Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]([CH2:10][CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N:12]([CH:15]([CH2:21][CH2:22]Br)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14].C([N:26](CC)CC)C>C(#N)C>[N:12]([CH:15]([CH2:21][CH2:22][NH:26][CH2:11][CH2:10][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14]
Reactant: CCN(CC)CC
Reactant: CCC(N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(CCBr)N=[N+]=[N-]
Solvent: CC#N
Product: CCOC(=O)C(CCNCCCC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 2-amino-butanoate (0.397 g) and ethyl 2-azido4-bromo-butanoate (0.286 g) in acetonitrile (5 ml) was added triethylamine (0.347 ml). The mixture was heated at 50° C. for 18 h, cooled and evaporated onto silica gel (Merck.7734). The pre-absorbed material was purified by flash column chromatography (Merck. 9385, eluting with cyclohexane:ethyl acetate 6:1) to give the title compound (0.200 g) as a mixture of four diastereomers.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.CC(C)(OC([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23](O)=[O:24])=O)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:48]>ClCCl>[ClH:48].[ClH:48].[NH2:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(F)c(F)c1
Reactant: ClCCCl
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cl
Product: N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To a solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (64.3 mg, 0.34 mmol, from Step B) and (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (105.9 mg, 0.34 mmol) in dichloromethane (5 mL) was added HOBT (54.5 mg, 0.42 mmol) at 0° C. The reaction was stirred at 0° C. for 10 min, then EDC (96.6 mg, 0.50 mmol) was added. After removal of the ice-bath, the reaction was allowed to stir at ambient temperature for 14 h. The mixture was concentrated and purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1% trifluoroacetic acid) to give 115 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.36 (s, 9H), 2.62 (m, 2H), 2.86 (m, 2H) 3.34 (bs, 1H), 3.86 (m, 1H), 4.05 (m, 4H). 4.85 (m, 1H) 5.30-5.38 (m, 1H) 6.97 (m, 3H), 7.28 (m, 1H). LC/MS 489 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:27]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][OH:36])=[O:29])[NH:10][C@H:11]([CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[C@:12]2([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
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: ClCCl
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)N2CCC[C@H]2CO)[C@@H](c2cccc(Cl)c2)[C@]1(C#N)c1ccc(Cl)cc1
Yield: 11.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with (S)-1-pyrrolidin-2-yl-methanol (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3S,4S,5S)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-pyrrolidine-3-carbonitrile (12.0 mg, 11.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>COCCOC>[Cl:31][C:32]1[CH:33]=[C:34]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccc(F)c(Cl)c1
Yield: 40.3 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-chloro-4-fluoro-phenylboronic acid (34 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (23 mg, 41%). LC-MS m/e 439.25 (M+H+)
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH2:11][CH2:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH3:26][O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[CH2:16][N:10]1[C:9](=[O:27])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])=[C:14]([OH:15])[C:13]=2[CH2:12][CH2:11]1
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2c(c1O)CCN(Cc1ccc(OC)cc1OC)C2=O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CN2CCc3c(cnc(C(=O)NCC(=O)O)c3O)C2=O)c(OC)c1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-5,6,7,8-tetrahydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (19 mg, 0.051 mmol), glycine (510 mg, 6.79 mmol), and NaOMe solution (10 mL, 5.11, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water, and 1 M HCl was added with vigorous stirring until pH about 1. The organic layer was dried over MgSO4 and concentrated. The crude was first purified by silica gel chromatography (5-80% EtOAc/hexanes+2% AcOH), and the product isolated was then dissolved in saturated NaHCO3. The aqueous solution was washed with ether, acidified to pH about 1 with 4 M HCl, and the resulting precipitate was collected by filtration and dried under vacuum to give 7.8 mg of the title compound. MS: (+) m/z 416.27 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12])=[O:4].C([O-])([O-])=O.[Ca+2].CN(C=O)C>C1COCC1>[CH3:14][O:13][C:11]([CH:6]1[CH2:7][C:8](=[O:10])[CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])=[O:12]
Reactant: COC(=O)[C@H]1CC(=O)C[C@H]1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C1=CC(=O)CC1C(=O)OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
(1R,2S)-4-oxo-cyclopentane-1,2-dicarboxylic acid dimethyl ester (4.8 g, 23.8 mmol) and CuBr2 (11.9 g, 53.2 mmol) were dissolved in dry THF (70 ml) and the mixture was refluxed for two hours at 90° C. The formed CuBr was filtrated off and the organic phase was concentrated. CaCO3 (2.7 g, 27.2 mmol) and DMF (70 mL) were added and the mixture was held at 100° C. for one hour. The dark brown mixture was poured over ice (35 g) and the formed precipitate was filtrated off. The aqueous layer was extracted with ethyl acetate (1×300 ml+3×150 ml). The organic phases were dried, filtrated and concentrated. Purification by flash chromatography (toluene/EtOAc 9:1) gave the title compound (2.1 g, 45%) as yellow crystals
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([CH2:29][NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[O:23][CH2:24][CH:25]([CH3:26])[CH3:27])[NH:14][C:13](=[O:28])[N:12]=4)[CH:9]=3)[NH:4][N:3]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)nc(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cccc(CNc2n[nH]c3ccc(-c4cc(-c5ccccc5OCC(C)C)[nH]c(=O)n4)cc23)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a 50 mL round bottom flask were added commercially available 4-(3-amino-1H-indazol-5-yl)-6-(2-isobutoxyphenyl)pyrimidin-2(1H)-one (130 mg, 0.35 mmol), m-anisaldehyde (420 μL, 3.5 mmol, 10 eq), dimethylformamide (10 mL) and glacial acetic acid (10 drops). The reaction mixture was heated to 50° C. in an oil bath and stirred for 1 h. The mixture was allowed to cool before adding sodium cyanoborohydride (1M THF solution (Aldrich), 3 mL, 3 mmol) and subsequently stirred at room temperature for 1 h. Formation of product was confirmed by LC/MS and was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 40 mg (98%) of the title compound: 1H-NMR (400 MHz, d6-DMSO): δ 11.78 (s, 1H), 11.64 (s, 1H), 8.73 (s, 1H), 8.06 (d, 1H), 7.60 (d, 1H), 7.46-7.54 (m, 1H), 7.28-7.34 (m, 1H), 7.15-7.26 (m, 2H), 7.06-7.12 (m, 1H), 6.96-7.01 (m, 1H), 6.73-6.81 (m, 1H), 4.42-4.48 (m, 2H), 3.82-3.88 (m, 2H), 3.72 (s, 3H), 1.94-2.07 (m, 1H), 0.90-0.95 (m, 6H). MS (EI) for C29H29N5O3: 495 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:64][O:65][NH:66][CH3:67].Cl>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:25]([C:26](=[O:27])[N:66]([O:65][CH3:64])[CH3:67])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
DIPEA (28.2 ml, 20.9 g, 162 mmol) was added to a stirred solution of (RS)-3-(4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid (20.0 g, 53.9 mmol), BOP (25.00 g, 56.5 mmol) and MeONHMe.HCl (5.52 g, 56.6 mmol) in DMF (300 mL). After stirring 2 hr, the DMF was evaporated and the residue was dissolved in EtOAc and washed with water, 5% aq. HCl, saturated aq. NaHCO3 and brine, then dried with Na2SO4 and evaporated to afford (RS)-[2-(4-Benzyloxy-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (22.39 g, 100%), mp 107.1-108.7° C. 1H NMR (CDCl3) δ 0.40 (s, 9H), 2.83 (dd, J=6.2, 14.2 Hz, 1H), 3.00 (dd, J=6.1, 13.6 Hz, 1H), 3.17 (s, 3H), 3.65 (s, 3H), 4.91 (br s, 1H), 5.04 (s, 2H), 5.15 (br d, J=7.1 Hz, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 7.32-7.44 (m, 5H). 13C NMR (CDCl3) δ 172.3, 157.7, 155.2, 137.1, 130.4, 128.9, 128.5, 127.9, 127.4, 114.7, 79.6, 70.0, 61.5, 51.6, 38.0, 32.1, 28.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH2:36][OH:37])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[N:11]/[C:12]2[S:13][C:14]([CH:23]=[C:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:16]=2)=[CH:6][CH:5]=1)[CH3:2].Cl[S:39]([OH:42])(=[O:41])=[O:40]>C1COCC1>[S:39]([OH:42])([O:37][CH2:36][CH2:35][N:3]([C:4]1[CH:5]=[CH:6][C:7](/[N:10]=[N:11]/[C:12]2[S:13][C:14]([CH:23]=[C:24]3[C:25](=[O:34])[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:32]3=[O:33])=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:16]=2)=[CH:8][CH:9]=1)[CH2:1][CH3:2])(=[O:41])=[O:40]
Reactant: CCN(CCO)c1ccc(/N=N/c2nc(N3CCCCC3)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: C1CCOC1
Product: CCN(CCOS(=O)(=O)O)c1ccc(/N=N/c2nc(N3CCCCC3)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 0 °C

Procedure:
0.32 g (0.62 mmol) 2-{[2-((E)-{4-[ethyl(2-hydroxyethyl)amino]phenyl}-diazenyl)-4-(1-piperidinyl)-1,3-thiazol-5-yl]methylene}-1H-indene-1,3(2H)-dione were dissolved in 33 ml THF and cooled to 0° C. Then 0.11 g (0.93 mmol) chlorosulfonic acid were added slowly drop by drop with stirring. After the addition was completed, the reaction mixture was heated under reflux for 4 hours, allowed to cool to room temperature and stirred overnight. After further cooling in an ice bath the formed precipitate was filtered off, washed with a little cold THF and dried at 40° C. in vacuum.
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][C@@H:6]([CH:11]([C:17]([O:19]CC)=[O:18])[C:12]([O:14]CC)=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10].Cl>O.CCOCC>[CH3:5][C@@H:6]([CH:11]([C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCC[C@@H](C)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CCCC[C@@H](C)C(C(=O)O)C(=O)O
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
At room temperature, 81 g of sodium hydroxide (2 mol) were dissolved in 360 ml of water and 160 ml of methanol in a three-neck flask with internal thermometer, dropping funnel and stirrer. 124 g of diethyl [(R)-1-methylpentyl]malonate (0.51 mol) were then added. The mixture was heated to 70° C. and stirred at this temperature for 3.5 h, in the course of which a solid formed. After cooling to 25° C., the suspension was admixed with 250 ml of ether and, with cooling, with 400 ml of 20% by weight hydrochloric acid. After phase separation, the aqueous phase was extracted twice with 100 ml of ether. The combined organic phases were washed with 100 ml of water and then dried over sodium sulfate. After solvent had been distilled off, [(R)-1-methylpentyl]malonic acid was obtained in a yield of 85 g (89% of theory) (m.p.: 123° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:27][CH2:26][C:10]2[C:11]3[C:12](O)([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:13][CH2:14][C:15]=3[C:16]([I:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:28].O1CCOCC1>>[ClH:28].[CH2:1]([O:3][C:4]([N:6]1[CH2:27][CH2:26][C:10]2[C:11]3[C:12]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:13][CH2:14][C:15]=3[C:16]([I:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(O)(c1cccnc1)CC3
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(c1cccnc1)=CC3
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Into a glass vial, the product from step (a) (0.38 mmol) dissolved in 4N HCl/dioxane (2 ml) was added. The reaction mixture was stirred at 60° C. for 1 h. The mixture was cooled to room temperature and the solvent was evaporated in vacuo to give sub-titled compound as a brown solid that was used without further purification. MS: ESI (positive): 461 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:15][C:9]=2[CH:8]=[N:7]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:11]([OH:12])(=[O:36])[CH3:10].[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([O:1][C:2]2[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=2)[CH2:5][N:6]2[C:11](=[O:12])[C:10]3[S:13][C:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)=[CH:15][C:9]=3[CH:8]=[N:7]2)[CH2:32][CH2:31]1
Reactant: O=c1c2sc(-c3ccc(C(F)(F)F)cc3)cc2cnn1Cc1cccc(O)c1
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(=O)O
Product: CN1CCC(Oc2cccc(Cn3ncc4cc(-c5ccc(C(F)(F)F)cc5)sc4c3=O)c2)CC1
Yield: 15.7 %

Procedure:
6-(3-Hydroxybenzyl)-2-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-7(6H)-one (0.203 g, 0.50 mmol), 1-methylpiperidin-4-ol (0.074 g, 0.64 mmol) and TPP (0.172 g, 0.66 mmol) were stirred in THF (3 mL) at 0° C. DEAD (0.3 mL, 40% in toluene, 0.66 mmol) was added and the resulting mixture was allowed to attain room temperature and the stirring continued over night. Concentration and purification on C8-HPLC (0.1% HOAc, gradient 30→40% CH3CN) gave 0.022 g (8%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.77 (d, 2H, J=8.3 Hz), 7.70 (d, 2H, J=8.3 Hz), 7.51 (s, 1H), 7.22 (dd, 1H, J=8.2, 7.7 Hz), 7.04 (d, 1H, J=7.7 Hz), 7.00 (bs, 1H), 6.78 (dd, 1H, J=8.2, 0.9 Hz), 5.37 (s, 2H), 4.44 (br, 1H), 2.88-2.72 (m, 4H), 2.45 (s, 3H), 2.15-2.05 (m, 2H), 1.99 (s, 3H), 1.98-1.88 (m, 2H). MS (ESI+) 500 (M+1H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1Oc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)cnc1Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a stirred solution of methyl 2,5-dichloronicotinate (J. Med. Chem. 1993, 36, 2676, 353 mg, 1.71 mmol) and 3-fluorophenol (291 mg, 2.6 mmol) in toluene (5 mL) was added potassium carbonate (360 mg, 2.6 mmol) in one portion. The resulting mixture was heated at reflux temperature for 16 h with azeotroping using a Dean Stark apparatus. The mixture was poured into water (50 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL). The organic extracts were washed with water (50 mL) and brine (50 mL), dried (sodium sulfate), and concentrated under reduced pressure to give crude methyl 5-chloro-2-(3-fluorophenoxy)nicotinate. To a stirred solution of the crude ester in methanol (10 mL) was added 2 N sodium hydroxide aqueous solution (2 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between ether (30 mL) and water (30 mL). The organic phase was separated and the aqueous phase was acidified with 2 N hydrochloric acid (10 mL). The acidic mixture was extracted with dichloromethane (50 mL×3). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated to afford 448 mg (93%) of the title compound as off white solids: 1H-NMR (CDCl3) δ 8.44 (1H, d, J=2.6 Hz), 8.26 (1H, d, J=2.6 Hz), 7.46–7.36 (1H, m), 7.07–6.89 (3H, m); MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][NH:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][C:14]=2[NH:25][C:26]([C:28]2[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=2)[CH2:31][S:32][CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])=[O:27])[CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][NH:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:16]=[CH:15][C:14]=2[NH:25][C:26]([C:28]2[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=2)[CH2:31][S:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:27])[CH:8]=1
Reactant: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)ncn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-(2-(6-(3-methylbenzylamino)pyrimidin-4-yl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)propanoate (180 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (5 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 84 mg (51%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 9.42 (s, 1H), 8.84 (s, 1H), 7.80 (s, 1H), 7.71 (m, 2H), 7.52 (m, 1H), 7.45 (m, 1H), 7.24 (m, 6H), 6.90 (s, 1H), 5.42 (s, 2H), 4.64 (m, 1H), 3.82 (s, 2H), 3.26 (m, 4H), 2.59 (m, 2H), 1.67 (m, 6H). MS (ES, m/z): 596 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([NH:34][CH2:35][CH2:36][CH2:37]Cl)=[O:33])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([N:31]5[CH2:37][CH2:36][CH2:35][NH:34][C:32]5=[O:33])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(NC(=O)NCCCCl)c4)cc3C2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N5CCCNC5=O)c4)cc3C2)c1
Temperature: 30 °C

Procedure:
To a solution of N-(3-tert-butylphenyl)-7-{[2-({[(3-chloropropyl)amino-]carbonyl}-amino)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.71 g, 1.3 mmol) in tert-butyl alcohol (15 mL) was added potassium tert-butoxide (1M in THF, 4 mL). The reaction mixture was heated at 30° C. for 12 h and then acidified with 1N HCl and concentrated. The residue was redissolved in water and DCM and the aqueous solution was further extracted with DCM. The combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography. To a solution of the resulting product in MeOH, was added a 1N solution of HCl in Et2O (2 mL). The solvent was evaporated to give N-(3-tert-butylphenyl)-7-{[2-(2-oxotetrahydropyrimidin-1(2H)-yl)-pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-408 as the HCl salt (0.304 g, 46%). 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 10.04 (s, 1H), 8.28 (d, 1H), 7.65 (t, 1H), 7.53-7.62 (br s, 1H), 7.48-7.53 (m, 1H), 7.29-7.32 (m, 1H), 7.17-7.26 (m, 2H), 7.04-7.08 (m, 1H), 7.00-7.04 (m, 1H), 6.94-6.99 (m, 1H), 6.77-6.82 (m, 1H), 3.81 (t, 2H), 3.21 (t, 2H), 2.74-2.97 (m, 5H), 2.05-2.13 (m, 1H), 1.95 (t, 2H), 1.70-1.83 (m, 1H), and 1.25 (s, 9H). LCMS: (FA) ES+499.7, ES−497.0.