Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cnc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cnc3ccccc3c2)CC1
Reaction time: 16 h
Yield: 56 %

Procedure:
A mixture of quinolin-3-ylamine (3.62 g, 25.09 mmol, 1.0 equiv, commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 25.09 mmol, 1.0 equiv; commercially available) in conc. acetic acid (1.44 mL, 1.51 g, 25.09 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (6.38 g, 30.11 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:1→9:1). Trituration from heptane/ethyl acetate provided 4.60 g (56%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.36-1.46 (m, 2H), 1.49 (s, 9H), 2.12 (d, J=10.5 Hz, 2H), 3.00 (t, J=11.9 Hz, 2H), 3.47-3.64 (m, 1H), 3.89 (d, J=7.7 Hz, 1H), 4.10 (br s, 2H), 7.03 (d, J=2.7 Hz, 1H), 7.37-7.47 (m, 2H), 7.59-7.64 (m, 1H), 7.89-7.98 (m, 1H), 8.42 (d, J=2.7 Hz, 1H).
Reaction SMILES: OC(CCCCCCCO)CCCCCCCC(O)=O.O[CH:22]([CH:33]([OH:43])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].OCCCCCCCCCCCCCCCCCCCCCC(O)=O.OCCCCCCCCC=CCCCCCCCC(O)=O.C(O)(=O)CCCCCCCCCCCCCCCCCCCCC(O)=O.C(O)(=O)CCCCCCCC=CCCCCCCCC(O)=O>>[O:43]1[CH:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42])[CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: O=C(O)CCCCCCCC(O)C(O)CCCCCCCCO
Agent: O=C(O)CCCCCCCC(O)CCCCCCCO
Agent: O=C(O)CCCCCCCC=CCCCCCCCC(=O)O
Agent: O=C(O)CCCCCCCC=CCCCCCCCCO
Product: O=C(O)CCCCCCCC1OC1CCCCCCCCO

Procedure:
The present invention provides a process for isolating, from outer birch bark, at least one of 9,10-epoxy- 18-hydroxyoctadecanoic acid; 9,16-dihydroxyhexadecanoic acid; 9,10,18-trihydroxyoctadecanoic acid (phloionolic acid); 20-hydroxyeicasanoic acid; 22-hydroxydocosanoic acid; 18-hydroxyoctadec-9-enoic acid; docosandioic acid; and octadec-9-enedioic acid; comprising: (1) subjecting the outer birch bark to hydrolysis to provide a second outer birch bark and a second solution; (2) separating the second solution from the second outer birch bark; (3) condensing the second solution at a temperature below about 50° C. to provide at least one of 9,10-epoxy-18-hydroxyoctadecanoic acid; 9,16-dihydroxyhexadecanoic acid; 9,10,18-trihydroxyoctadecanoic acid (phloionolic acid); 20-hydroxyeicasanoic acid; 22-hydroxydocosanoic acid; 18-hydroxyoctadec-9-enoic acid; docosandioic acid; and octadec-9-enedioic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]2[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Cl)nc(Cl)c2)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
500 mg of 2,6-dichloro-4-iodopyridine, 379 mg of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole, 753 mg of potassium carbonate and 74 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex were added in turn to a degassed mixed solvent of 7.5 ml of 1,4-dioxane and 2.5 ml of water, and the mixture was stirred at 90° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 257 mg of the objective compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)=[O:10])[CH2:3][CH2:2]1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[CH:25]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]3[CH:15]=[N:14][NH:13][CH:12]=3)=[O:10])[CH2:3][CH2:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NCC1CCNCC1)c1cn[nH]c1
Reactant: O=C[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(NCC1CCN(C[C@@H]2C[C@H]2c2ccccc2)CC1)c1cn[nH]c1
Reaction time: 1 h

Procedure:
A solution of 1H-pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide (290 mg, 1.39 mmol), trans-2-phenylcyclopropanecarbaldehyde (224 mg, 1.53 mmol) and sodium triacetoxyborohydride (590 mg, 2.78 mmol) in MeOH (15 mL) was heated to 50° C. and stirred for 1 h. The resulting reaction mixture was concentrated and purified by silica gel chromatography (gradient: CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) to give the trans 1H-pyrazole-4-carboxylic acid [1-(2-phenyl-cyclopropylmethyl)-piperidin-4-ylmethyl]-amide product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:21](=[O:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[C:11]([CH:21]([OH:23])[CH3:22])=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC=O
Reactant: Fc1cccc2ccc(Cl)nc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cc2cccc(F)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-8-fluoroquinoline (182 mg, 1.0 mmol) was dissolved in THF (2 mL) and cooled to −78° C. To this solution was added Lithium diisopropylamide (1M solution in TIM, 1.1 mL, 1.1 mmol, 1.1 eq). The reaction was allowed to stir at −78° C. for 20 min, after which time acetaldehyde (113 μl, 2.0 mmol, 2 eq.) was added via syringe. After 30 minutes, the reaction was quenched with water and diluted with ethyl acetate. The layers were separated and washed with brine. The crude reaction mixture was purified by column chromatography (8:2 hexanes:ethyl acetate) to afford 1-(2-chloro-8-fluoroquinolin-3-yl)ethanol. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s, 1H), 7.64 (td, J=7.8, 5.1 Hz, 1H), 7.41 (ddd, J=10.2, 7.4, 1.2 Hz, 1H), 5.39 (qdd, J=6.3, 3.9, 0.8 Hz, 1H), 2.22 (d, J=3.9 Hz, 1H), 1.62 (d, J=6.3 Hz, 3H).
Reaction SMILES: CC(C)(S([NH:6][C:7]1([CH3:21])[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1)=O)C.[ClH:23]>CO.O1CCOCC1>[ClH:23].[NH2:6][C:7]1([CH3:21])[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9][CH2:8]1
Reactant: CC1(NS(=O)C(C)(C)C)CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1(N)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of tert-butyl 4-(1,1-dimethylethylsulfinamido)-4-methylcyclohexylcarbamate (0.2 g, 0.6 mmol) in 100 mL of MeOH was added a saturated solution of HCl (g) in dioxane (0.72 mL). The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was triturated with EtOAc (15 mL), then decanted and dried to give tert-butyl 4-amino-4-methylcyclohexylcarbamate hydrochloride (0.1 g, 63%) as a white solid. MS: (M+H)+=229.2. 1H NMR (300 MHz, CD3OD): δ 3.36 (m, 1H), 1.91-1.66 (m, 9H), 1.40 (s, 9H), 1.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)O)=[CH:17][CH:16]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:5]2[C:4]3[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)=[CH:19][CH:20]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 11A and 667 mg (2.56 mmol) of the compound from Example 81A in analogy to the synthesis of the compound from Example 278. A difference was that stirring at 80° C. was for only 4 h. 535 mg (50% of theory) of the target compound were obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[N:16]=[C:17]([NH2:21])[N:18]=[C:19](Cl)[C:14]=2[CH:13]=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([NH:29][NH2:30])=[O:28]>C(O)CCC>[NH2:21][C:17]1[N:18]=[C:19]([NH:30][NH:29][C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[C:14]2[CH:13]=[CH:12][N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:15]=2[N:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc2c(Cl)nc(N)nc21
Reactant: NNC(=O)c1ccco1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2c(NNC(=O)c3ccco3)nc(N)nc21
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The title A compound, 7-[2-(t-Butyldimethylsilanyloxy)ethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (100 mg, 0.3 mmol) and 2-furoic acid hydrazide (76 mg, 0.6 mmol) are taken into 3 mL of n-butanol. The mixture is stirred at 120° C. under N2 for 2 h. The solvent is evaporated under vacuum and the residue is purified by flash chromatography using EtOAc/MeOH (95/5) as eluent to give furan-2-carboxylic acid N′-{2-amino-7-[2-(t-butyldimethylsilanyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-hydrazide: LC/MS (M+1=417). 1H NMR (CDCl3, 400 MHz) δ-0.08 (s, 6H), 0.84 (s, 9H), 3.85 (t, 2H, J=4.8 Hz), 4.12 (t, 2H, J =4.8 Hz), 4.81 (br s, 2H, NH2), 6.26 (d, 1H, J=2.4 Hz), 6.51 (m, 1H), 6.74 (d, 1H, J=2.4 Hz), 7.20 (d, 1H, J=2.8 Hz), 7.27 (d, 1H, J=2.8 Hz), 7.49 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][C:4]=1[B:12]([OH:14])[OH:13].[H-].[Na+].I[CH3:18]>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([CH3:18])[C:6]2=[CH:5][C:4]=1[B:12]([OH:14])[OH:13]
Reactant: CI
Reactant: COc1nc2cc[nH]c2cc1B(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc2ccn(C)c2cc1B(O)O
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a white suspension of 5-methoxy-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (500 mg, 2.60 mmol) in tetrahydrofuran (25 mL) was added sodium hydride (281 mg, 11.72 mmol) in several portions at 0° C., the resulting light grey suspension was stirred for 30 min, followed by dropwise addition of iodomethane (1664 mg, 11.72 mmol) in syringe. The mixture was continued stirring at 0° C. for 2 hr and the reaction was quenched with conc. HCl at 0° C. to ˜pH 6, MeOH (20 mL) was added, stirred for 2 min, the resulting suspension was passed through a thin layer silica gel with 10 mL MeOH. The collected solution was concentrated on rotary vacuo, and purified on PrepHPLC to afford the expected product, 5-methoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (398 mg, 74%) as a grey gum. 1H-NMR (500 MHz, MeOD) δ ppm 3.33 (ddd, J=3.20, 1.83, 1.68 Hz, 3 H) 4.24 (s, 3 H) 6.62 (d, J=2.44 Hz, 1 H) 7.71 (d, J=3.36 Hz, 1 H) 8.39 (s, 1 H); Mass spec 207.16 (MH+) Calc for C9H11BN2O3 206.09.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([CH2:22][C:23]#[N:24])[CH:19]=[CH:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-:26].[K+].[K+].OO.O>CS(C)=O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([CH2:22][C:23]([NH2:24])=[O:26])[CH:19]=[CH:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCc1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Cc1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Reaction time: 72 h
Yield: 70.1 %

Procedure:
To a solution of (3-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (58.3 mg) obtained in Example 128 in DMSO (5 mL) were added potassium carbonate (30.4 mg) and 30% aqueous hydrogen peroxide (0.056 mL), and the mixture was stirred for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (43.2 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@@:12]3([C:20]#[CH:21])[F:19])[C:4]=2[N:5]=[CH:6][N:7]=1.ClC1N=CN=C2C=1[N:25]=CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C#C)F>>[NH2:25][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@@:12]3([C:20]#[CH:21])[F:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Product: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21

Procedure:
7l was synthesized from 6g as described for 6a. White lyophilised powder. Molecular Formula C13H13FN4O3. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 3.61 (d, J=5.52 Hz, 1H), 3.63-3.67 (m, 1H), 3.80-3.83 (d, J=12.14 Hz, 1H), 3.86-3.88 (d, J=9.38 Hz, 1H), 4.46-4.54 (dd, J=23.23 Hz and J=9.39 Hz, 1H), 5.30 (brs, 1H), 6.1 (brs, 1H), 6.41-6.47 (d, J=16.47 Hz, 1H), 6.57-6.61 (d, J=16.47 Hz, 1H), 7.04 (s, 2H), 7.37-7.38 (d, J=3.65 Hz, 1H), 8.05 (s, 1H) 19F NMR (DMSO-d6, 235 MHz) δ (ppm) −157.15 (s, 1F) Scan ES+ 293 (M+H)+, UV λmax 275 nm
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.[CH:16](C1NC=CN=1)=[O:17]>>[CH:16]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)=[O:17]
Reactant: O=Cc1ncc[nH]1
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Product: CC1CCC2(O1)C(C)(C)CCCC2(C)OC=O
Reaction time: 48 h

Procedure:
0.4 g (0.002 M) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol -- isomer A; see Example 1 -- were intimately mixed with 0.5 g (0.005 M) of freshly sublimated formylimidazole and then kept for 2 days at room temperature. The reaction mixture was then extracted with ether and the organic layer washed, dried, evaporated and finally subjected to a fractional distillation to give 0.3 g of a product having b.p. 70°-80°/0.5 Torr and containing 60% of the desired ester. An analytical sample was purified by vapour phase chromatography.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[O:10]=[C:11]1[NH:20][CH:19]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:18]2[C:17](=[O:29])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)=[O:42].O>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([C:24]1[CH:23]=[CH:22][C:21]([CH:19]2[C:18]3[C:17](=[O:29])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)[C:11](=[O:10])[N:20]2[C:41]([O:43][C:44]2[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=2)=[O:42])=[CH:28][CH:27]=1)#[N:26]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
N,N-Diisopropylethylamine (1.65 mL, 9.72 mmol) and 4-dimethylaminopyridine (59 mg, 0.49 mmol) are added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 1.00 g, 2.43 mmol) in dichloromethane (6 mL), and the mixture is cooled in an ice bath. A solution of 4-nitrophenyl chloroformate (540 mg, 2.67 mmol) in dichloromethane (2 mL) is added, and the mixture is warmed to room temperature. After 3 h another portion of 4-nitrophenyl chloroformate (980 mg, 4.86 mmol) and N,N-diisopropylethylamine (830 μL, 4.86 mmol) are added, and the mixture is stirred over night. Water is added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified twice by flash chromatography on silica (first purification: gradient cyclohexane/ethyl acetate 100:0 to 70:30, second purification: gradient cyclohexane/ethyl acetate 100:0 to 50:50). Yield: 374 mg; ESI mass spectrum [M+H]+=577, Retention time HPLC: 0.92 min (Z018_S04).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]2[C:11]=1[CH3:12].[CH3:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([CH3:23])[C:15]=1[CH2:16]Br.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:16][C:15]3[C:14]([CH3:13])=[CH:21][C:20]([F:22])=[CH:19][C:18]=3[CH3:23])=[CH:8][CH:7]=[CH:6][N:5]2[C:11]=1[CH3:12]
Reactant: Cc1nc2c(O)cccn2c1C
Reactant: Cc1cc(F)cc(C)c1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cc(F)cc(C)c1COc1cccn2c(C)c(C)nc12

Procedure:
2,3-Dimethyl-8-hydroxyimidazo[1,2-a]pyridine (1.7 g, 10 mmol), 2,6-dimethyl-4-fluorobenzylbromide (2.3 g, 10 mmol), sodium iodide (0.5 g, 0.3 mmol) and sodium carbonate (2.6 g, 28 mmol) were added to acetone (75 ml) and the mixture was refluxed for 6 h. Methylene chloride was added and the mixture was filtered and the solvents were evaporated under reduced pressure. Purification by column chromatography on silica gel using methylene chloride:ethylacetate(1:2) as eluent gave the title compound as a white powder. (0.85 g, 28%)
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:33])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C=O.[C:36]([BH3-])#N.[Na+].O>CO>[F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][N:30]([CH3:36])[CH2:29][CH2:28]5)[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:33])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCC(n2cc(-c3ccc4ncc(Cc5c(F)cc6ncccc6c5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5,7-Difluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 245, 40 mg, 0.090 mmol) was dissolved in MeOH (1.5 mL) with formaldehyde (0.034 mL, 0.449 mmol) and sodium cyanoborohydride (33.2 mg, 0.449 mmol). The RM was stirred at rt for 2 h. Water was added and it was extracted with EtOAc twice. Combined organic layers were washed with brine and dried over Na2SO4, filtered and the solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound (tR 0.8 min (conditions 2), MH+=460).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[CH3:23][NH:24][CH3:25].Cl>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[N:24]([CH3:25])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
3.84 ml of triethylamine was added, at -15° to -20° C., to a solution of 5.8 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 85 ml of dry tetrahydrofuran, and then a solution of 2.63 ml of ethyl chloroformate in 25 ml of dry tetrahydrofuran was added to the resulting mixture at the same temperature. The reaction mixture was then stirred for 2 hours, after which 19.75 ml of 50% by volume aqueous dimethylamine was added to it at -20° to -25° C. The mixture was then stirred for 3 hours under ice cooling, after which is was allowed to stand overnight at room temperature. At the end of this time, the mixture was poured into a mixture of 30 ml of concentrated hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 429 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[O:17][C:18]([F:21])([F:20])[F:19].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:10][C:11]1[CH:12]=[C:13]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=2)[CH:14]=[CH:15][C:16]=1[O:17][C:18]([F:19])([F:20])[F:21]
Reactant: OB(O)c1ccc(OC(F)(F)F)c(F)c1
Reactant: OCc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: OCc1ccc(-c2ccc(OC(F)(F)F)c(F)c2)cn1
Temperature: 89 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
A stirred mixture of (5-bromo-2-pyridinyl)methanol (105) (753 mg, 4.00 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (56) (see Example 2G) (1.165 g, 5.20 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol) in toluene (40 mL) and EtOH (20 mL) was degassed for 15 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (10 mL, 20.0 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added. The resulting mixture was stirred at 89° C. for 2 h, and then cooled, diluted with aqueous NaHCO3 (120 mL) and extracted with CH2Cl2 (6×100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 50-75% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 75% CH2Cl2/petroleum ether and 0-0.5% MeOH/CH2Cl2 gave {5-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-pyridinyl}methanol (106) (687 mg, 60%) as a light yellow-brown solid: mp 51-53° C.; 1H NMR (CDCl3) δ 8.76 (d, J=1.9 Hz, 1H), 7.84 (dd, J=8.1, 2.3 Hz, 1H), 7.46-7.34 (m, 4H), 4.83 (d, J=5.1 Hz, 2H), 3.47 (t, J=5.2 Hz, 1H); HRESIMS calcd for C13H10F4NO2m/z [M+H]+ 288.0642, found 288.0641.