Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:40][CH2:41][CH3:42])[C:34]=1[C:35]1[CH:36]=[N:37][NH:38][CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:44]1[C:48]([C:49]2[CH:50]=[C:51]3[C:61](=[CH:62][CH:63]=2)[O:60][C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][C:52]3=[O:64])=[N:47][N:46]=[N:45]1>O.CN(C=O)C.CCN(CC)CC>[CH2:41]([O:40][C:33]1[CH:32]=[C:28]([C:29]([N:57]2[CH2:58][CH2:59][C:54]3([CH2:53][C:52](=[O:64])[C:51]4[C:61](=[CH:62][CH:63]=[C:49]([C:48]5[NH:47][N:46]=[N:45][N:44]=5)[CH:50]=4)[O:60]3)[CH2:55][CH2:56]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][NH:38][CH:39]=1)[CH3:42]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cn[nH]c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (83 μL), HOBT (46 mg) and WSC hydrochloride (58 mg) were added to a DMF (4 mL) solution of 3,5-diethoxy-4-(1H-pyrazol-4-yl)benzoic acid (97 mg) and 6-(tetrazol-5-yl)spiro [chroman-2,4′-piperidin]-4-one hydrochloride (70 mg), stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1H, d, J=4.0 Hz), 8.23 (1H, dd, J=8.0, 4.0 Hz), 8.04 (2H, s), 7.32 (1H, d, J=8.0 Hz), 6.68 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz). MS [M+H]+=544.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[O:24][CH3:25])[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:15]([NH:14][C:11]1[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH:27]=[CH:26][C:9]=3[N:10]=1)[CH2:16][CH2:17]2
Reactant: CN1CCNCC1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Solvent: CC#N
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCN(C)CC4)cc3CO1)CC2
Yield: 77.3 %

Procedure:
Prepared from rac-2-chloro-N-[2-(7-methoxy-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 55 step A) (100 mg, 0.259 mmol) and 1-methylpiperazine (0.289 ml 2.595 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a light yellow foam (90 mg, 77%), MS (ISP) m/e=450.2 [(M+H)+].
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([Br:49])=[C:31]([CH:48]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN(C)C(=O)C>[Br:49][C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=2)=[CH:48][C:31]=1[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:46][CH2:47]3)=[O:44])[N:41]=2)[N:38]=1
Reactant: Nc1ccc(Br)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 84.1 %

Procedure:
Using 3-(1-cyano-1-methylethyl)benzoic acid (330 mg, 1.8 mmol), oxalyl chloride (170 μL, 2.0 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (15 mL), N-[6-(5-amino-2-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (650 mg, 1.7 mmol) and N,N-dimethylacetamide (5.0 mL) as starting materials and in the same manner as in Example 335, the title compound (800 mg, 85%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([C:17]#[C:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)=[CH:10][C:11]=2[C:12]([CH3:16])([CH3:15])[CH2:13][CH:14]=1)(=[O:3])[CH3:2].CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(=O)CC1>>[C:1]([O:4][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([C:17]#[C:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[CH:10][C:11]=2[C:12]([CH3:16])([CH3:15])[CH2:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OC(C)=O)cc1
Agent: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC(=O)OC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 274 mg (0.86 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonapth-2-yl)ethynyl]benzoic acid (Compound 7) was converted into the title compound (light yellow solid) using 0.22 ml (2.58 mmol) acetic anhydride and 84 mg (0.43 mmol) of p-toluenesulfonic acid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:20]([OH:22])=[O:21])[N:7]([CH2:17][CH2:18]Br)[CH:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:32]([SH:34])[CH3:33]>ClCCl>[C:1]([O:5][CH:6]([C:20]([OH:22])=[O:21])[N:7]([CH2:17][CH2:18][S:34][CH2:32][CH3:33])[CH:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(C(=O)O)N(CCBr)C(OC(C)(C)C)C(=O)O
Reactant: CCS
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCSCCN(C(OC(C)(C)C)C(=O)O)C(OC(C)(C)C)C(=O)O

Procedure:
3.52 g (10 mmol) of N,N-bis-(tert-butoxycarboxy-methyl)-2-bromoethylamine is dissolved in 50 ml of absolute dichloromethane and mixed with 1.29 g (10 mmol) of diisopropylethylamine and 0.621 g (10 mmol) of ethylmercaptan. The reaction mixture is refluxed overnight. Then, the solution is extracted twice with semi-saturated, aqueous sodium bicarbonate solution. The organic phase is dried on sodium sulfate, and the solvent is evaporated in a vacuum. The residue is chromatographed on silica gel (eluant: dichloromethane/methanol 99:1).
Reaction SMILES: [N:1]1[C:9]([CH:10]([OH:12])[CH3:11])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O>[O:12]([CH:10]([C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2)[CH3:11])[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(O)c1ncnc2nc[nH]c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.1 %

Procedure:
To a solution of 0.543 g of 1-(purin-6-yl)ethanol in N,N-dimethylformamide (10 ml) were added 0.27 g of imidazole and 0.598 g of tert-butyldimethylsilyl chloride and the resulting mixture was stirred at room temperature for 15 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.793 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O-:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])c1ccc(CCCc2ccccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-[3-(2-hydroxyphenyl)propyl]benzoate (1.0 g) in DMF (20 ml) was added potassium carbonate (0.76 g) and benzyl bromide (0.66 ml). The mixture was stirred for 18 hours, poured into water (100 ml) and ethyl acetate (100 ml). The ethyl acetate solution was washed with water (3×100 ml), dried (magnesium sulphate), filtered and evaporated. The residue was purified by subjecting to chromatography on silica gel using diethyl ether: hexane (1:9) as eluant. There was thus obtained methyl 4-[3-(2-benzyloxy-phenyl)propyl]benzoate (0.7 g) as an oil.
Reaction SMILES: C([NH:4][S:5]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([C:26]#[N:27])=[C:24]([O:28][CH3:29])[N:23]=[C:22]3[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])(=O)C.OS(O)(=O)=O.OP([O-])(O)=O.[K+]>O>[CH2:30]([C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:9]3[C:8]([S:5]([NH2:4])(=[O:7])=[O:6])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:15][CH:16]=2)[C:25]([C:26]#[N:27])=[C:24]([O:28][CH3:29])[N:23]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1nc(OC)c(C#N)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)cc1
Agent: O=P([O-])(O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCCCc1nc(OC)c(C#N)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 83.7 %

Procedure:
2.1 g of 4′-(2-butyl-5-cyano-4-methoxyimidazol-1-ylmethyl)biphenyl-2-sulfonic acid acetylamide are suspended in 40 ml of a 20% aqueous H2SO4 solution and the mixture is refluxed for 3 h. The reaction mixture is added dropwise to 400 ml of a 2/3 M solution of KH2PO4 in water and extracted 3 times using 300 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using MTB yields 1.6 g of a colorless oil.
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.[F:7][C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20](=[NH:22])[NH2:21])=[N:12]1>C(O)(=O)C>[Br:1][C:2]1[CH:5]=[N:21][C:20]([C:13]2[C:14]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:11]([CH2:10][C:9]3[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=3[F:7])[N:12]=2)=[N:22][CH:3]=1
Reactant: O=CC(Br)C=O
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: CC(=O)O
Product: Fc1ccccc1Cn1nc(-c2ncc(Br)cn2)c2cccnc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
10.09 g (66.84 mmol) of 2-bromomalonaldehyde are added to a solution of 15.00 g (55.70 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (example I, step 5) in 200 ml of glacial acetic acid and stirring at 100° C. for 2 hours. The solvent is removed in vacuo. The residue is purified by chromatography on silica gel (eluent: DCM/methanol 40:1 to 30:1). 9.51 g (44% of theory) of the product are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][C:13]([CH3:15])=O.N1CCCCC1>N1C=CC=CC=1>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:13]([CH3:15])([CH3:12])[CH2:10][C:9]2=[O:11]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC1(C)CC(=O)c2cc(O)ccc2O1
Reaction time: 48 h
Yield: 75.7 %

Procedure:
To a 250 mL, 2-necked round bottom flask equipped with a magnetic stir bar and a water-jacketed condenser capped with a balloon was added 2′,5′-dihydroxyacetophenone (2, 8.00 g, 52.6 mmol), reagent grade acetone (19.45 mL, 263 mmol), piperidine (5.2 mL, 52.6 mmol) and freshly distilled pyridine (50 mL). The mixture was heated to a vigorous reflux with stirring under a nitrogen atmosphere for 2 d. The solvent was evaporated and the concentrate was dried under high vacuum. Reagent grade acetone (19.45 mL, 263 mmol), piperidine (5.2 mL, 52.6 mmol) and freshly distilled pyridine (50 mL) were added, and vigorous reflux with stirring under a nitrogen atmosphere was continued for 2d more. The solvent was evaporated, ethyl acetate (30 mL) and 30% aqueous CuSO4 (30 mL) were added to the concentrate. The organic phase was washed with brine (1×30 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum. The dry crude product was passed through a silica gel column using 2:1 hexanes/ethyl acetate as eluent (Rf=0.3). The product gives off a purple color on an analytical silica gel plate illuminated with a short wave UV lamp. The fractions containing the pure product were transferred to a pre-weighed flask, the solvent was evaporated and the concentrate was dried under high vacuum. The reaction furnished 7.65 g of 3 (76%) as a brown solid. 1H NMR (300 MHZ, CDCl3): δ 7.32 (m, 1H), 7.04 (m, 1H), 6.82 (m, 1H), 5.48 (bs, 1H), 2.68 (s, 2H), 1.42 (s, 6H). 13C NMR (75.5 MHZ, CDCl3): δ 193.8, 154.4, 149.9, 125.2, 120.0, 119.6, 110.7, 79.0, 48.7, 26.5; HRMS (EI+): calculated for C11H12O3 [M+] m/z 192.0786, found 192.0788.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:12]([F:15])([F:14])[F:13])[O:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].[CH3:18][N:19]([CH2:21][CH2:22][CH2:23][NH2:24])[CH3:20]>C(Cl)(Cl)Cl>[CH3:18][N:19]([CH3:20])[CH2:21][CH2:22][CH2:23][NH:24][S:8]([CH2:7][CH2:6][CH2:5][O:4][CH:3]([C:12]([F:15])([F:14])[F:13])[C:2]([F:17])([F:16])[F:1])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)CCCOC(C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCCN
Solvent: ClC(Cl)Cl
Product: CN(C)CCCNS(=O)(=O)CCCOC(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
The 3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-propane-1-sulfonyl chloride (18.4 grams) can be dissolved in 100 mL of chloroform and added to 22.5 mL of dimethylaminopropylamine in 100 mL of chloroform at 0° C.-5° C. over 1 hour to form a mixture. When the addition is complete the mixture can be allowed to warm to room temperature and stir at ambient for 1 hour. The mixture can be washed with saturated bicarbonate solution (200 mL), deionzied water (200 mL), and brine (200 mL). The organic layer can be dried over magnesium sulfate, filtered, and concentrated under vacuum to afford a yellow oil that can be placed on the Kugelrohr for 15 minutes at ambient temperature and 0.1 Torr to afford 3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-propane-1-sulfonic acid (3-dimethylamino-propyl)-amide (20.88 g (92.8%)) by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8](C(=O)C)[C:7]=2[CH:15]=1.O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][NH:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)N(C(C)=O)CCO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)NCCO2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step C (1.5 g; 7.26 mmol) is dissolved in 7 ml of methanol, and then water (14 eq.; 101.6 mmol; 1.9 ml) and potassium hydroxide (6 eq.; 43.5 mmol; 2.44 g) are added. The solution is stirred vigorously at 60° C. for 2 hours. After extraction three times with dichloromethane, the organic phase is dried over MgSO4 and then removed under reduced pressure. The residue obained is purified by flash chromatography on silica gel (eluant: PE/AcOEt (1/1)). The title product is obtained in the form of a red solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[N:1]=[C:29]=[O:31]
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C=Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a suspension of 4-(3-amino-4-fluoro-benzyl)-2H-phthalazin-1-one (1)(4.0 g, 14.8 mmol) in anhydrous DCM (1.6 L) and triethylamine (4.62 mL, 40.86 mmol), was added a dropwise preformed solution of triphosgene (2.75 g, 9.28 mmol) in anhydrous DCM (327 mL) and stirred for 70 minutes and room temperature. The reaction mixture was then concentrated to dryness in vacuo yielding a grey solid. Single peak in LC-MS analysis, (yield taken to be quantitative) no purification performed. m/z (LC-MS, ESP), RT=4.49 mins, (M+MeOH) 328.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:12]=[CH:13][C:14]=1[NH2:15]
Reactant: COc1cc(CN2CCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CN2CCCC2)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
10% Pd on carbon (12 mg, 0.866 mmol) was added to a solution of 1-(3-methoxy-4-nitrobenzyl)pyrrolidine (Preparation 105, 180 mg, 0.76 mmol) in EtOH (3 mL). The reaction mixture was degassed and then stirred for 1 hour at room temperature under an atmosphere of hydrogen. The reaction was filtered on a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel column chromatography eluting with 5% methanol in dichloromethane to afford the title compound as a colourless oil (0.12 g, 76.3%). 1H-NMR (500 MHz, CDCl3): δ 1.79 (t, J=6.7 Hz, 4H), 2.5 (t, J=6.7 Hz, 4H), 3.53 (s, 2H), 3.75 (s, br, 2H), 3.86 (s, 3H), 6.65 (d, J=9.3 Hz, 1H), 6.72 (d, J=9.3 Hz, 1H), 6.81 (d, J=1.5 Hz, 1H).
Reaction SMILES: C(O[N:5]=[C:6]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15])[CH3:7])(=O)C.Cl>N1C=CC=CC=1>[CH3:7][C:6]1[C:8]2=[C:13]([OH:14])[CH:12]=[CH:11][CH:10]=[C:9]2[O:15][N:5]=1
Reactant: CC(=O)ON=C(C)c1c(O)cccc1O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1noc2cccc(O)c12
Yield: 44 %

Procedure:
To 1-(2,6-dihydroxyphenyl)ethanone O-acetyloxime (Intermediate 9, 437 mg) pyridine (4.0 ml) was added and the reaction mixture was stirred at reflux for 2 hours. After the addition of HCl (4.0 ml of a 5M aqueous solution), the mixture was extracted 3 times with Et2O and the collected organic layers were washed with HCl (1M, aqueous solution). The organic phase was dried over sodium sulphate and filtered. Evaporation afforded the title compound (137 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[C:10]([F:16])([F:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[N:35]=[C:21]2[C:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[C:27]=3[F:34])=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1.[O-]C1C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:18]2[N:35]=[C:21]3[C:22]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[C:27]=4[F:34])=[CH:23][CH:24]=[CH:25][N:20]3[N:19]=2)[C:10]([F:16])([F:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(F)(F)C1
Reactant: Fc1ccc(-c2cccn3nc(Br)nc23)c(F)c1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4ccc(F)c(F)c4F)cccn3n2)C(F)(F)C1
Temperature: 160 °C

Procedure:
Through a suspension of 4-amino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 381 μmol), 2-bromo-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (prepared in analogy to example 66a-d, 162 mg, 495 μmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (15.8 mg, 15.2 μmol), sodium phenoxide (65.2 mg, 533 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17.6 mg, 30.5 μmol) in dry dioxane (5.0 mL) was bubbled argon for 5 minutes, then heated to 160° C. in the microwave for 60 minutes. The catalyst was filtered off, washed with CH2Cl2 and the solvents evaporated. The residue was purified by flash chromatography (silica gel, 70 g, 0% to 100% EtOAc in heptane). The title compound was obtained as orange solid (27 mg, 15%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:44](C)=O.[Na+]>C(Cl)Cl>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH3:44])[C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1N=C(N2CCN[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 4 mL of CH2Cl2 was added 5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)-piperazin-1-yl]-1,3-thiazol-4(5H)-one (Example 139, 50 mg), followed by 50 mg of 37% HCHO. The mixture was stirred at room temperature for 20 min, then 50 mg of NaBH(OAc)3 was added. The reaction mixture was kept stirring for 1 h and partitioned between CH2Cl2 and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc to MeOH/EtOAc (10/90) to afford the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:32])[N:5]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:6]([CH:12]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][NH:21]3)[CH2:13][C:14]#[CH:15])=[N:7]2.[NH2:33]C1N=C2C(NC=N2)=C(Br)N=1.BrC1N=CN=C2C=1NC=N2>>[NH2:33][C:24]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[C:17]([NH:16][CH:12]([C:6]2[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:4](=[O:32])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH3:1])[N:7]=2)[CH2:13][C:14]#[CH:15])[N:25]=1
Reactant: C#CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Agent: Brc1ncnc2nc[nH]c12
Product: C#CCC(Nc1nc(N)nc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1

Procedure:
Compound 165 was prepared following the general procedure described above for the preparation of compound 161, but 2-amino-6-bromopurine was substituted for 6-bromopurine in step D. ESI-MS m/z=437 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[H][H].[Pt](=O)=O>[C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:10]3=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnc3cnccn23)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: c1ccc(-c2cnc3n2CCNC3)cc1
Yield: 99.3 %

Procedure:
3-Phenylimidazo[1,2-a]pyrazine (1.391 g, 7.13 mmol) was dissolved in ethanol (100 ml) and hydrogenated at room temperature under 1 Atm hydrogen over platinum(IV) oxide (0.202 g, 0.713 mmol) for 24 hours. The catalyst was filtered, washed with ethanol and the filtrate concentrated to afford 3-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (1.41 g, 7.08 mmol, 99% yield)