Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:25]=1)=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:19][CH2:21][CH:22]([C:24]2[CH:25]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[OH:23])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CS(=O)(=O)Nc1cccc(C(=O)CBr)c1
Reactant: COc1ccc(C(N)Cc2ccccc2)cc1OC
Product: COc1ccc(C(Cc2ccccc2)NCC(O)c2cccc(NS(C)(=O)=O)c2)cc1OC

Procedure:
The title compound was prepared by coupling α-(3,4-dimethoxyphenyl)benzeneethanamine, prepared as described in step C of Example 1, with 2-bromo-1-[3-[(methylsulfonyl)amino]phenyl]ethanone via the procedure described in step D of Example 1. The title compound, after silica gel chromatography, was purified by preparative HPLC using 49% solvent B to elute the desired material from a YMC S10 C18 column.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([OH:10])=[N:8][CH:9]=1.[CH3:14]I>O>[Cl:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7](=[O:10])[N:8]([CH3:14])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1cc(Cl)cc([N+](=O)[O-])c1=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
NaH (52.6 mmol) was slowly added at 5° C. to a solution of 5-chloro-2-hydroxy-3-nitropyridine [21427-61-2] (43.8 mmol) and the mixture was stirred at 5° C. for 30 min. Methyl iodide (65.7 mmol) was added and the mixture was stirred at rt for 20 h. The mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic phases were washed successively with H2O and brine, dried (Na2SO4), filtered and concentrated to afford the title compound. ESI-MS: tR=0.55 min, [M+H]+ 189/191 (LC-MS 1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])OCC[O:44]2)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:44])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc2ccc(OCCCC)cc2)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
No. 5534988, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (21.5 g, 28.2 mmol) was dissolved in dichloromethane (215 mL), and trifluoroacetic acid (215 mL) was added. The mixture was stirred at room temperature for 2 hours. After confirming the consumption of the starting materials by LCMS, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, which was washed with water, an aqueous solution of 2% NaHCO3 (to about pH 7.3), water, a saturated aqueous solution of ammonium chloride, and a saturated brine, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified with SP1 (Diol cartridge, 50% ethyl acetate/n-hexane, Rf=0.4) to obtain No. 5444958, (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-methoxy-ethyl)-12-oxo-nonadec-4-enoic acid (11.1 g, 61% yield, white powder).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH2:13][CH:12]2[N:9]([C:10](=[O:14])[CH2:11]2)[C:8]=1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[N+:2]=[N-:3].C([N-]C(C)C)(C)C.[Li+].[CH:33](=[O:35])[CH3:34]>>[OH:35][CH:33]([CH:11]1[C:10](=[O:14])[N:9]2[CH:12]1[CH2:13][C:7]([O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])=[C:8]2[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH3:34]
Reactant: CC=O
Reactant: [N-]=[N+]=NCCOC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(OCCN=[N+]=[N-])CC12

Procedure:
Benzyl 3-(2-azidoethyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate is reacted with lithium diisopropylamide and acetaldehyde as described in Example 19 to provide benzyl 6-(1-hydroxyethyl)-3-(2-azidoethyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[CH:36]=1>CN(C)C=O.CN(C)C(=O)C>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:28]=[C:27]([NH:26][C:7]([C:5]5[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:48]=[CH:47][CH:46]=4)=[CH:36][N:35]3[N:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(CC(F)(F)F)n1
Yield: 86.2 %

Procedure:
In the same manner as in Example 18-4 and using 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (269 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (278 mg, 86%) was obtained as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21](OC)=[O:22])[CH:15]=[C:16]([F:18])[CH:17]=1.OS(O)(=O)=O>C1(C)C=CC=CC=1.CCOCC>[Br:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH2:21][OH:22])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: COC(=O)C=Cc1cc(F)cc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OCC=Cc1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
56 ml (0.056 mol) of a 1M solution of diisobutylaluminium hydride in toluene are added dropwise under a nitrogen atmosphere to a suspension of 7.2 g (0.0278 mol) of methyl 3-(3-bromo-5-fluorophenyl) -2-propenoate in 84 ml of anhydrous ether cooled to 0° C. The mixture is stirred for 30 min at 0° C. and then for 3 h at room temperature. The mixture is cooled in an ice bath and carefully hydrolyzed with 6N H2SO4. Separation is carried out by settling and the organic phase is washed with water, dried over Na2SO4, filtered and evaporated under vacuum. The residue is purified by chromatography on silica (eluent: 2/1 hexane/ethyl acetate). Yd.: 4.2 g (65%)
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 4 h
Yield: 100.6 %

Procedure:
A solution of hydrochloric acid (2.5 mL, 4.0 M in 1,4-dioxane) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[(E)-2-phenylvinyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (40 mg, 0.084 mmol) in 5:1 dichloromethane-methanol (2.5 mL) at 0° C. After 4 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 1:1 pentane-diethyl ether, filtered, washed with pentane and dried under reduced pressure to provide a light yellow solid (33 mg, 76%). MS (LCMS) m/z 391.4 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (s, 3H) 2.30-2.42 (m, 1H) 2.56-2.69 (m, 1H) 3.08 (s, 3H) 3.93-4.06 (m, 1H) 4.32 (td, J=11.76, 4.98 Hz, 1H) 6.75 (s, 1H) 7.00 (d, J=6.24 Hz, 1H) 7.11 (d, J=16.39 Hz, 1H) 7.30-7.42 (m, 3H) 7.47 (d, J=16.39 Hz, 1H) 7.62 (d, J=7.02 Hz, 2H) 7.75 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6]1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:9][CH2:10]1
Reactant: COC(=O)C=C1CCC(C(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-tert-Butylcyclohexylidene)acetic acid methyl ester (10.78 g, 51.3 mmol) was dissolved in methanol (50 ml). Palladium hydroxide on carbon (1.0 g) was added and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen overnight. The catalyst was then removed by filtration through celite and the filtrate was evaporated in vacuo to a clear oil (9.81 g, 91%). 1H-NMR; δ (CDCl3) (as a mixture of cis-trans isomers), 3.67 (3H, s), 2.38 (1H, d, J=8 Hz), 2.18 (1H, d, 7 Hz), 1.85-1.44 (5H, m), 1.20-0.89 (5H, m) and 0.86 (9H, s).
Reaction SMILES: O.[OH-].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:37]#[N:38])=[C:9]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][N:14]([CH:19]([CH2:34][CH3:35])[C:20]([NH:22][C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=3)=[O:21])[C:13](=[O:36])[CH:12]=2)[CH:10]=1.Cl>C(O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:37]#[N:38])=[C:9]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][N:14]([CH:19]([CH2:34][CH3:35])[C:20]([NH:22][C:23]3[CH:33]=[CH:32][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[O:21])[C:13](=[O:36])[CH:12]=2)[CH:10]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
At RT, 0.2 ml of water and 97 mg (1.22 mmol, 3.0 eq.) of sodium hydroxide were added to a suspension of 200 mg (0.41 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoate (racemate) in 2.0 ml of ethanol. The reaction mixture was stirred at RT for 1 h and at an oil bath temperature of 60° C. for 6 h, allowed to stand at RT overnight and then added to aqueous hydrochloric acid (1N). After dilution with water a precipitate was formed which was filtered off, washed twice with water and dried under reduced pressure. The precipitate was then purified by flash chromatography (25 g of silica gel, mobile phase: dichloromethane→dichloromethane/methanol 50:1). Yield: 144 mg (38% of theory based on 0.82 mmol, since two crude product batches of the stated size were purified together)
Reaction SMILES: Cl.[C:2]([CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)#[N:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:2]([CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([S:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:6]1)#[N:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N#CCC1CCNC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CCC1CCN(S(=O)(=O)c2ccc(Cl)cc2)C1
Yield: 101.1 %

Procedure:
Acylation, in chloroform, of 36.6 g (0.25 mol) of 3-cyanomethylpyrrolidine hydrochloride with 52.7 g (0.25 mol) of para-chlorophenylsulfonic acid chloride, in the presence of 50.5 g (0.5 mol) of triethylamine makes it possible to obtain 72 g of a solid which is purified by chromatography on silica, Merck 70-230 mesh, using as eluent a dichloromethane/methanol mixture (99/1 v/v).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:27]=1[C:28](O)=[O:29]>>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:27]=1[C:28]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:11][CH:12]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: CCCc1cccc(Cl)c1C(=O)O
Product: CCCc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[(2-chloro-6-propylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-chloro-6-propylbenzoic acid using the general procedures described in example 15 and was obtained as a white solid: mp 225-227° C. ES-HRMS m/e calcd for C26H28ClN3O5 (M+Na) 520.1611, found 520.1615.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[CH2:10][CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:20][N:12]([CH2:11][CH2:10][C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:21])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CCC(=O)Nc1cnn(C)c1N)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCC(=O)Nc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a solution of tert-butyl N-{3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxopropyl}-N-methylcarbamate (4.88 g) in N,N-dimethylformamide (50 ml) were added trityl chloride (6.86 g), triethylamine (6.86 ml) and 4-dimethylaminopyridine (80 mg) succesively. The mixture was stirred at room temperature overnight. To the resulting mixture was added ethyl acetate and washed with water (three times) and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl N-methyl-N-(3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropyl)carbamate (4.20 g) as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].C([Li])CCC.[I:29]I.OS([O-])=O.[Na+]>C1COCC1.CCCCCC.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][C:7]=1[I:29]
Reactant: II
Reactant: Fc1cccc(C2CCC3(CC2)OCCO3)c1
Agent: CC(C)(C)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Fc1cc(C2CCC3(CC2)OCCO3)ccc1I
Temperature: -100 °C

Procedure:
121.0 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decane and 61.7 g of potassium tert-butoxide in 700 ml of THF were introduced into the apparatus and cooled to -100° C. 335.6 ml of a 15% solution of butyllithium in hexane were then added dropwise with stirring at -100° C., and the mixture was stirred at the same temperature for a further 30 minutes. A solution of 139.6 g of iodine in 300 ml of THF was then added dropwise with stirring at from -90 to -100° C., and the mixture was stirred for a further 30 minutes, allowed to warm to -25° C. and hydrolysed using 500 ml of water. 37% NaHSO3 solution was then added until the mixture became colorless. The organic phase was then separated off, and the aqueous phase was extracted with 2×200 ml of methyl tert-butyl ether. The combined organic extracts were washed once with 200 ml of sodium chloride solution, dried using sodium sulfate, filtered and evaporated to a residue, giving 8-(3-fluoro-4-iodophenyl)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Reaction time: 3 h
Yield: 72.7 %

Procedure:
A solution of acryloyl chloride (0.026 mL, 0.32 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine (Intermediate 55, 150 mg, 0.32 mmol) and DIPEA (0.062 mL, 0.36 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (120 mg, 72%) as a yellow foam; 1H NMR: 2.28 (3H, s), 2.38 (2H, s), 2.54 (2H, t), 2.98 (2H, d), 3.81 (3H, s), 5.62-5.73 (2H, m), 6.14 (1H, dd), 6.43 (1H, dd), 6.88 (1H, s), 7.12 (1H, dt), 7.39-7.47 (1H, m), 7.83 (1H, s), 8.41-8.50 (2H, m), 8.63 (1H, s), 8.85 (1H, d), 8.95 (1H, s), 9.36 (1H, s); m/z: ES+ MH+ 516.25.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].CC1C=CC(C[Zn+])=CC=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: Cc1ccc(C[Zn+])cc1
Agent: [Cl-]
Product: Cc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 45 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (4-methylbenzyl)zinc(II) chloride in 45% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=2)[C:12]#[N:13])=[CH:4][C:3]1=[O:17].C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:26][C:4]1[C:3](=[O:17])[C:2]([CH3:18])([CH3:1])[O:6][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1C#N
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a stirred solution of 5-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.9 g, 3.70 mmol) in CHCl3 (10 mL), NBS (1.1 g, 6.29 mmol) was added portionwise at RT. The reaction mixture was then stirred for 1 h and diluted with DCM (50 mL). the combined organic layers were washed with water (20 mL) and brine (15 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.5 g, 42%) as a yellow solid.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:5])[CH3:4].[Cl-].[Zn+2:19].[Cl-]>O>[C:3]([NH:6][C:7](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([O-:10])=[O:9])(=[O:5])[CH3:4].[Zn+2:19].[C:3]([NH:6][C:7](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([O-:10])=[O:9])(=[O:5])[CH3:4]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(=Cc1ccccc1)C(=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
A solution of 47% (w/w) sodium hydroxide (5.5 g) is added to slurry of α-acetamidocinnamic acid (10.3 g, 0.05 mol) in water (100 mL) at 70° C. to give a clear slightly alkaline solution. A solution of zinc chloride (3.4 g, 0.025 mol) in water (50 mL) is added and a precipitate is formed immediately. The mixture is stirred at 70° C. for further 2.5 hours. The precipitate is then filtered and dried to yield 9.4 g (80%) zinc α-acetamidocinnamate as a fine white powder. IR absorption bands: 1560, 1510, 1402 and 1353 cm−1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:21][C:22]([F:25])([F:24])[F:23])[CH:7]=[C:8]2[C:13]=1[O:12][CH:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]([OH:20])=[O:19])=[CH:9]2)(=[O:3])[CH3:2].CCO.[BH4-].[Na+]>C1COCC1>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([O:21][C:22]([F:25])([F:23])[F:24])[CH:7]=[C:8]2[C:13]=1[O:12][CH:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]([OH:20])=[O:19])=[CH:9]2)[CH3:2]
Reactant: CC(=O)c1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 52 %

Procedure:
To a solution of 8-acetyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid prepared as in Example 62 lb (0.980 g, 2.65 mmole) in a mixture of THF (25 mL) and absolute EtOH (25 mL) at 0° C. was added NaBH4 (0.100 g, 2.65 mmole) in portions under a N2 atmosphere. The ice bath was removed after 15 minutes and the mixture was stirred at room temperature for 2.75 hrs. The mixture was then poured into ice water (100 mL), which was then saturated with NaCI and extracted with EtOAc (2×200 mL). The extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude product as a pale yellow solid. Purification by silica chromatography (0% to 25% EtOAc:hexanes gradient) gave the crude product, which was further purified by crystallization from acetonitrile to give 516 mg (52% yield) of the product as an off-white crystalline solid: ESHRMS m/z 371.0378 (M−H, C14H9F6O5, Calc'd 371.0354); 1H NMR (dmso-d6, 300 MHz) 13.42 (brs, 1H), 7.89 (s, 1H), 7.93 (d, 1H, J=2.6 Hz), 7.42 (s, 1H), 6.42 (q, 1H, J=7.3 Hz), 5.41 (m, 1H), 4.96 (d, 1H, J=3.4 Hz), 1.29 (d, 3H, J=6.2 Hz).