Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])[N:3]=1
Reactant: CCCCN
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCNc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1

Procedure:
A solution of (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (0.408 g, 1.5 mmol): butylamine (0.549 g, 7.5 mmol, 5 eqv.) and ethanol (10 mL) was stirred at reflux for 3 hours. The solution was allowed to cool to room temperature before the addition of 1.5 mL of 1.0 N NaOH. The solution was concentrated and the residues were purified by elution from a silica gel column with 5% methanol-chloroform (0.440 g, 97%). The title compound was dissolved in hot acetonitrile then cooled to produce a white powder, m.p. 116-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:10][CH2:9][C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([CH2:11][CH3:12])[CH2:13][CH3:14]
Reactant: CCC(C#N)(CC)c1cccc(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(CN)c1cccc(N)c1
Yield: 35.2 %

Procedure:
A solution of 2.5 g (13 mmol) of 2-(3-amino-phenyl)-2-ethyl-butyronitrile in 30 ml of tetrahydrofuran was treated with 30 ml (30 mmol) of a 1M solution of lithium aluminium hydride in tetrahydrofuran and the mixture was heated at reflux for 2 hours then cooled. The mixture was cautiously quenched by the addition of 1 ml water, 0.5 ml 2M sodium hydroxide and 1.5 ml water and then filtered through hyflo filter aid. The filtrate was evaporated to give 0.88 g (35%) of 3-(1-aminomethyl-1-ethyl-propyl)-aniline as a pale yellow oil. [Mass spectrum (ESI) MH+ =193].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=O)[CH2:10]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].C([N:53](CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:47])([CH3:48])[C:44]#[N:53])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CCN(CC)CC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C#N)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A suspension of 500 mg 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b), 111.2 mg ammonium chloride and 0.7 ml triethylamine in 5 ml tetrahydrofuran are cooled to −10° C. and 1.21 ml of a T3P® solution (50% in ethyl acetate) is added dropwise. The reaction mixture is warmed to room temperature and stirred for 8 hours. The resulting suspension is stirred at 70° C. for 2 days. During this time, the addition of 111.2 mg ammonium chloride, 0.7 ml triethylamine and 1.21 ml of a T3P® solution (50% in ethyl acetate) is repeated twice. The reaction mixture is quenched by addition of 5 ml of water and extracted with 50 ml ethyl acetate (3×). The combined organic layers are washed with brine and dried with sodium sulfate. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless foam. Rf=0.12 (EtOAc-heptane 1:2); Rt=5.42.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[S:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O>>[Cl:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[S:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(O)CS[C@@H]1CCC[C@H]1Cl
Reactant: CO
Product: COC(=O)CSC1CCCC1Cl
Temperature: 5 °C

Procedure:
trans-[(2-Chlorocyclopentyl)thio]acetic acid was dissolved in methanol (35 ml) and the solution was cooled to 5° C. with an ice bath. Hydrogen chloride gas was bubbled into the solution for 15 minutes. The methanol was removed with a gentle flush of nitrogen gas. The residue was dissolved in diethyl ether (50 ml) and washed twice with 50 ml of 15% sodium hydroxide, dried over anhydrous magnesium sulfate, filtered and concentrated to give the product as an oil. The structure was supported by NMR.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:4]=[N:5][C:6](Cl)=[CH:7][CH:8]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:6]1[N:5]=[N:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: [Na]
Product: Clc1ccc(OCc2ccccc2)nn1
Temperature: 100 °C
Yield: 90 %

Procedure:
Sodium metal (130 mmol, 3.1 g) was added to benzyl alcohol (75 mL) and gently warmed to 50° C. for 30 minutes until all the sodium metal had dissolved. To this was added a solution of 3,6-dichloropyridazine (135 mmol) in benzyl alcohol (75 mL). The reaction was heated at 100° C. for 24 h. Excess benzyl alcohol was evaporated and the residue was extracted with EtOAc (3×100 mL). The EtOAc extract was washed with H2O. The EtOAc layer was collected, dried, filtered and the filtrate was evaporated to yield 3-benzyloxy-6-chloro-pyridazine (90%, 26.7 g); mp 77° C.-78° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)[CH2:32][CH2:31]1>C1COCC1>[NH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[O:13])[CH2:35][CH2:34]2)=[CH:39]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A suspension of quinoline-4-carboxylic acid (0.87g, 5.03 mmol) and triethylamine (0.6g, 5.94 mmol) in dry THF (10 cm3) was stirred at -20° C. while a solution of isobutylchloroformate (0.65g, 5.01 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 31/2 hours then was cooled to -20° C. again and a solution of 3-[2-(4-amino-1-piperidyl)ethyl]indole (1.2g, 4.94 mmol) in dry THF (20 cm3) was added dropwise. The mixture was stirred at room temperature overnight then the solvent was evaporated and the residue triturated with water and aqueous potassium carbonate to give 1.39g of crude title compound.
Reaction SMILES: C([NH:8][CH:9]([C:14]1[N:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[O:30][C:29]([CH3:32])([CH3:31])[N:28]([C:33](=[O:37])[CH:34]([F:36])[F:35])[C@H:27]3[CH2:38][F:39])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])C1C=CC=CC=1>CO.[Pd]>[NH2:8][CH:9]([C:14]1[N:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C@H:26]3[O:30][C:29]([CH3:31])([CH3:32])[N:28]([C:33](=[O:37])[CH:34]([F:36])[F:35])[C@H:27]3[CH2:38][F:39])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(C(NCc4ccccc4)C(F)(F)F)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Agent: [Pd]
Solvent: CO
Product: CC1(C)O[C@H](c2ccc(-c3ccc(C(N)C(F)(F)F)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
A stirred solution of 1-((4R,5R)-5-{4-[6-(1-Benzylamino-2,2,2-trifluoro-ethyl)-pyridin-3-yl]-phenyl}-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl)-2,2-difluoro-ethanone (0.22 g, 0.63 mmol) in methanol (10 mL) at room temperature is degassed with nitrogen for 10 minutes followed by addition of palladium on carbon (0.022 g, 0.0063 mmol). The reaction mixture is stirred at room temperature under hydrogen atmosphere for 16 hours. Reaction mixture is filter through celite, concentrated in vacuo. The crude material is purified by Combi flash eluting in 80% Ethyl acetate in Hexane afford the title compound (0.035 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.52 (s, 3H), 1.60 (s, 3H), 2.60-2.80 (m, 2H), 4.54-4.58 (m, 0.5H), 4.64-4.73 (m, 2H), 4.81-4.85 (m, 0.5H), 4.91-4.95 (m, 1H), 5.27 (d, J=3.6 Hz, 1H), 6.65 (t, J=52.44 HZ, 1H), 7.60 (d, J=8.28 Hz, 2H), 8.03 (m, 2H), 8.14 (d, J=8.32 Hz, 2H), 8.75 (s, 1H). LC-MS (m/z): [M+H]=462.0.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:23][CH2:24][C:25]2[CH:26]=[C:27]([C:31](O)=[O:32])[CH:28]=[CH:29][CH:30]=2)=[N:5][C:6]([NH:17][CH2:18][C@@H:19]([OH:22])[CH2:20][OH:21])=[C:7]([C:15]#[N:16])[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=[N:44]C=2C=1.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C.O1CCCC1.O>[C:1]([C:3]1[C:4]([S:23][CH2:24][C:25]2[CH:26]=[C:27]([C:31]([NH2:44])=[O:32])[CH:28]=[CH:29][CH:30]=2)=[N:5][C:6]([NH:17][CH2:18][C@@H:19]([OH:22])[CH2:20][OH:21])=[C:7]([C:15]#[N:16])[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: N#Cc1c(NC[C@@H](O)CO)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccccc1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(NC[C@@H](O)CO)nc(SCc2cccc(C(N)=O)c2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
68 mg (0.15 mmol) of 3-{[(3,5-dicyano-6-{[(2R)-2,3-dihydroxypropyl]amino}-4-phenylpyridin-2-yl)sulfanyl]methyl}benzenecarboxylic acid Example 23 were dissolved in 3.4 ml of DMF. After addition of 42.5 mg (0.22 mmol) of EDC and 29.9 mg (0.22 mmol) of HOBT, the mixture was stirred at RT for 10 min. 39.5 mg (0.74 mmol) of ammonium chloride and 133.6 mg (1.03 mmol) of N,N-diisopropylethylamine were added, and the reaction mixture was stirred at RT overnight. Water and tetrahydrofuran were added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:53])[C:22]([C:28]4[N:29]=[C:30]([NH:33]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:31][CH:32]=4)=[N:23][O:24][CH2:25][CH2:26][NH2:27])[C:18](=[O:54])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.C(O)=O.O>Cl>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:53])[C:22]([C:28]4[N:29]=[C:30]([NH2:33])[S:31][CH:32]=4)=[N:23][O:24][CH2:25][CH2:26][NH2:27])[C:18](=[O:54])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1

Procedure:
A mixture of 2 g of the product of Step B and 5 ml of formic acid was heated with stirring to 40°-45° C. and after the addition of 5 ml of water, the mixture was stirred at 40°-45° C. for 15 minutes and was then cooled. The mixture was vacuum filtered to remove triphenylcarbinol and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in 10 ml of ethanol with efflorescence and the mixture was vacuum filtered. The recovered product was rinsed with ethanol and then with ether to obtain 1.36 g of raw product which was taken up in 15 ml of 2 N hydrochloric acid. The mixture was vacuum filtered and the filtrate was adjusted to a pH of 4 with 3 ml of an aqueous molar solution of lithium acetate and then with aqueous lithium hydroxide. The mixture was vacuum filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in 30 ml of ethanol with efflorescence and the mixture was vacuum filtered to obtain 515 mg of syn isomer of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7-[2-(2-amino-4-thiazolyl)-2-(2-aminoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid. The mother liquors were evaporated to dryness to obtain another 133 mg of the said product and the combined products were treated again in the same manner to obtain a final yield of 430 mg of the product in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[C:23]([O:26]CC)(=[O:25])[CH3:24]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:23]([OH:26])=[O:25])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(CC#N)cc2Cl)n[nH]c1=O
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(C)c1cc(Cc2c(Cl)cc(CC(=O)O)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetonitrile (55) (assume 0.180 mmol) in concentrated hydrochloric acid (4 mL) was heated to reflux for 24 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (75 mL) and washed with a saturated aqueous sodium chloride solution (20 mL) and water (10 mL). The water layers were combined and extracted with ethyl acetate (50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was purified by HPLC (acetonitrile/water with 0.1% trifluoroacetic acid). The desired fractions were collected, concentrated and freeze dried. The resulting solid was purified by flash chromatography using silica gel eluted with 10% methanol in methylene chloride. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetic acid (56) (8.6 mg, 13% for 2 steps) as a white solid; EI(+)-HRMS m/z calcd for C16H16Cl2N2O3 M+H)+ 355.0611, found 355.0611. MW=355.2235, Exact Mass=354.0538
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][N:12]2[CH:16]=[C:15](C)[N:14]=[CH:13]2)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:18].[CH3:19]C1N=CNC=1.CN1CCNCC1.CN(C=O)C>CCO>[CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][N:12]2[C:16]([CH3:19])=[CH:15][N:14]=[CH:13]2)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:18]
Reactant: Cc1cn(Cc2cc(C)c3c(c2)C(=O)CC3)cn1
Reactant: Cc1c[nH]cn1
Agent: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cc(Cn2cncc2C)cc2c1CCC2=O

Procedure:
A mixture of Example 922A and Example 922B was obtained by substituting Example 917G for Example 54, 4-methylimidazole for N-methypiperazine, and DMF for EtOH in Example 56. The isomers were separated by flash chromatography.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][CH:9]([CH:11]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)[N:19]=3)[CH:15]=[N:14]2)[CH3:12])[CH2:8][C:7]1=[O:36]>C(O)(C(F)(F)F)=O>[CH3:24][C:22]1[CH:21]=[C:20]([NH:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][N:27]=2)[N:19]=[C:18]([C:16]2[CH:15]=[N:14][N:13]([CH:11]([CH:9]3[CH2:10][NH:6][C:7](=[O:36])[CH2:8]3)[CH3:12])[CH:17]=2)[CH:23]=1
Reactant: COc1ccc(CN2CC(C(C)n3cc(-c4cc(C)cc(Nc5cc(C(F)(F)F)ccn5)n4)cn3)CC2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(C(C)C3CNC(=O)C3)c2)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(2,4-dimethoxybenzyl)-4-{1-[4-(4-methyl-6-{[4-(trifluoromethyl)-pyridin-2-yl]amino}pyridin-2-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-2-one (100 mg, 0.17 mmol) in TFA (5 mL) was stirred at 60° C. for 3 hours. The solvent was removed under reduced pressure and the crude product was purified by reverse phase HPLC (ACN/water with 0.1% formic acid modifier) to afford 4-{1-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-2one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[CH:33][C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cccc2c1CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Agent: Cl
Product: COc1cccc2c1CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 23.7 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 6 (23.7% yield). 1H NMR (400 MHz, CDCl3) δ 2.79 and 3.05 (2t, 2H), 3.56 and 4.21 (2t, 2H), 3.84 and 3.89 (2s, 3H), 4.52 and 5.13 (2s, 2H), 6.41-6.43 (m, 0.3H), 6.77-6.80 (m, 1H), 6.91-6.93 (m, 0.7H), 7.10 (m, 0.3H), 7.19-7.30 (m, 2.7H), 7.58-7.65 (m, 1H), 7.93-7.98 (m, 1.3H), 8.02-8.04 (m, 0.7H), 8.15-8.19 (m, 1H), 8.63-8.71 (m, 2H); 19F (376 MHz, CDCl3) δ −110.0; MS (ESI) m/z 414 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11])[C:5]([F:8])=[N:6][CH:7]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:12][C@H:13]([OH:18])[C:14]([F:15])([F:17])[F:16])[CH2:10][F:11])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(CC(=O)C(F)(F)F)c1cc(Br)cnc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)cnc1F
Temperature: 0 °C
Yield: 58 %

Procedure:
(R)-N-((S)-2-(5-bromo-2-fluoropyridin-3-yl)-1,5,5,5-tetrafluoro-4-oxopentan-2-yl)-2-methylpropane-2-sulfinamide (6.32 g, 14.01 mmol) was dissolved in anhydrous methanol 75 mL and the solution was cooled in an ice bath. Sodium tetrahydroborate (0.795 g, 21.01 mmol) was added portionwise as solid. After stirring in the ice bath for 10 min, the reaction was worked up with saturated sodium bicarbonate and extracted with EtOAc three times. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 15-50% EtOAc/hexane to give (R)-N-((2S,4S)-2-(5-bromo-2-fluoropyridin-3-yl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (12e, 3.68 g, 58% yield). MS m/z=454.9 [M+H]+. Calculated for C14H18BrF5N2O2S: 453.3; and (R)-N-((2S,4R)-2-(5-bromo-2-fluoropyridin-3-yl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (1.5 g, 24% yield). MS m/z=454.9 [M+H]+. Calculated for C14H18BrF5N2O2S: 453.3.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[CH2:5]Cl.N#N.[NH2:13][C:14]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:15]=1[C:16]#[N:17]>C1COCC1.[Zn]>[NH2:13][C:14]1[CH:21]=[CH:20][C:19]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=2)=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1cc(I)ccc1N
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: N#N
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1cc(Cc2ccccc2)ccc1N
Temperature: 68 °C
Reaction time: 10 h

Procedure:
A suspension of active Zn metal in THF (0.76 M, 6.3 mL calculated to contain 4.8 mmol or a 20% theoretical excess) was placed in a thoroughly dried three-necked flask which was flushed continuously with a gentle stream of dry N2. A solution of 3,4-dichlorobenzyl chloride (790 mg, 4 mmol) in dry THF (2 mL) was then added slowly to the flask at room temperature, and the reaction mixture was stirred at 68° C. for 10 h and left to stand for 3 h to allow the excess Zn metal to settle to the bottom. The dark-brown solution of organozinc reagent was transferred via a cannula using gentle N2 pressure into another three-necked flask, to which was then added dropwise a solution of 9 (244 mg, 1 mmol) in dry THF (1 mL). Standard workup as for 10a afforded 10e as a pale-yellow powder (172 mg; 65%): mp 104-107° C.; 1H NMR (CDCl3) δ 3.80 (s, 2H, CH2), 4.35 (br s, 2H, NH2), 6.68 (d, J=8.4 Hz, 1H-3), 6.97 (dd, J=8.0 Hz, 2.0 Hz, 1H, H-6′), 7.11 (s, J=8.4 Hz, H-4), 7.16 (s, 1H, H-6), 7.22 (d, J=2.0 Hz, 1H, H-2), 7.35 (d, J 8.0 Hz, 1H, H-5′).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1>C1(C)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cc(OC)c(OC)cc1OC)C(=O)OCC
Yield: 87.8 %

Procedure:
In 80 ml of toluene is dissolved 5.9 g of 2,4,5-trimethoxybenzaldehyde, followed by addition of 4.8 g of diethyl malonate, 0.3 ml of piperidine and 0.3 g of benzoic acid. The mixture is heated under reflux for 4 hours, water being removed via an ester tube. After cooling, the solvent is distilled off under reduced pressure and the residual crystals are recovered by filtration with n-hexane to give 8.9 g (87.3%) of diethyl 2,4,5-trimethoxybenzylidenemalonate, m.p. 86°-87° C.
Reaction SMILES: Cl[Si](C)(C)C.[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:15]([O:26]C)=[N:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:19]=1)#[N:7].[I-].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:15](=[O:26])[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:19]=1)#[N:7]
Reactant: COc1ncc(-c2ccccn2)cc1-c1ccccc1C#N
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
Chlorotrimethylsilane (0.1 ml) was added to a suspension of 0.20 g of 3-(2-cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine and 0.12 g of sodium iodide in 10 ml of acetonitrile and the mixture was stirred at room temperature for 3 hours. A saturated sodium bicarbonate solution was added to the mixture followed by extracting with ethyl acetate. The ethyl acetate layer was washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:1) to give 0.11 g of the title compound in pale yellow powder.