20])([CH3:19])[CH2:12]1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:17][C:15]1([CH3:18])[CH2:16][CH:11]([O:10][CH2:9][CH:3]2[O:1][CH2:4]2)[CH2:12][C:13]([CH3:20])([CH3:19])[NH:14]1
Reactant: [OH-]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(OCC2CO2)CC(C)(C)N1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
64.0 g of sodium hydroxide (1.6 mol) are dissolved in 64 ml of water under argon in a 750 ml sulfonation flask fitted with mechanical stirrer, condenser, thermometer and 100 ml dropping funnel. 170 ml of toluene, 10.3 g (31.8 mmol) of tetrabutylammonium bromide and 50 g (318 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine are added. 8.8 g (636 mmol) of epichlorohyrdin are added dropwise at 45° C. The mixture is then stirred at 50° C. for 4 hours. The reaction mixture is cooled to room temperature and poured into 11 of ice water, and the organic phase is separated off, dried using sodium sulfate and evaporated on a rotary evaporator. The residue is distilled at 8×103 mmHg. Boiling point: 48° C., yield: 28 g (41%). GC: 98 %.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][CH2:28][CH2:29][CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][CH2:29][CH2:28][F:27])[CH:7]=1
Reactant: OCCCF
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCCF)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-fluoropropan-1-ol (59 mg; 0.736 mmol), example 54 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3)nc2c1
Reactant: C1CCNC1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCC4)cc3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C, Example 8 (126 mg) and pyrrolidine (1.5 mL) were heated at 85° C. for 4 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (6 mL) and half-saturated sodium bicarbonate solution (6 mL). The aqueous portion was extracted with additional ethyl acetate (6 mL) and the organic portions combined and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (50.3 mg). 1H-NMR (CD3OD) δ 8.18 (d, 7.0 Hz, 1H), 7.91 (s, 1H), 7.77 (m, 2H), 7.25 (s, 1H), 6.94 (m, 2H), 6.68 (m, 1H), 4.01 (t, J=6.0 Hz, 2H), 2.71 (m, 2H), 2.64 (m, 4H), 2.37 (s, 3H), 2.01 (m, 2H), 1.83 (m, 4H)
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4]1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C>[N:10]([CH2:2][CH:3]1[O:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4]1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CCC(CBr)O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCC(CN=[N+]=[N-])O1
Temperature: 90 °C

Procedure:
5-(Bromomethyl)-2,2-dimethyltetrahydrofuran (36 g, 186 mmol) in DMF (300 ml) was treated with solid sodium azide (12.73 g, 196 mmol) and heated at 90° C. for 4 hrs. The mixture was allowed to cool to RT and partitioned between water (1.5 l) and ether (2×500 ml). The ether layer was separated and washed with (0.5M) LiCl (500 ml), dried MgSO4, filtered and evaporated to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[F:10][CH:11]([F:15])[C:12](O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12]([CH:11]([F:15])[F:10])=[N:9][N:8]=2)[N:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)C(F)F
Product: FC(F)c1nnc2ccc(Cl)nn12
Temperature: 100 °C
Yield: 84.5 %

Procedure:
A mixture of 3-chloropyridazin-6-yl hydrazine (5.0 g, 34.72 mmol) and difluoroacetic acid (21.93 mL; ca. 347 mmol) was heated at 100° C. for 3 hours and then evaporated to dryness. The involatile residue was dissolved in ethyl acetate (200 mL) and washed sequentially with saturated aqueous sodium carbonate and then saturated brine. The organic phase was dried over MgSO4, filtered, and evaporated to give 6-chloro-3-difluoromethyl-[1,2,4]-triazolo[4,3-b]pyridazine (6.0 g, 84.7%) as a white solid that was used without further purification.
Reaction SMILES: C([O:8][C:9](=[O:27])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:26])[C@H:16]([CH3:25])[NH:17][C:18](=[O:24])[C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)C1C=CC=CC=1.C(O)C.[H][H]>>[NH:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[C:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:27])=[O:8])=[O:26])[CH3:25])=[O:24]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: CCO
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Into a Parr flask flushed with argon containing 450 mg of 10% palladium on charcoal catalyst was added a solution of Ac-L-prolyl-L-alanyl-L-proline benzyl ester in (1.0 g, 2.41 mmol) absolute ethanol (100 ml). The contents were shaken under 40 psi of hydrogen overnight at room temperature. The mixture was filtered through celite and the filtrate concentrated on a rotary evaporator to give crude Ac-L-prolyl-L-alanyl-L-proline which was crystallizedfrom tetrahydrofuran-methanol-ether to give the desired product (0.57 g) in 73% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+].O>C1COCC1.CCOCC>[OH:11][CH:8]1[CH2:9][CH2:10][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1
Reactant: CCOC(=O)C1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCC(O)C1
Temperature: 0 °C

Procedure:
To a 0° C. solution of ethyl-3-oxo-cyclopentane-1-carboxylate (2.0 g) in THF (50 mL) was added NaBH4 (970 mg). The reaction mixture was maintained at 0° C. for 30 min, and then overnight at ambient temperature. The reaction was then treated with H2O and diluted with Et2O. The resulting layers were separated, and the aqueous layer was further extracted with Et2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude product (a mixture of cis/trans isomers) was used in the next step without further purification.
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]1[CH2:10][N:9]([C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:12])[C:8](=[O:21])[CH2:7]1)[CH2:3][CH:4]=[CH2:5].[CH2:22]([Zn]CC)C.ICI>>[CH:4]1([CH2:3][C@H:2]([C@H:6]2[CH2:10][N:9]([C@@H:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH3:12])[C:8](=[O:21])[CH2:7]2)[OH:1])[CH2:22][CH2:5]1
Reactant: CC[Zn]CC
Reactant: C=CC[C@@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Solvent: ICI
Product: COc1ccc([C@@H](C)N2C[C@H]([C@H](O)CC3CC3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-4-((R)-1-hydroxybut-3-enyl)-1-4R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.08 (145 mg, 0.50 mmol) at 0° C. was added 1M diethyl zinc (2.51 ml, 2.51 mmol). Diiodomethane (0.404 ml, 5.01 mmol) was added, and the mixture was stirred at rt for 60 min and quenched by the addition of sat NH4Cl (10 mL). EtOAc was added, stirred 5 min and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organics were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (20-->100% EtOAc in hexanes) to afford (R)-4-((R)-2-cyclopropyl-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.09.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:51]=[CH:50][C:42]([C:43]([N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])=[O:44])=[C:41]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:51]=[CH:50][C:42]([C:43]([N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])=[O:44])=[C:41]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:53])=[O:54])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCN(CC)C(=O)c1ccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1S(=O)(=O)C(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-N,N-diethyl-2-(isopropylsulfonyl)benzamide (Intermediate 257), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13](C3C=CC=C(C(F)(F)F)C=3)[OH:14])[CH:9]=2)[N:4]=1.[ClH:25].[OH-].[Na+]>>[Cl:25][C:9]1[C:8]([CH2:13][OH:14])=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][CH:3]=[N:4]2
Reactant: Cl
Reactant: COc1ccc2cc(C(O)c3cccc(C(F)(F)F)c3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Product: OCc1ccc2ncccc2c1Cl

Procedure:
A mixture of intermediate 28 (1 g) and HCl (25 ml; 3 N) was stirred and refluxed for 2 hours. The solution was basified with NaOH and extracted with CH2Cl2. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the solvent was evaporated, yielding 1.8 g of (±)-6-[hydroxy[3-(trifluoromethyl)phenyl]methyl]-2(1H-quinolinone (intermediate 29).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19].C(OC1C2C(=NC=C(I)C=2)N(C)C(=O)C=1)(=O)CCC(OC)=O.C([O-])(=O)C.[Na+]>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15](=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)CCC(=O)c1c(O)c2cc(I)cnc2n(C)c1=O
Agent: CC(=O)[O-]
Agent: COC(=O)CCC(=O)Oc1cc(=O)n(C)c2ncc(I)cc12
Agent: [Na+]
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(I)cnc21
Temperature: 140 °C
Yield: 27 %

Procedure:
Methyl 4-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-4-oxobutanoate. A mixture of 6-iodo-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl methyl succinate (0.096 g, 0.23 mmol) and sodium acetate (0.019 g, 0.23 mmol) was heated at 140° C. for 5 minutes. The reaction was cooled to room temperature and the solids rinsed with DCM. The filtrate was purified by flash chromatography using EtOAc/hexane to afford the title compound in 27% yield. 1H-NMR (300 MHz, CDCl3) δ ppm 8.85 (1H, d, J=2.3 Hz), 8.71 (1H, d, J=2.2 Hz), 3.72 (3H, s), 3.71 (3H, s), 3.65 (2H, t, J=6.3 Hz), 2.73 (2H, t, J=6.3 Hz). MS m/z: 417 (M+).