Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]1([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Li+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]1([C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccnc1-c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-chloronicotinate (3.10 g, 18.1 mmol), phenyltributyltin (6.30 g, 17 mmol), lithium chloride (5.04 g, 120 mmol), and tetrakis(triphenylphosphine)palladium (1.12 g, 1 mmol) in toluene (65 ml) was degassed and then stirred under a nitrogen atmosphere overnight at 90° C. and at reflux for 5 hours. The cooled reaction mixture was filtered, the filtrate evaporated, and the residue partitioned between acetonitrile (50 ml) and hexane (5×20 ml). The combined hexane layers were extracted with hydrochloric acid (lM, 4×10 ml), the extracts washed with ethyl acetate (15 ml), and basified (4M NaOH). The resulting suspension was extracted with dichloromethane (4×10 ml), the combined extracts dried over MgSO4 and evaporated to leave a colourless oil. Meanwhile, the acetonitrile layer from above was evaporated and the residual oil dissolved in diethyl ether (50 ml) and ethyl acetate (25 ml) and the solution extracted with hydrochloric acid (1M, 4×10 ml). Basification of the acid extracts (4M NaOH) and extraction of the resulting suspension with dichloromethane (4×10 ml) followed by drying of the combined extracts with MgSO4 and evaporation gave an oil which was combined with that obtained as described above (2.62 g).
Reaction SMILES: N#N.Br[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([F:14])=[CH:6][CH:5]=1.C([Li])CCC.[B:20](OCC)([O:24]CC)[O:21]CC>CCCCCC.O1CCCC1>[F:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([B:20]([OH:24])[OH:21])=[CH:5][CH:6]=1
Reactant: CCOB(OCC)OCC
Reactant: Fc1ccc(Br)c2ccccc12
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(F)c2ccccc12
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 250 mL three-necked round-bottomed flask equipped with septum and N2 (nitrogen) inlet were added 4.62 g (20.53 mmol) 4-bromo-1-fluoronaphthalene and 100 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 15.4 mL (24.64 mmol) of a 1.6 M solution of butyl lithium in hexane was added dropwise over 5 min. The reaction was stirred at −70° C. for 10 min, then 4.2 mL (3.59 g, 24.64 mmol) triethyl borate was added, and the reaction stirred at −70° C. for 20 min and warmed to room temperature. After stirring overnight at room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution, acidified with 1 N hydrochloric acid, and extracted into ethyl acetate (twice). The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to give an off-white powder, 1.97 g (51%), as a mixture of monoaryl and diaryl boronic acids. 1H-NMR (δ, CDCl3): 7.2-7.4 (m, 1H), 7.5-7.7 (m, 3H), 8.0-8.5 (m, 1H), 8.5 and 9.2 (m, 1H); APCI (−) (%): 189 (parent−1, 60).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[NH:6]1[C:10]2=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[CH:7]1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:3][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:6][CH:7]=[CH:8][C:9]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2cc[nH]c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccnc2[nH]ccc12
Temperature: 25 °C

Procedure:
To a cooled POCl3 (50 mL) in a dried round bottom flask, 1H-pyrrolo[2,3-b]pyridine 7-oxide (5.73 g) was added in potions. The mixture was heated to reflux for 5 h. After cooled down to RT, POCl3 was evaporated under high vacuum under gentle heating (40-50° C.) to obtain black residue. 50 mL of H2O was added slowly and pH was adjusted to 8-9 with Na2CO3 (first with solid, then saturated aqueous solution). The resulting priticipate was collected by filtration, washed with cold H2O and dried in a vacuum oven (50° C.) to give 4-chloro-1H-pyrrolo[2,3-b]pyridine as tan powder.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([CH3:49])[C:46]([OH:50])=[C:45]([CH3:51])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]([O:39]CC)=[O:38])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([CH3:49])[C:46]([OH:50])=[C:45]([CH3:51])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1
Reactant: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(OCC(=O)O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 15 mg (0.63 mmol) LiOH in 5 mL water was added to a solution of 180 mg (0.25 mmol) (R)-2-(4-ethoxycarbonylmethoxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 15 mL THF and the reaction mixture was stirred for 4 h at RT. 0.66 mL of 1 M HCl were added and the mixture was concentrated by evaporation i. vac. The residue was taken up in a little DCM/MeOH (7:3) and filtered through silica gel. The filtrate was concentrated by evaporation i. vac., the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][C:3]=1[NH2:4].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O.Cl>N1C=CC=CC=1>[NH2:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][C:3]=1[NH:4][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1cc(N)c(N)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(C)cc([N+](=O)[O-])c2N)cc1
Temperature: 45 °C

Procedure:
0.15 mol (25.05 g) of 2-amino-3-nitro-5-methylaniline is dissolved in 75 ml of pyridine, and 0.165 mol (31.4 g) of para-toluenesulphonyl chloride is then added gradually, whilst stirring, at between 40° and 45° C. When the addition has ended, the stirring is maintained for 1 hour at 45° C., the reaction medium is then poured into 450 ml of iced water and ther pyridine is neutralised with the aid of hydrochloric acid. The expected product which has precipitated is filtered off, washed with water and then recrystallised from acetic acid. After drying in vacuo, it melts at 184° C.
Reaction SMILES: [Li]CCCC.CN(C)CCN(C)C.[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2.[C:23](=[O:25])=[O:24]>CCCCCC.O>[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:15]1=2
Reactant: O=C=O
Reactant: c1ccc2c(c1)CCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a solution of n-BuLi (1.7 M, 123 ml, 0.21 mol) in 400 ml of hexane at room temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA), followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol). The mixture was stirred under argon at room temperature for 4 hours, and then poured into dry ice (pre-washing with anhydrous ether). After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated. The aqueous layer was acidified with conc. HCl to pH 1, cooled and the precipitate collected on a filter. This was recrystallized from CH2Cl2 to give 15a (9.43 g, 54.7%) as a white solid, mp 167°-169.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC#N>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2ccccc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(1H-indazol-3-yl)ethanone [4498-72-0](2 g, 12.46 mmol) in CH3CN (50 mL) was added K2CO3 (3.97 g, 28.7 mmol) and tert-butyl 2-bromoacetate (2.58 mL, 17.48 mmol). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was filtered, the residue was washed with CH3CN and the filtrate was concentrated under vacuum. The material thus obtained was used directly in the next step without further purification. MS: 275 [M+H]+; tR (HPLC conditions d): 3.78 min.
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[N:12]=1>O1CCCC1.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:9][CH:6]2[CH2:7][CH2:8][S:3][CH2:4][CH2:5]2)[N:12]=1
Reactant: OC1CCSCC1
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cccc(COC2CCSCC2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.24 g, 5.98 mmol) was suspended in tetrahydrofuran (19.9 mL) and cooled to 0° C. Tetrahydro-2H-thiopyran-4-ol (0.24 g, 1.99 mmol) was added and the reaction was stirred for 30 minutes. 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (0.5 g, 1.99 mmol) was added and the reaction was warmed to and maintained at ambient temperature overnight. The reaction was diluted with ethyl acetate, quenched slowly with water, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].CN(C)[CH:26]=[O:27]>C1COCC1>[CH:26]([C:13]1[CH:14]=[CH:15][S:11][C:12]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccs1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1sccc1C=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of tert-butyllithium in pentane (1.7 M, 35.4 mL, 60.2 mmol, 2.40 equiv) was added to a solution of tert-butyl 2-thienylcarbamate (10-2, 5.00 g, 25.1 mmol, 1 equiv) in THF (75 mL) at −78° C., and the resulting mixture was stirred at −78° C. for 1.5 h. N,N-Dimethylformamide (5.83 mL, 75.3 mmol, 3.00 equiv) was added, and the mixture was then warmed to 0° C. The reaction mixture was partitioned between water (300 mL) and EtOAc (2×200 mL). The combined organic layers were then dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (hexane, initially, grading to 30% hexane in EtOAc) to give tert-butyl 3-formyl-2-thienylcarbamate (10-3) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 9.80 (s, 1H), 7.11 (d, 1H, J=5.7 Hz), 6.68 (d, 1H, J=5.9 Hz), 1.55 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](C(OC)=O)[C:16]([O:18]C)=[O:17])=[C:11]([N+:24]([O-:26])=[O:25])[CH:10]=2)=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([N+:24]([O-:26])=[O:25])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(-c2ccc(OC)cc2)cc1[N+](=O)[O-]
Agent: Cl
Product: COc1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1

Procedure:
Crude dimethyl 4′-methoxy-3-nitro-biphenyl-4-malonate was heated at 100° C. in 60 mL of 6 N hydrochloric acid for 15 hours and cooled. The precipitate was collected by filtration, washed with water and hexane, and dried to give 7.2 g of crude 4′-methoxy-3nitrobiphenyl-4-acetic acid as a light tan solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:32]C(=O)C)([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:7][O:8]C(=O)C)(=O)C.[Li+].[OH-]>C1COCC1.O>[NH2:32][C:6]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([CH2:7][OH:8])[CH2:5][OH:4]
Reactant: CCCCCCc1ccc(-c2ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCc1ccc(-c2ccc(CCC(N)(CO)CO)cc2)cc1

Procedure:
Acetic acid 2-acetoxymethyl-2-acetylamino-4-(4′-hexyl-biphenyl-4-yl)-butyl ester (0.2 mmol) is dissolved in THF (1 mL) and treated with 2 N LiOH aqueous solution (0.5 mL). The resulting mixture is stirred at reflux for 1 h and diluted with H2O (10 mL). It is then extracted with EtOAc (3×5 mL) and the combined organic phase is washed with brine and dried over Na2SO4. After concentrating, the crude product is purified with LC-MS to give the desired product as a white solid. MS: (ES+): 356.2 (M+1)+.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([C:5]1[N:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]>>[C:3]([C:5]1[N:10]=[CH:9][C:8]([S:11]([NH2:2])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: [NH4+]
Agent: [OH-]
Product: N#Cc1ccc(S(N)(=O)=O)cn1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To an ice-cold solution of ammonium hydroxide (75 ml, 25% w/v) is added 6-cyanopyridine-3-sulfonyl chloride (12.5 g) portionwise and the mixture is stirred for 30 minutes at 0-5° C. The reaction mixture is then concentrated to ⅕th of its original volume and cooled. The precipitate is filtered and dried under vacuum to afford the title compound as light brown solid (9 g, Yield 80%). 1H NMR (DMSO-d6:400 MHz) δ 9.10 (1H, s), 8.33-8.35 (1H, m), 8.23-8.25 (1H, d); 7.88-8.03 (2H, bs); HPLC (max plot) 98%, Rt 4.67 min; LCMS: (ES+) 183.8.
Reaction SMILES: [OH:1][C:2]12[CH2:8][N:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[Li+].CC([N-]C(C)C)C.[CH2:17]([N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[N:5]12[CH2:8][C:2]([O:1][C:25](=[O:26])[N:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: O=C(Cl)N(Cc1ccccc1)c1ccccc1
Reactant: OC12CCN(CC1)C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OC12CCN(CC1)C2)N(Cc1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 2 h
Yield: 1.3 %

Procedure:
In a two necked flask under nitrogen, 3 ml of THF and 150 mg (1.33 mmoles) of 4-hydroxy-1-azabicyclo[2.2.1]heptane were placed. The suspension was cooled to −60° C. and 0.7 ml (1.46 mmoles) of LDA was added dropwise. After the addition the temperature was allowed to rise to 0° C. and was kept during two hours. A solution of 295 mg (1.20 mmoles) of benzylphenylcarbamyl chloride in 2 ml of THF was added in 30 minutes. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 hours. The suspension was filtered and the filtrate concentrated under reduced pressure. The residue was extracted with dichloromethane and water. The organic layer was extracted with 2N HCl and the aqueous layer basified with 8N NaOH and extracted with dichloromethane. The organic layers were dried over Na2SO4 anhydre and evaporated. The oil obtained (162 mg) was purified by HPLC-MS to obtain 4.86 mg (0.015 mmoles) 1.3% of a pure product as formiate, structure confirmed by 1H-NMR 300 MHz, (DMSO-d6): δ 1.86 (m, 4H), 2.65 (s, 2H), 2.77 (bs, 2H), 3.03 (bs, 2H), 4.84 (s, 2H), 7.14-7.32 (m, 10H). 8.19 (s, 1H); MS [M-HCOO]+: 323.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7])=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>ClC(Cl)C>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([Cl:13])=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)(CC(=O)O)N=[N+]=[N-]
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Temperature: 50 °C

Procedure:
To a stirred solution of 3-azido-3-methylbutanoic acid (10 g, 69.8 mmol) in anh. dichloroethane (50 mL) was added thionyl chloride in one portion (10.0 mL, 2 equiv, 0.14 mol). The flask was fitted with a condenser and the reaction was heated in a 50° C. oil bath for 2 h. The reaction was concentrated to a brown-black suspension. The residue was vacuum distilled through a short path distillation apparatus. The forerun was discarded and the major fraction distilled at 66° C. at 18 mbar as a pale yellow liquid (9.66 g, 85.6%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7](SC)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]>[Ni].COCCOCCOC>[CH2:1]([C:5]1[N:6]=[CH:7][NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Ni]
Solvent: COCCOCCOC
Product: CCCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 62.4 %

Procedure:
A mixture of 4′-{[4-butyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.98 g), Raney-nickel (15 g) and 1-methoxy-2-(2-methoxyethoxy)ethane (25 mL) was stirred at 160° C. for 16 hr. The insoluble material was filtrated, and the filtrate was concentrated to give the title compound as colorless crystals (1.09 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=O)[C:9]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c2ccccc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)nc2ccccc2c1-c1ccc(F)cc1

Procedure:
Ethyl 4-(4-fluorophenyl)-1,2-dihydro-2-oxo-3-quinolinecarboxylate (12.8 g) is dissolved in 40 ml of phosphorus oxychloride under an atmosphere of nitrogen. The resulting solution is refluxed one hour, cooled, concentrated, and the residue neutralized with cold 1N sodium hydroxide solution and extracted with ethyl acetate. The organic extracts are filtered through a bed of silica to give 13.2 g of ethyl 2-chloro-4-(4-fluorophenyl)-3-quinolinecarboxylate as a white solid; mp 113°-114° C.; 1H NMR (chloroform-d): δ 8.02 (d, 1H), 7.75-7.70 (m, 1H), 7.52-7.43 (m, 2H), 7.34-7.28 (m, 2H), 7.20-7.12 (m, H), 4.14-4.07 (q, 2H), 1.02 (t, 3H) ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([NH:15][NH2:16])=[O:14])=[CH:5][CH:4]=1.[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26])(=[O:22])[CH3:21]>CN(C)C(=O)C.C(OCC)(=O)C>[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([NH:16][NH:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][N:19]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH:11]=1)=[O:26])(=[O:22])[CH3:21]
Reactant: CSc1ccc(Nc2cc(C(=O)NN)ccn2)cc1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2cc(C(=O)NNC(=O)C(C)(C)OC(C)=O)ccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 2-[[4-(methylthio)phenyl]amino]isonicotinohydrazide (513 mg, 1.87 mmol) in N,N-dimethylacetamide (5 mL) was added dropwise 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.294 mL, 2.06 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (624 mg, yield 83%) as colorless crystals.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32].[CH3:41][CH:42]([C:44]1[S:45][C:46]([CH:50]=O)=[C:47]([CH3:49])[N:48]=1)[CH3:43]>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32])=[CH:50]/[C:46]1[S:45][C:44]([CH:42]([CH3:41])[CH3:43])=[N:48][C:47]=1[CH3:49]
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: Cc1nc(C(C)C)sc1C=O
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1sc(C(C)C)nc1C)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
1,1,3,3-Tetramethylguanidine (55 μL, 0.44 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 100 mg, 0.20 mmol) in tetrahydrofuran (4 mL) at about −20° C. After 5 min, a solution of 2-(1-methylethyl)-4-methylthiazole-5-carboxaldehyde (Example 57; 38 mg, 0.225 mmol) in tetrahydrofuran (1 mL) was added. After 2 min, the cooling bath was removed and the solution was stirred at room temperature for 66 h. The solvent was evaporated and ethyl acetate (10 mL) and 10% aqueous acetic acid (5 mL) were added to the residue. The mixture was filtered to give (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(1-methylethyl)-4-methylthiazol-5-yl]propenoic acid methyl ester (65 mg, 62% yield) as a colorless solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]1[CH2:15][CH2:14][NH:13][C:12]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31][CH3:32])=[O:30])=[N:24][CH:25]=3)=[CH:19][C:11]1=2>C(Cl)Cl>[CH3:33][C:28]([CH3:34])([CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[CH:17]=[CH:16][C:12]3[N:13]([C:8](=[O:9])[NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:14][CH2:15][O:10][C:11]=3[CH:19]=2)=[CH:25][N:24]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(c2)OCCN3)cn1
Solvent: ClCCl
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(c2)OCCN3C(=O)Nc2ccccc2)cn1
Reaction time: 8 h

Procedure:
Phenyl isocyanate (16.1 μL, 0.148 mmol) was added at room temperature to a solution of methyl 3-(5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-2 (39.2 mg, 0.114 mmol) in anhydrous methylene chloride (0.57 mL) under an atmosphere of argon. The reaction mixture was stirred overnight, then concentrated to dryness under reduced pressure to give crude methyl 2,2-dimethyl-3-(5-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)propanoate B-3 (62.0 mg), which was sufficiently pure to be used for the next step without additional purification. MS (ESI), [M+1]+ 462.