Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[N:15]=[C:14]([CH3:16])[C:13](=S)[NH:12]3)=[CH:4][CH:3]=1.[NH3:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[N:12]=[C:13]([NH2:18])[C:14]([CH3:16])=[N:15]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1=NC2(CCCc3ccc(Br)cc32)NC1=S
Product: CC1=NC2(CCCc3ccc(Br)cc32)N=C1N
Temperature: 110 °C
Yield: 65.6 %

Procedure:
7′-Bromo-4-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalene]-5(1H)-thione (Example 51 Step 3, 1 g, 3.23 mmol) was taken up in ammonia (7M in MeOH, 15 mL, 105 mmol) and the resulting mixture was heated in the microwave reactor at 110° C. for 30 min. The solvent was evaporated. Ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again using MW for 30 min at 110° C. The solvent was evaporated. Ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again using MW for 30 min at 110° C. The solvent was evaporated and the residue was dissolved in EtOAc (20 mL). The resulting mixture was extracted with 0.1 M citric acid (2×10 mL). The organic layer was discarded while the aqueous phase was basified to pH 12 by addition of 50% NaOH (aq) and extracted with DCM (3×20 mL). The organic phase was dried with a phase separator and concentrated in vacuo to give the title compound (0.619 g, 65% yield). 20 mg of the product was purified using flash chromatography (4 g SiO2, DCM in 0.1M NH3 in MeOH) to give the title compound (10 mg). 1 H NMR (500 MHz, CDCl3) δ ppm 1.88-1.99 (m, 2 H), 2.07-2.16 (m, 1 H), 2.20 (dqd, 1 H), 2.31-2.37 (m, 3 H), 2.92 (t, 2 H), 6.68 (d, 1 H), 7.04 (d, 1 H), 7.25 (dd, 1 H); 1 H NMR (500 MHz, CD3OD) δ ppm 1.84 (ddd, 1 H), 1.94 (ddd, 1 H), 2.03-2.12 (m, 1 H), 2.15 (dtd, 1 H), 2.34 (s, 3 H), 2.91 (t, 2 H), 6.69 (d, 1 H), 7.11 (d, 1 H), 7.29 (dd, 1 H), MS (ES+) m/z 292 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][CH3:25])[CH3:21].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C=[O:39])C>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[C:24]1[O:39][C:32]2[CH:33]=[CH:34][N:29]=[CH:30][C:31]=2[CH:25]=1)[CH3:21]
Reactant: CCOC(CC)OCC
Reactant: C1CCNCC1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(OCC)c1cc2cnccc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
C10 (3.5 g, 15.8 mmol) is added to a suspension of triphenylphosphine (166 mg, 0.63 mmol) and palladium acetate (71 mg, 0.32 mmol) in 25 mL DMF in dry flask under N2. Propioaldehyde diethyl acetal (2.3 mL, 15.8 mmol), cuprous iodide (120 mg, 0.63 mmol), and piperidine (1.6 mL, 16 mmol), are added successively, and the reaction is stirred 6 h at rt. The mixture is diluted with 125 mL EtOAc, is extracted with 4×50 mL 50% saturated 1:1 NaCl/NaHCO3, and the organic layer is dried over anhydrous Na2SO4 and then filtered. The dried organic layer is concentrated in vacuo to a dark oil. The crude material is chromatographed over 40 g silica gel (Biotage), eluting with 50% EtOAc/hexane. The fractions with the desired compound are combined and concentrated to afford 2-(diethoxymethyl)furo[3,2-c]pyridine (C11) (64% yield). HRMS (FAB) calculated for C12H15NO3+H: 222.1130, found 222.1123 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][NH:20][CH2:21][C:5]=3[C:4]=2[CH:3]=1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23].C(O)(=O)C>CO>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:6]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:22][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: Fc1ccc(-n2c3c(c4cc(F)ccc42)CNCC3)cc1
Reactant: C=Cc1ccccn1
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(-n2c3c(c4cc(F)ccc42)CN(CCc2ccccn2)CC3)cc1
Yield: 89.9 %

Procedure:
A mixture of 8-fluoro-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3 g, 0.01 mole), 2-vinylpyridine (1.7 g, 0.01 mol) and 2 mL of glacial acetic acid were refluxed for 48 hours in 30 mL of methanol. The solvent was removed in vacuo and the separated solid was purified by HPLC using ethyl acetate as the eluant to afford 3.5 g (89.9% yield) of the title compound. It was converted to the dihydrochloride salt; mp. 267°-270° C.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([O:16]CC)(=[O:15])C>>[F:2][CH2:3][CH2:4][CH2:5][NH:6][C:13](=[O:15])[O:16][C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: NCCCF
Reactant: CCCCCC
Reactant: CCOC(C)=O
Agent: Cl
Product: O=C(NCCCF)Oc1ccccc1
Yield: 29.42 %

Procedure:
3-Fluoropropylamine hydrochloride (0.92 g (wet), 8.10 mmol) was used for reaction in the same manner as Production Example 310-1, and purification was performed by silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (0.470 g, 2.3832 mmol, 29.42%) as pink crystals.
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1)=[O:2].C(N(CC)CC)C.Cl[C:20](OCC(C)C)=[O:21].[NH2:27][CH:28]1[C:35](=[O:36])[N:34]2[CH:29]1[S:30][CH2:31][C:32]([CH3:40])=[C:33]2[C:37]([OH:39])=[O:38]>O1CCCC1>[CH:1]([C:3]1[N:4]([CH2:8][C:9]([NH:27][C:28]2([O:21][CH3:20])[C:35](=[O:36])[N:34]3[CH:29]2[S:30][CH2:31][C:32]([CH3:40])=[C:33]3[C:37]([OH:39])=[O:38])=[O:11])[CH:5]=[CH:6][CH:7]=1)=[O:2]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: O=Cc1cccn1CC(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1(NC(=O)Cn2cccc2C=O)C(=O)N2C(C(=O)O)=C(C)CSC21
Temperature: 0 °C

Procedure:
A solution of (2-formyl-1-pyrryl)acetic acid (0.02 m) and triethylamine (0.02 ml) in tetrahydrofuran (THF) is cooled to 0° C. While stirring, isobutyl chloroformate (0.02 m) is added and the temperature is maintained at 0° C. for 15 minutes. A cold solution of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.02 m) and triethylamine (0.02 m) in 50% aqueous THF is added to the previous solution with stirring.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:23]=2)=[CH:17][CH:16]=1.N1C=CC=CC=1>ClCCCl>[C:3]([NH:5][C:9](=[O:10])[NH:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH:23]=2)=[CH:17][CH:16]=1)(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(N)=O
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.750 g, 7.42 mmol) in DCE (10 mL) was treated with oxalyl chloride (0.600 mL, 7.09 mmol), stirred at RT for 10 min, then heated at 80° C. for 1 h. The mixture was cooled to RT, partially concentrated, then added drop-wise to a solution of tert-butyl (4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)carbamate (1.6 g, 5.29 mmol) in pyridine (0.60 mL, 7.44 mmol) and stirred at RT for 45 min. The mixture was concentrated to dryness, treated with MeCN, sonicated and the solids collected via filtration. The filtrate was concentrated to dryness, suspended in MeCN, sonicated, the resulting solid collected via filtration and combined with the above-isolated solid to afford tert-butyl (4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (1.6 g, 70%). MS (ESI) m/z: 430.2 (M+H+).
Reaction SMILES: ClC1N=C(C2C=CC=CC=2)N=C(OCCC(C)C)C=1.ClC1C=C(Cl)N=C(C2C=CC=CC=2)N=1.Cl[C:35]1[CH:40]=[C:39]([Cl:41])[N:38]=[C:37]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[N:36]=1.[CH2:52]([CH:54]([CH2:57][CH2:58][CH2:59][CH3:60])[CH2:55][OH:56])[CH3:53]>CC(C)CCO>[Cl:41][C:39]1[N:38]=[C:37]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[N:36]=[C:35]([O:56][CH2:55][CH:54]([CH2:52][CH3:53])[CH2:57][CH2:58][CH2:59][CH3:60])[CH:40]=1
Reactant: CCCCC(CC)CO
Reactant: CCCCCCCCCCc1nc(Cl)cc(Cl)n1
Agent: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Agent: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CC(C)CCO
Product: CCCCCCCCCCc1nc(Cl)cc(OCC(CC)CCCC)n1

Procedure:
The compound of Example 25 is prepared analogously to the compound of Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-decylpyrimidine and 3-methylbutanol by 2-ethylhexanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:21])[CH:11]([OH:20])[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Bi]=O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:21])[C:11]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)C(O)c2ccc(SC)cc2)cc1F
Agent: O=[Bi]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(=O)c2ccc(SC)cc2)cc1F
Temperature: 90 °C
Yield: 32.5 %

Procedure:
1-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-2-[4-(methylthio)phenyl]ethanone from step 2 (6.5 mmol, 2.00 g) was diluted with glacial acetic acid (30 ml). Bismuth oxide (11.4 mmol, 5.30 g) was added and the mixture was heated at 90° C. for 2 hours. The crude mixture was filtered through Celite® filter agent, lyophilized and subjected to chromatography, affording the title compound as a yellow solid (642 mg, 32%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[CH3:17][I:18]>CN(C=O)C>[I-:18].[CH3:17][N:13]1[C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]=2[N:6]([CH2:5][O:4][CH2:3][CH2:2][OH:1])[CH2:14]1
Reactant: CI
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Solvent: CN(C)C=O
Product: CN1CN(COCCO)c2nc(N)[nH]c(=O)c21
Product: [I-]
Temperature: 57 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 9-(2-hydroxyethoxymethyl)guanine (1.0 g; 4.44 mmol) in dry DMF (50 ml) was added a solution of methyl iodide (680 mg, 4.77 mmol) in dry DMF (2 ml). This mixture was heated under a reflux condenser under N2 at 57° C. overnight. The mixture was concentrated in vacuo to an oil and the evaporation was repeated several times from MeOH. The residue was dissolved in MeOH (20 ml) and 2-propanol (150 ml) was added and the mixture was stirred overnight. A yellow solid was obtained which was filtered off (200 mg). This was recrystallized from MeOH (25 ml) (solution filtered through a little charcoal). Crystallization was induced by concentration of the solution, cooling and by the addition of a little 2-propanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C.O>C1COCC1>[C:14]([O:13][C:11](=[O:12])[CH2:10][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NCC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of p-toluidine (200 mmol) in THF (500 mL) was treated with tert-butyl bromoacetate (220 mmol) and DIPEA (440 mmol) at RT. The reaction mixture was heated to reflux for 16 h and cooled to RT. Water (200 mL) and EE (500 mL) were added, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with water and brine. The solvents were removed in vacuo and the residue (44 g) was used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][OH:12].[OH-].[Na+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.ClCCl>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:12][CH2:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: BrCCCCCCBr
Reactant: OCCc1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: BrCCCCCCOCCc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-benzoxazoleethanol (1.46 g), 50% sodium hydroxide (3 ml), 1,6-dibromohexane (3 ml), TAB (100 mg) and dichloromethane (2 ml) was vigorously stirred at room temperature for 22 h, diluted with water (15 ml) and extracted with ether (40 ml). The organic phase was washed with brine (10 ml), dried and evaporated in vacuo. The residual oil was purified by FCC. Elution with hexane and hexane-ether (19:1) followed by hexane-ether (2:1) and ether gave the title compound as a pale yellow oil (1.60 g) which solidified on refrigeration.
Reaction SMILES: N#N.[F:3][C:4]([F:14])([F:13])[C:5]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH3:12])=[O:6].CN1CCOCC1.Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:26]([O:25][C:23](=[O:24])[N:11]([CH3:12])[CH2:10][CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]([F:13])([F:14])[F:3])([CH3:28])[CH3:27]
Reactant: CC(C)OC(=O)Cl
Reactant: CNCCCNC(=O)C(F)(F)F
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N(C)CCCNC(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a rapidly stirred, 0° C., N2 blanketed, solution of 2,2,2-trifluoro-N-(3-methylamino-propyl)-acetamide (6.0 g, 32.4 mmol) and N-methylmorpholine [109-02-4] (7.1 mL, 64.6 mmol) in ethyl acetate (65 mL) was steadily added a 1.0M solution of isopropyl chloroformate in toluene (32.4 mL) over the course of 10 minutes. The reaction was allowed to stir and warm to ambient temperature over night at which time it was washed with brine, dried (MgSO4) and evaporated to provide 9.0 g of clear yellow oil. LRMS (ESI) m/z 271.1 [(M+H)]+, calc'd for C10H17F3N2O3: 270.25.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]#[N:11])[CH:5]=1)([O-:3])=[O:2].Cl[Si](C)(C)C.[OH2:17]>CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH2:11])=[O:17])[CH:5]=1)([O-:3])=[O:2]
Reactant: O
Reactant: N#Cc1cc([N+](=O)[O-])ccn1
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc([N+](=O)[O-])ccn1
Yield: 119.7 %

Procedure:
4-Nitropicolinonitrile (100 mg, 0.67 mmol), chlorotrimethylsilane (0.17 mL, 1.4 mmol) and H2O (0.024 mL, 1.4 mmol) was sonicated in a sonicator at rt for 1.0 h. It was diluted with EtOAc, washed with NaHCO3, brine and dried over Na2SO4. After removal of solvent, 99A (134 mg, 100% yield) was obtained as a solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.29 (dd, J=5.27, 2.20 Hz, 1H) 8.74 (d, J=2.20 Hz, 1H) 8.98 (d, J=5.27 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCc1ccccn1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1ccccn1

Procedure:
Compound IIp was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and pyridin-2-ylmethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:20][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][N:23]=2)=[O:18])=[C:10]([CH3:31])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:31])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:20][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][N:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1ncc(Cc2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1ncc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5-{[(5-Benzyl-oxazole-2-carbonyl)-amino]-methyl}-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (170 mg, 0.34 mmol), 2 mL TFA and 5 mL DCM was stirred of room temperature for 2 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). The product containing fractions were lyophilised, then dissolved in 1 mL MeOH and the resulting mixture was filtered over a MeOH flushed PL-HCO3 MP-resin column. The column was washed with MeOH, the solvent was removed and the crude product was dissolved in water/ACN and lyophilised to yield the title compound. 1H-NMR (DMSO-d6, 400 MHz) 8.80 (t, 1H), 7.27-7.37 (m, 5H), 7.10 (s, 1H), 6.11 (s, 1H), 5.72 (s, 2H), 4.31 (d, 2H), 4.12 (s, 2H), 2.30 (s, 3H), 2.17 (s, 3H); LCMS (method A) RtA=1.001 min; [M+H]+=337.0.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][CH:15]=3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][N:31]=1>>[ClH:29].[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:30]4[N:31]=[CH:32][C:33]([C:34]#[N:35])=[CH:36][CH:37]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCCN(C4CCC4)CC3)cc2)OC1(C)C
Product: Cl
Product: N#Cc1ccc(-c2ccc(C(=O)N3CCCN(C4CCC4)CC3)cc2)nc1
Yield: 29.7 %

Procedure:
The title compound (E12) was prepared in a similar manner to Example 11 from 1-cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D7) (0.15 g) and 6-chloronicotinonitrile (0.054 g). The crude reaction mixture was purified by flash chromatography [silica gel, step gradient 0-15% MeOH (containing 10% 0.88 ammonia solution) in DCM]. The free base compound was converted into the HCl salt in dry DCM (2 ml) with ethereal HCl (1 ml), 1N). Evaporation of solvent afforded the title compound (E12) as a white solid (0.046 g). 1H NMR δ (methanol-d4): 1.78-1.90 (2H, m), 2.1-2.4 (6H, m), 3.03-3.2 (2H, m), 3.5-3.9 (6H, m), 4.28-4.35 (1H, m), 7.65 (2H, d, J=8 Hz), 8.13 (1H, d, J=8 Hz), 8.23-8.26 (3H, m), 8.99 (1H, d, J=2.4 Hz). LCMS electrospray (+ve) 361 (MH+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Br[C:10]1[N:15]2[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.[O-]C1C=CC=CC=1.[Na+]>CN(C=O)C>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:15]2[C:16]=1[NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Clc1ccccc1-c1nc2cccc(Br)n2c1NC1CCCCC1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nc2cccc(Oc3ccccc3)n2c1NC1CCCCC1
Temperature: 90 °C

Procedure:
Phenol (40.43 mg, 0.687 mmol) was dissolved in DMF (5 ml) and sodium metal (10.31 mg, 0.687 mmol) was added portion-wise. 5-Bromo-2-(2-chlorophenyl)-N-cyclohexylimidazo[1,2-a]pyridin-3-amine 42 (139.1 mg, 0.344 mmol) was added to this sodium phenoxide solution and heated at 90° C. for 4 h. The reaction was quenched with water and extracted into ethyl acetate. The product was purified by column chromatography, elution ethyl acetate:hexane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:11])=[C:4](CC#N)[CH:5]=[CH:6][CH:7]=1.[OH:12]S(O)(=O)=O.[O:17]1[CH2:22][CH2:21]OCC1>O>[Cl:1][C:2]1[C:3]([I:11])=[C:4]([CH2:21][C:22]([OH:17])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: C1COCCO1
Reactant: N#CCc1cccc(Cl)c1I
Solvent: O
Product: O=C(O)Cc1cccc(Cl)c1I
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(3-chloro-2-iodophenyl)acetonitrile (3.2 g, 12 mmol) in 20 mL dioxane was treated with 25 mL 9M H2SO4. The mixture was stirred at 115° C. for 2 hours, cooled to room temperature, and diluted with 100 mL water. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated NaCl (20 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product in 4 g as pale yellow solid. MS m/e: (M+H)+ 297.
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:37]=1.[Cl:55][C:56]1[C:61]([Cl:62])=[CH:60][CH:59]=[CH:58][C:57]=1[OH:63]>C1COCC1>[Cl:55][C:56]1[C:61]([Cl:62])=[CH:60][CH:59]=[CH:58][C:57]=1[O:63][CH2:36][CH2:37][N:28]1[CH:29]=[CH:30][N:31]=[C:26]([N:23]2[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]2)[C:27]1=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1cccc(Cl)c1Cl
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Product: O=c1c(N2CCNCC2)nccn1CCOc1cccc(Cl)c1Cl
Reaction time: 2 h
Yield: 16.2 %

Procedure:
TMAD (0.207 g, 1.20 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (0.324 g, 1.00 mmol), triphenylphosphine (0.315 g, 1.20 mmol) and 2,3-dichlorophenol (0.326 g, 2.00 mmol) in THF (1 mL) at room temperature. After being stirred for 2 h, the mixture was concentrated in vacuo and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H2O (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) as eluent to give 60 mg (16%) of the title compound. HRMS m/z calcd for C16H18Cl2N4O2 (M)+ 368.0807, found 368.0818.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:13]I.[Cl-].[Na+]>C(OCC)C.O1CCCC1>[F:12][C:7]1[CH:6]=[CH:5][C:4]([NH2:3])=[CH:9][C:8]=1[CH2:10][O:11][CH3:13]
Reactant: CI
Reactant: Nc1ccc(F)c(CO)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCc1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask, 374 mg of sodium hydride at 60% are introduced into 10 ml of tetrahydrofuran, 1g of (5-amino-2-fluorophenyl)methanol and 0.441 ml of methyl iodide. After stirring at ambient temperature for one hour, a solution of sodium chloride and diethyl ether are added. The organic phase is extracted and then washed with water until pH=7. It is then dried over magnesium sulphate, filtered, and concentrated under reduced pressure. 900 mg of 4-fluoro-3-(methoxymethyl)aniline are obtained in the form of a black oil, which is used as it is in the next stage.