Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([NH:32][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:30][CH2:31]1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(Nc1ccccc1OCC1CO1)c1ccccc1
Product: O=C(Nc1ccccc1OCC(O)CNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)c1ccccc1
Temperature: 77.5 °C

Procedure:
To a solution of N-(2-Oxiranylmethoxy-phenyl)-benzamide (0.2 ml, 0.1M in DMSO) was added (0.2 ml, 0.1M in EtOH) of 1-(3,4-Dichloro-benzyl)-piperidin-4-ylamine. The resulting mixture was heated at 75-80° C. for 24 hours. The ethanol was removed and the product was purified with preparative LC/MS.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30][CH:31]3[CH2:35][CH2:34][O:33]C3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O1CCC[C@H]1C(NN)=O.O1CCC(CC(NN)=O)C1>>[CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([C@@H:30]3[CH2:31][CH2:35][CH2:34][O:33]3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: NNC(=O)CC1CCOC1
Agent: NNC(=O)[C@@H]1CCCO1
Product: Cc1cc(C)c(-c2nnc([C@@H]3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using (S)-tetrahydrofuran-2-carbohydrazide (compound 136.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 456 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:42]([CH3:43])[CH2:41][CH2:40][N:39]([CH3:44])[C:38]2=[O:45])=[CH:33][CH:32]=1>>[CH3:43][N:42]1[CH2:41][CH2:40][N:39]([CH3:44])[C:38](=[O:45])[CH:37]1[C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:18]2[N:17]=[CH:16][C:15]3=[CH:14][CH:13]=[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[N:5]([CH3:29])[S:2]([CH3:1])(=[O:4])=[O:3])[N:20]3[N:19]=2)=[CH:32][CH:33]=1
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Product: CN1CCN(C)C(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)C1=O

Procedure:
N-(2-{2-[4-(1,4-Dimethyl-3-oxo-piperazin-2-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide was prepared from trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and 3-(4-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1061. Product isolated as an orange foam (80 mg, 53%). LCMS (m/e) 520 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 7.95-7.88 (m, 1H), 7.58-7.46 (m, 3H), 7.45 (d, 2H, J=8.4 Hz), 7.20 (d, 2H, J=8.4 Hz), 7.03 (d, 1H, J=4.7 Hz), 6.87 (d, 1H, J=4.7 Hz), 6.82 (bs, 1H), 3.77-3.67 (m, 1H), 3.64 (s, 1H), 3.24-3.17 (m, 1H), 3.11 (s, 3H), 3.05-2.96 (m, 1H), 2.98 (s, 3H), 2.70 (s, 3H), 2.69-2.61 (m, 1H), 2.16 (s, 3H).
Reaction SMILES: OCCCC[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15].C(O)CCCCC[OH:24]>>[OH:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)OCCCCCCCCCCO
Reactant: OCCCCCCO
Product: C=C(C)C(=O)OCCCCCCO

Procedure:
6-Hydroxyhexylmethacrylate was prepared using the same method as in the preparation of 10-hydroxydecylmethacrylate. 1,6-hexanediol was used instead of 1,10-decanediol. The same molar quantities of reactants were used. 11.5 g of product (62% yield) were collected.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)[CH:2]=[CH2:3].[C:16]([O:30][CH2:31][CH:32]([CH2:37][CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])(=[O:29])[CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19].C1(C)C=CC=CC=1.N1CCCCC1>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:17]([C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19])[C:16]([O:30][CH2:31][CH:32]([CH2:37][CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:29])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)cc(OC)c1OC
Reactant: CCCCC(CC)COC(=O)CC(=O)OCC(CC)CCCC
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=CCc1cc(C=C(C(=O)OCC(CC)CCCC)C(=O)OCC(CC)CCCC)cc(OC)c1OC
Yield: 58.1 %

Procedure:
A mixture of 3-allyl-4,5-dimethoxybenzaldehyde (10.3 g, 0.05 mole), of di-(2-ethylhexyl) malonate (16.4 g, 0.05 mole), of toluene (20 ml), of acetic acid (0.41 ml) and of piperidine (0.77 ml) was heated at reflux for 5 hours with a Dean Stark. After cooling, washing the toluene phase with water, drying and evaporating off the solvent, an orange-colored oil was obtained, which was purified by chromatography on a column of silica 60 (eluent: 90.10 heptane/ethyl acetate) to give di-(2-ethylhexyl) 3-allyl-4,5-dimethoxybenzalmalonate (colorless oil, 15 g, yield=64%) which had the following characteristics:
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.C([O-])=O.[NH4+]>O1CCOCC1.[Ni]>[NH2:8][C:6]1[CH:5]=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=[C:2]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=1
Reactant: Cc1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [Ni]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(N)cc(S(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
A mixture of N-(3-methyl-5-nitro-phenyl)-methylsulfonamide (0.12 g; 0.4 mmol), ammonium formate (0.26 g; 4 mmol) and Raney-Nickel in 1 mL dioxane was heated at 120° C. in a microwave oven for 20 minutes. The mixture was then filtrated on a celite pad and concentrated. 70 mg (0.35 mmol; 87% yield) of a red oil were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.CN(C=O)C.[H-].[Na+].[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[N:35]=[C:34](S(C)(=O)=O)[N:33]=1>C(O)(=O)C.O>[O:8]([C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH:10]([O:15][C:34]1[N:35]=[C:36]([O:38][CH3:39])[CH:37]=[C:32]([O:31][CH3:30])[N:33]=1)[C:11]([O:13][CH3:14])=[O:12])[C:1]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(Oc1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 24.5 %

Procedure:
4.4 g (15.4 mmol) of methyl 3-phenoxy-3-phenyl-2-hydroxybutyrate (Compound 1.1) are dissolved in 40 mol of DMF, and 0.46 g (18.4 mmol) of sodium hydride is added. The mixture is stirred for 1 hour and then 3.4 g (15.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are added. The mixture is stirred at room temperature for 24 hours and then cautiously hydrolyzed with 10 mo of water, the pH is adjusted to 5 with acetic acid, and the solvent is removed by distillation under high vacuum. The residue is taken up in 100 mo of ethyl acetate, washed with water, dried over sodium sulfate and distilled to remove solvents. 10 ml of methyl t-butyl ether are added to the residue, and the precipitate is filtered off with suction. Drying results in 1.6 g of a white powder.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[C:12]([CH2:22][CH3:23])=[N:11][N:10]=2)=[CH:5][CH:4]=1.Br>>[CH2:22]([C:12]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[N:10][N:11]=1)[CH3:23]
Reactant: CCc1nnc(-c2ccc(OC)cc2)n1-c1ccc(OC)cc1
Agent: Br
Product: CCc1nnc(-c2ccc(O)cc2)n1-c1ccc(O)cc1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of 6 g of 3,4-bis-(4-methoxyphenyl)-5-ethyl-4H-1,2,4-triazole and 25 ml of a solution of hydrobromic acid at 48% was refluxed with stirring for one hour and the hydrobromic acid was distilled under reduced pressure. The crystalline residue was dissolved in 30 ml of hot water and ammonium hydroxide was added thereto until the pH was alkaline. The mixture stood overnight with stirring and was vacuum filtered. The product was washed with water and dried at 90° C. under reduced pressure to obtain a product which was crystallized from dimethylformamide. The mixture was iced for one hour and was vacuum filtered. The product was washed with a 3-4 dimethylformamide-water mixture and dried to obtain 4.395 g of 4,4'-(3-ethyl-4H-1,2,4-triazol-4,5-diyl)-bis-phenol melting at 317°-318° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH3:38])[CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH3:38])[CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1
Reactant: CN(Cc1nccs1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Solvent: O
Solvent: CC(=O)O
Product: CN(Cc1nccs1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Reaction time: 48 h

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[methyl(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide was dissolved in acetic acid (8 mL) and water (2 mL). The reaction mixture was left to stir 2 days. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[methyl(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.3469 g). LCMS: (M+H)+=486.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31]([O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) by alkylation with methyl-5-chloropyrazine-2-carboxylate [CAS Reg. No. 33332-25-1]. MS (m/e)=502.0 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[CH:9]2[OH:18])=[N:6][CH:7]=1.[CH2:19]([O:21][C:22]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[N:14][CH:13]=[CH:12][N:11]=3)[CH:16]2[CH2:24][C:22]([O:21][CH2:19][CH3:20])=[O:23])=[N:6][CH:7]=1
Reactant: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2nccnc2C(=O)N1c1ccc(Cl)cn1
Yield: 90.4 %

Procedure:
6-(5-Chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one (1.05 g) and ethoxycarbonylmethylenetriphenylphosphorane (1.39 g) were dissolved in dry toluene (30 ml) and the solution was refluxed for 6 hours. After cooling, the solvent was distilled off and the residue was purified by silica gel column chromatography. Fractions eluted with dichloromethane-ethyl acetate (2:1) were collected and the solvent was distilled off to give crude crystals. Recrystallization from ether-dichloromethane (5:1) gave 1.2 g of 6-(5-chloro pyridyl)-6,7-dihydro-7-ethoxycarbonylmethyl-5H-pyrrolo[3,4-b]pyrazin-5-one
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]([CH:13]([C:15]2[O:19][C:18]([CH3:20])=[C:17]([CH3:21])[CH:16]=2)O)=[CH:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]1=2.[BH4-].[Na+]>C(=S)=S>[S:8]1[C:12]([CH2:13][C:15]2[O:19][C:18]([CH3:20])=[C:17]([CH3:21])[CH:16]=2)=[CH:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]1=2
Reactant: Cc1cc(C(O)c2cc3ccccc3s2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: S=C=S
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cc2cc3ccccc3s2)oc1C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
Trifluoroacetic acid (30 mL) was added dropwise to a rt, stirred suspension of benzo[b]thiophen-2-yl-(2,3-dimethyl-furan-5-yl)-methanol (9.56 g, 40.0 mmol) and sodium borohydride (7.0 g, 200 mL) in carbon disulfide (100 mL) under a try N2 atmosphere over a period of 30 min. After an additional 3 hours, the reaction mixture was carefully quenched and further diluted with aqueous ammonium chloride (250 mL). Aqueous mixture was extracted with ethyl ether (500 mL). The ethyl ether extract was washed with water and brine. Silica gel (100 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent 99:1 petroleum ether: ethyl acetate) to provide the title compound as an oil (3.75 g, 42%): NMR (CDCl3); δ7.74 (d, J=8 Hz, 1H), 7.67 (d, J=8, Hz, 1H), 7.35-7.22 (m, 2H), 7.08 (d, J=1 Hz, 1H), 5.93 (s, 1H), 4.15 (s, 2H), 2.17 (s, 3H), 1.90 (s, 3H); MS (EI): [M+], 242.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]3([CH2:15][CH2:14][CH2:13]3)[CH2:7][CH2:8][NH:9]2)=[CH:4][C:3]=1[OH:16].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>CC(C)=O>[CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]3([CH2:13][CH2:14][CH2:15]3)[CH2:7][CH2:8][N:9]2[CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:4][C:3]=1[OH:16]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cc1c(O)cc2c(c1C)NCCC21CCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(O)cc2c(c1C)N(Cc1ccc3ccccc3n1)CCC21CCC1

Procedure:
A mixture of 7′,8′-dimethyl-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinolin]-6′-ol (300 mg), 2-(chloromethyl)quinoline (600 mg), K2CO3 (637 mg), and sodium iodide (40 mg) in acetone (50 mL) was refluxed overnight under nitrogen. The reaction mixture was then cooled down and concentrated by evaporation. Distilled water was added to the residue and the aqueous solution was extracted with ethyl acetate (3×20 mL).The organic layer was combined, dried over Na2SO4, and evaporated. The crude compound was purified by column chromatography (2% MeOH in CH2Cl2) yielding 7′,8′-dimethyl-1′-(quinolin-2-ylmethyl)-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinolin]-6′-ol as an off-white solid. 1H-NMR (300 MHz, CDCl3) δ=8.28 (d, J=6 Hz, 1H); 8.15 (d, J =6 Hz, 1H); 8.05 (d, J=9 Hz, 1H); 7.88 (t, J=6 Hz, 1H); 7.76 (t, J=6 Hz, 1H); 7.02 (s, 1H); 4.21 (s, 2H); 2.99 (m, 2H); 2.35 (m, 2H); 2.24 (s, 3H); 2.20 (s, 3H); 1.99 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=161.20; 149.46; 147.54; 139.58; 137.16; 135.93; 131.04; 129.73; 128.54; 127.70; 127.52; 126.18; 122.83; 119.73; 111.48; 92.98; 77.48; 71.26; 68.59; 60.73; 45.03; 43.92; 40.12; 36.74; 29.88; 15.28; 14.79; 12.54 ppm. MS: (m/z)=359 (100, M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:12][C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH3:17].C1(C)C=CC=CC=1>C1COCC1.OS(O)(=O)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([N:8]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:12])[CH:7]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 5-chloro-2-nitrophenylamine (200 mg, 1.15 mmol) and hexane-2,5-dione (326 μL, 2.78 mmol) in THF (3 mL) was added 1 drop of conc H2SO4. Toluene (3 mL) was then added and the reaction was allowed to stir at 120° C. overnight. At this time the reaction was diluted with CH2Cl2 (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative thin layer chromatography (50% EtOAc-hexane) afforded 73 mg (25%) of the title compound as a tan solid. 1H-NMR (CDCl3; 400 MHz): δ 7.96 (d, 1H, J=8.7 Hz), 7.59-7.54 (m, 1H), 7.39 (d, 1H, J=2.0 Hz), 5.92 (s, 2H), 1.97 (s, 6H);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:4][C:3]=1[C:18](=[O:26])[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH3:32]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH3:32])=[C:10]([F:17])[CH:9]=2)=[CH:4][C:3]=1[C:18]([NH:19][C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1)=[O:26]
Reactant: Nc1ncc(-c2ccc(C(=O)O)c(F)c2)cc1C(=O)Nc1ccncc1
Reactant: CNCCOC
Product: COCCN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1F

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-2-fluoro-benzoic acid with N-(methoxyethyl)-methylamine gives “A102”; method 1: HPLC/MS: 1.34 min, [M+H]=424;
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[N:15][C:14]=3[C:25]([OH:27])=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:40]([O:47][C:48]([C:50]1[CH:51]=[C:52](O)[CH:53]=[CH:54][CH:55]=1)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O>CN(C=O)C>[CH2:40]([O:47][C:48]([C:50]1[CH:55]=[C:54]([O:26][C:25]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[O:27])[CH:53]=[CH:52][CH:51]=1)=[O:49])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(OCc1ccccc1)c1cccc(O)c1
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nc(C(=O)Oc2cccc(C(=O)OCc3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Temperature: 115 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A solution of 5-(2-adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazole-4-carboxylic acid (Example 93) (57 mg, 0.16 mmol) and 1,1′-carbonyldiimidazole(25 mg, 0.16 mmol) in DMF (0.5 ml) was stirred at room temperature for 30 min. 3-Benzyloxycarbonyl-phenol (36 mg, 0.16 mmol) was added and the mixture was stirred at 115° C. for 16 h, then cooled to room temperature. Water (5 ml) was added and the mixture was extracted with ethyl acetate (3×5 ml). The combined extracts were washed with brine, dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash chromatography (silica, DCM/ethyl acetate 9:1) to afford colourless foam (15 mg, 17%). 1H NMR (300 MHz, CDCl3) 7.97 (1H, m), 7.91 (1H, m), 7.39 (4H, m), 5.37 (2H, s), 3.01 (2H, m), 2.52 (3H, s), 1.94 (3H, br s), 1.66 (6H, m), 1.54 (8H, m).
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[S:23][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:25][N:26]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:24]2[S:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:21])[CH3:20])=[N:26][CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OCCn2c1nc(-c1ncc(Cc3ccc(F)cc3)s1)c(OCc1ccccc1)c2=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OCCn2c1nc(-c1ncc(Cc3ccc(F)cc3)s1)c(O)c2=O
Yield: 77.4 %

Procedure:
A solution of 3-(benzyloxy)-2-(5-(4-fluorobenzyl)thiazol-2-yl)-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (0.051 g, 0.11 mmol) in TFA (5 mL) was stirred 24 h at 40 C. Then, the reaction mixture was cooled, concentrated and purified by preparative HPLC on C18 column using water/MeOH containing 0.1% TFA as eluent to afford the title compound (0.033 g, 80% yield) as pale yellow solid. 1HNMR (500 MHz, CDCl3) δ: 11.51 (1H, s), 7.61 (1H, s), 7.22 (2H, dd, J=8.6, 5.5 Hz), 7.03 (2H, t, J=8.6 Hz), 4.17 (2H, s), 4.06-4.01 (4H, m), 1.60 (6H, s). HRMS (M+H) calcd for C19H19N3O3FS: 388.1131. found: 388.1118. Anal calcd for C19H18N3O3FS: C, 58.90; H, 4.68; N, 10.84. found: C, 58.87; H, 4.47; N, 10.87.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17](Cl)[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C@@H:39]([OH:41])[CH3:40].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[C@@H:39]([OH:41])[CH3:40])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](O)c1nc2ccccc2[nH]1
Reactant: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 140 °C
Yield: 54 %

Procedure:
A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-1-carboxylic acid tert-butyl ester (180 mg, 0.43 mmol), (S)-1-(1H-benzoimidazol-2-yl)ethanol (84 mg, 0.52 mmol), tris(dibenzylideneacetone)dipalladium (40 mg, 0.04 mmol), XPhos (82 mg, 0.17 mmol) and Cs2CO3 (279 mg, 0.86 mmol) in toluene (3 mL) was purged with argon then heated at 140° C. for 1 h in a microwave reactor. Further tris(dibenzylideneacetone) dipalladium (40 mg, 0.04 mmol) and XPhos (82 mg, 0.17 mmol) were added and the mixture heated at 140° C. for a further 1 h. The reaction mixture was filtered through Celite®, washing with EtOAc and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) affording the title compound (127 mg, 55%). LCMS (method A): RT 3.27 min [M+H]+ 547.4