Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][CH2:10][C@@H:9]1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH2:1]([N:8]1[CH:9]2[CH2:10][CH2:11][CH:12]1[C:13](=[O:15])[O:18][C:16]2=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)N1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C1OC(=O)C2CCC1N2Cc1ccccc1

Procedure:
A solution of cis-1-benzyl-2,5-pyrrolidinedicarboxylic acid (60 g, 0.24 mol; from Preparation A, step (c) above) and dicyclohexylcarbodiimide (49.7 g, 0.24 mol) in THF (1.2 L) was heated at reflux for 18 hours. The reaction was cooled and filtered to remove the urea by-product. The filtrate was concentrated in vacuo to afford a dark brown viscous oil which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7](=[O:22])[CH2:8][C:9](=[O:21])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[C:7]([C:8]1[C:9](=[O:21])[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:27][N:26]([CH3:28])[CH:25]=1)(=[O:22])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(CC(=O)c1ccccc1)Cc1cccc(C(F)(F)F)c1
Product: Cn1cc(C(=O)c2ccccc2)c(=O)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 18 h

Procedure:
To a 9 g. portion of 1-phenyl-4-(3-trifluoromethylphenyl)-1,3-butanedione was added 60 ml. of N,N-dimethylformamide dimethyl acetal. The reaction mixture was stirred under reflux for 16 hours, and was then evaporated to a dark brown oil under vacuum. The oil was dissolved in 150 ml. of tetrahydrofuran, and to it was added 10 ml. of 40% aqueous methylamine. The mixture was allowed to stand at ambient temperature for 18 hours, and was then evaporated under vacuum to an oil, which was taken up in diethyl ether, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum to an oil again. The oil was triturated under 1.2 liters of diisopropyl ether to obtain 2.4 g. of the desired product, which was identified by nmr analysis in CDCl3, showing characteristic peaks at δ7.2-8.0 (m, 11H, aromatic); 3.63 (s, 3H, N--CH3).
Reaction SMILES: [C:1]([CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[F:19])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]>C(O)C.[Ni]>[NH2:2][CH2:1][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[F:19])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCC(C#N)c1cccc(F)c1F
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)CCCC(CN)c1cccc(F)c1F
Reaction time: 18 h

Procedure:
Raney-Nickel (2800, slurry in water; washed with ethyl alcohol (3×); 3.8 g) was added to a solution of ethyl 5-cyano-5-(2,3-difluorophenyl)pentanoate (4.75 g, 17.8 mmol) in ethanol (100 mL). Ammonia gas was bubbled to the reaction mixture and the mixture was stirred under hydrogen at 48 psi. After 18 h, the reaction was filtered and concentrated. MS 272.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([Cl:9])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=[O:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]([C:17]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:16]=2[Cl:15])[OH:19])=[C:4]([Cl:9])[CH:3]=1
Reactant: Clc1cc(Br)ccc1I
Reactant: COc1ccc(Cl)c(C=O)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(O)c2ccc(Br)cc2Cl)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-bromo-2-chloro-1-iodo-benzene (10.0 g, 31.5 mmol) in THF (120 ml) was added 2 M solution of isopropylmagnesium chloride in THF (17.3 ml, 34.60 mmol) at −65° C. The reaction mixture was stirred at −40° C. for 20 min. After 2-chloro-5-methoxy-benzaldehyde (5.5 g, 32.20 mmol) was added, the reaction mixture was warmed to room temperature and stirred overnight. Then the solution was quenched with saturated aqueous solution of NH4Cl. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude material was purified by chromatography (petroleum ether/CH2Cl2 1:1) to provide title compound as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:4][CH:3]=1.ClCCl.C(NC(C)C)(C)C.[Cl:39][C:40]1[N:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>>[Cl:39][C:40]1[N:45]=[CH:44][C:43]([S:46]([N:17]2[CH2:16][CH2:15][C:14]3[C@:19]([C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[O:22])([CH2:20][C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[C:12]=4[CH:13]=3)[CH2:18]2)(=[O:48])=[O:47])=[CH:42][CH:41]=1
Reactant: O=C(c1ccccn1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reaction time: 16 h

Procedure:
A solution of (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone in dichloromethane (2.5 mL) (2.7 mL, ˜0.2 mmol) containing diisopropylamine (174 μL, 1 mmol) was added to 6-chloro-pyridine-3-sulfonyl chloride (53 mg, 0.25 mmol) and diisopropylethylamine (100 μL, 0.57 mmol) and the mixture stirred for 16 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (gradient: 20-30% ethyl acetate in cyclohexane) to afford (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a white solid (85 mg). LCMS (Method B ESI): RT 3.92 min, m+H=550.0; 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J=2.5 Hz, 1 H); 8.61 (d, J=4.7 Hz, 1 H); 7.85-7.86 (m, 3 H); 7.48-7.49 (m, 1 H); 7.42-7.43 (m, 2 H); 7.35 (d, J=8.4 Hz, 1 H); 7.27 (s, 1 H); 7.15-7.16 (m, 2 H); 6.50 (s, 1 H); 5.57 (d, J=12.4 Hz, 1 H); 4.23 (d, J=16.9 Hz, 1 H); 3.85-3.95 (m, 1H); 2.86-2.87 (m, 3 H); 2.66 (d, J=11.9 Hz, 1 H); 2.53 (d, J=15.1 Hz, 1 H).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][S:11][C:5]=2[C:4]=1[CH3:12].[BH4-].[Na+]>CO>[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][S:11][C:5]=2[CH:4]1[CH3:12]
Reactant: CC1=[N+](C)CCc2ccsc21
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC1c2sccc2CCN1C
Reaction time: 1.5 h

Procedure:
A mixture of 7.2 g (24 mmol) 6,7-dimethyl-4,5-dihydro-thieno[2,3-c]pyridinium iodide and 80 ml of methanol is mixed batchwise 1.87 g (49 mmol) NaBH4 while cooling with an ice bath (vigorous release of gas). The mixture is stirred for another 1.5 h, concentrated, mixed with sat. NaHCO3 solution and extracted 3× with methylene chloride. The organic phases are dried on NaSO4, filtered and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[S:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(CNCc2ccc(F)c(F)c2)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(CN(Cc2ccc(F)c(F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from N-(3,4-difluorobenzyl)(4-methoxyphenyl)-methanamine (example 5-36a) and methyl 4-(chlorosulfonyl)benzoate (example 5-10c). MS (M−H, 446); 1H NMR (400 MHz, DMSO-d6): δ ppm: 3.69 (s, 3H), 4.20 (s, 4H), 6.73 (d, J=8.8 Hz, 2H), 6.93 (m, 2H), 6.98 (d, J=8.8 Hz, 2H), 7.22 (m, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]([O:11][CH3:12])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2.Cl.O1CCOCC1>O1CCOCC1.O.C(Cl)Cl>[ClH:8].[CH3:12][O:11][C:9]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][NH:18][CH2:17]2)=[O:10]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.85 ml of triethylamine and 0.35 ml of methyl chloroformate were added to 8 ml of a methylene chloride solution containing 0.72 g of 5-amino-2-tert-butoxycarbonylisoindoline, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform-ethyl acetate=2:1) to obtain an oil. This oil was dissolved in 5 ml of dioxane, then, 8 ml of 4N hydrochloric acid-dioxane was added thereto, and the mixture was stirred at room temperature. The precipitates precipitated by addition of 20 ml of ether were collected by filtration and washed with ether to obtain 5-(methoxycarbonylamino)isoindoline.hydrochloride.
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([N:12]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=c1ccocc1
Reactant: CC(C)(C)N
Product: CC(C)(C)n1ccc(=O)cc1

Procedure:
The starting material may be prepared as follows: A solution of 4-pyrone (730 mg.) in t-butylamine (3.0 ml.) was set aside for 3 days. The excess t-butylamine was evaporated under reduced pressure and the residue was purified by chromatography on Kieselgel 60 (20 g.) eluting with methylene chloride/MeOH 100:0 to 90:10 v/v to give 1-t-butyl-4-pyridone (530 mg.) N.m.r. in solvent A:-1.55(s, 9H); 6.4(d, 2H); 7.6(d, 2H). This material was chlorinated as described in the second part of Example 56 to give 4-chloro-1-t-butylpyridiniumtoluene-p-sulphonate.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13](=[O:14])[N:6]12)=[O:4].O.[Li+].[OH-]>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[C:13](=[O:14])[N:6]3[CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][N:7]3[C:11]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:23]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C1CCCn2c(-c3ccnc(Oc4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCCn2c(-c3ccnc(Oc4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n21
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(2-phenoxy-pyrimidin-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 22, (0.02 g, 0.0143 mmol) in methanol (1 mL) and water (1 mL) is added LiOH (0.016 g, 0.65 mmol). The reaction solution is stirred at room temperature for 3 hours then quenched by the addition of 1 N HCl (20 mL). The reaction solution is extracted with ethyl acetate (3×50 mL), the organic layers are combined, washed with brine, dried, and concentrated in vacuo to afford 0.012 g (63% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.45 (dd, J=4.6, 2.1 Hz, 1 H), 7.14-7.44 (m, 7 H), 6.84-6.95 (m, 3 H), 4.93 (dd, J=11.7, 9.3 Hz, 1 H), 4.23 (br d, J=12.9 Hz, 1 H), 3.04-3.11 (m, 1H), 2.46-2.52 (m, 2 H), 1.71-1.93 (m, 2 H), APCI/MS: 447 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:5][C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][S:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:32]([N+:46]([O-:48])=[O:47])[CH:31]=2)(=[O:29])=[O:28])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH3:56][N:57]([CH3:61])[C:58](Cl)=[O:59]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:58]([N:57]([CH3:61])[CH3:56])=[O:59])[CH2:16][CH2:17]2)[CH:6]=[CH:5][C:4]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][S:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[C:32]([N+:46]([O-:48])=[O:47])[CH:31]=2)(=[O:28])=[O:29])=[O:25])=[CH:22][CH:23]=1
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(CCCN2CCNCC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCCSc3ccccc3)c([N+](=O)[O-])c2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CCCN2CCN(C(=O)N(C)C)CC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCCSc3ccccc3)c([N+](=O)[O-])c2)cc1
Reaction time: 0.5 h

Procedure:
A solution of Example 183D (108 mg, 0.157 mmol) and triethylamine (45 μL, 0.32 mmol) in THF (2 mL) at room temperature was treated with dimethylcarbamic chloride (14 uL, 0.157 mmol), and stirred for 30 minutes. The mixture was purified by flash column chromatography on silica gel with 10:10:80 methanol/acetonitrile/ethyl acetate to provide the desired product. MS (ESI(−)) m/e 759 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 1.93 (m, 2H), 2.65 (t, 2H), 2.74 (s, 6H), 2.89 (m, 2H), 3.08 (m, 4H), 3.34 (m, 6H), 3.61 (m, 2H), 3.75 (s, 3H), 6.88 (d, 1H), 6.96 (s, 1H), 7.01 (d, 1H), 7.21 (m, 2H), 7.30 (t, 2H), 7.41 (m, 3H), 7.88 (d, 1H), 7.89 (d, 2H), 8.51 (d, 1H), 8.54 (t, 1H).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)#[N:3].CO[C:14](=[CH2:17])[C:15]#[N:16].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[NH2:16][C:15]1[CH:14]=[CH:17][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2)[N:11]=1
Reactant: C=C(C#N)OC
Reactant: N#Cc1ccc(NN)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#Cc1ccc(-n2ccc(N)n2)cc1

Procedure:
Suspend 4-cyanophenyl hydrazine hydrochloride (5 g, 29.58 mmol) in tert-butanol (60 mL). Add methoxyacrylonitrile (2.458 g, 29.58 mmol) and potassium tert-butoxide (3.975 g, 35.49 mmol) and heat the mixture at 90° C. overnight. Concentrate in vacuo and partition the residue between EtOAc/water. Extract the organic phase with 10% hydrochloric acid. Neutralize the aqueous phase with saturated aqueous NaHCO3 and extract twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain a solid that was washed with ether/hexane. Filter and dry the solid in vacuo to obtain the desired intermediate.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:15]([C:28](O)=[O:29])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:34]2N(O)N=[N:37][C:35]=2[CH:36]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:35]1([NH:37][C:28]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:29])[CH2:36][CH2:34]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 191.9 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(5-phenylpentyl)-1H-1,2,3-triazole-4-carboxylic acid (392 mg, 0.964 mmol) obtained in Example 101b), HOBt (67.3 mg, 0.482 mmol, 0.5 eq.) and cyclopropylamine (0.090 ml, 1.25 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 6 ml), WSC (226 mg, 1.16 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 13.5 hr. Water (10 ml) was added to the reaction mixture, and the mixture was stirred. The precipitate was collected by filtration, washed with water and methanol-water (1:1) and dried to give the title compound as a white powder (412 mg, 0.925 mmol, 95.9%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17][C:18](O)([CH3:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17][C:18]([F:29])([CH3:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-3-methyl-butan-1-one (2.5 g) in dry methylene chloride (30 mL) cooled to -78° C. is added diethylaminosulfur trifluoride (Aldrich Chemical Co.) (1.2 mL) and the stirring is continued for an additional 45 minutes. The mixture is washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The crude product is purified by silica gel column chromatography (hexane:ethyl acetate, 9:1) followed by crystallization from petroleum ether to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-fluoro-3-methyl-butan-1-one as a white solid, mp 94° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[C:14](OCC)=[O:15])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.CCCCCC>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][OH:15])[CH3:2]
Reactant: CCOC(=O)c1c(CC)nc2c(C)cc(C)nn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nn2c1CO
Yield: 84.2 %

Procedure:
To a solution of 2.702 g (10.9 mmol) of the product of Step A dissolved in 21 mL of anhydrous THF was added 6.0 mL of a 1.0M solution of lithium aluminum hydride in THF at 0° C., and the reaction mixture was stirred under a nitrogen atmosphere. After 1 hour TLC analysis (75% EtOAc-hexane) indicated complete reduction of the ester, and the reaction mixture was quenched by stepwise addition of 0.23 mL water, 0.23 mL of 15% sodium hydroxide solution, and finally 0.69 mL of water. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residual oil was redissolved in EtOAc and dried (MgSO4), filtered, evaporated and dried in vacuo to afford 1.884 g (84%) of a tan solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[C:16]([C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:33][CH3:34])=[C:27]([C:30](=O)[CH3:31])[CH:28]=2)[O:23][C:22]([CH3:36])([CH3:35])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[F:7]/[C:6](=[C:30](/[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:33][CH3:34])[O:23][C:22]([CH3:36])([CH3:35])[CH:21]=[C:20]2[C:16]([CH3:17])([CH3:19])[CH3:18])\[CH3:31])/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: COc1cc2c(cc1C(C)=O)C(C(C)(C)C)=CC(C)(C)O2
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.47 mL, 2.3 mmol) and 1-(4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 55, 133 mg, 0.46 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH:23]C(=O)OC(C)(C)C)[CH2:10]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].O>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH2:23])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N[C@H]1C[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of tert-butyl [(6S,8S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl]carbamate (59.0 mg, 0.137 mmol) in dichloromethane (1.37 mL) was added trifluoroacetic acid (105 μL, 1.37 mmol), and the mixture was stirred 1 h. Saturated aqueous sodium bicarbonate was added. Water was added, and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 95% water/acetonitrile 30% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (23 mg). MS 332.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25](OC)([O:28]C)[CH2:26][F:27])[N:20]=2)=[C:15]([C:32]([NH2:34])=[O:33])[CH:14]=1.Cl>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:28])[CH2:26][F:27])[N:20]=2)=[C:15]([C:32]([NH2:34])=[O:33])[CH:14]=1
Reactant: COC(CF)(OC)c1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Agent: Cl
Solvent: CC#N
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C(=O)CF)n3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(2-fluoro-1,1-dimethoxyethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (61 mg, 0.12 mmol) was taken up in acetonitrile (1.2 ml) at room temperature. Hydrochloric acid (0.31 ml, 0.62 mmol) was added in one portion, and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound. Calc'd for C21H19F3N3O3S [M+H]+: 450. Found: 450.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>CC(O)C>[CH3:9][S:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:11][NH2:12])[CH:7]=1
Reactant: CSc1cc(Cl)ncn1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CSc1cc(NN)ncn1
Temperature: 90 °C

Procedure:
A mixture of 4-Chloro-6-methylsulfanyl-pyrimidine (1.1 g, 6.85 mmol), hydrazine monohydrate (1.2 g, 23.5 mmol), and 2-propanol (10 mL) is heated to 90° C. for 4 hours. The reaction mixture is then cooled to room temperature, concentrated, triturated with water, and filtered. The undissolved solid is washed with water, air-dried to give (6-Methylsulfanyl-pyrimidin-4-yl)-hydrazine as light yellow solid: 1H NMR 400 MHz (d6-DMSO) δ 8.29 (s, 1H), 8.16 (s, 1H), 6.55 (s, 1H), 4.34 (s, 2H), 2.43 (s, 3H); MS m/z 157.05 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.O[NH2:18].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)#[N:18]
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
A mixture of 4′-methyl-2-biphenylcarbaldehyde (2.0 g) and hydroxyamine hydrochloride (1.0 g) in pyridine (10 ml) was stirred at room temperature for 15 min., followed by addition of acetic anhydride (4.1 g). The reaction mixture was stirred at 90-100° C. for 1 hr. and concentrated to dryness. After addition of water to the residue, the precipitated crystals were collected by filtration. Recrystallization from hexane gave colorless needles (1.5 g, 79%).