Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[NH:9][N:8]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.C(N(CC)CC)C.[OH-].[Na+]>CC(N(C)C)=O.ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([NH:29][C:14](=[O:16])[CH2:13][CH2:12][C:10]2[NH:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)[CH2:27][CH2:28]1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)CCc1nc(-c2ccccn2)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(CCc1nc(-c2ccccn2)n[nH]1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 4.4 %

Procedure:
3-[3-(2-Pyridinyl)-1,2,4-triazol-5-yl]propanoic acid (0.218 g) in 1 ml dimethylacetamide) and N,N′-carbonyldiimidazole (0.250 g) in dichloromethane was stirred under nitrogen for 30 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.316 g), and triethylamine (0.218 g) was then added and allowed to stir for 2 hours under nitrogen. 1M sodium hydroxide was added to the reaction with the resulting solution being washed three times with dichloromethane. The aqueous phase was acidified with glacial acetic acid, with the water/acetic acid being removed under reduced pressure. Water was then added and extracted three times with dichloromethane. The pooled organic phases were extracted once with water and the water removed under reduced pressure to leave a white solid. This was then triturated with diethyl ether/dichloromethane, filtered and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile), solvent removed to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1H-1,2,4-triazol-5-yl]propanamide (0.02 g).
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH3:14].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(P(=[CH:42][C:43]([O:45][CH3:46])=[O:44])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:46][O:45][C:43](=[O:44])[CH:42]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH3:14]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNc1cc(F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNc1cc(F)ccc1C=CC(=O)OC
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
To a solution of N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide (0.23 g, 1.02 mmol) in THF (4 mL) was added dropwise LiAlH4 (1 M in THF, 0.51 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C. and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was reacted with methyl (triphenylphosphoranylidene)acetate (375 mg, 1.12 mmol) in toluene (4 mL) overnight at 100° C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.13 g, 57%) after purification by column chromatography (EtOAc:hexane=1:10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:20]1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:20]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: c1ccc(C2CCCNC2)nc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CCCC(c2ccccn2)C1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 35.7 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.87 g, 3.5 mmol) and 2-piperidin-3-ylpyridine (2.80 g, 17.26 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.35 g of the intended substance (yield 35.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:26]2[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2Br)CC1
Reactant: COc1ncc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(-c2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
4-(2-Bromophenyl)-piperazine-1-carboxylic acid, t-butyl ester (10 g, 29.30 mmol) and 2-methoxypyrimidine-5-boronic acid (5 g, 32.48 mmol) are dissolved in DMF (200 mL) under a stream of nitrogen. To this mixture is added a 2M aqueous solution of sodium carbonate (73.26 mL, 150 mmol) followed by bis(triphenylphosphine)palladium (II) chloride (2.06 g, 2.93 mmol). The resulting mixture is allowed to stir at 100° C. for 30 min. A precipitate forms. Water is added and the resulting mixture is filtered to provide a gray colored solid which is air dried. The solid is then re-dissolved in dichloromethane (20 mL) and loaded on a 340 g Biotage SNAP column and eluted with 35% ethyl acetate in hexanes to provide 4-[2-(2-methoxy-pyrimidin-5-yl)-phenyl]-piperazine-1-carboxylic acid t-butyl ester (5.87 g, 54% yield).
Reaction SMILES: C[C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=[CH:4][C:3]=1[O:21]C.B(Br)(Br)Br.[CH2:27](Cl)Cl>>[CH2:9]([NH:8][C:7]1[CH:2]=[C:3]([OH:21])[CH:4]=[CH:5][C:6]=1[CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCNc1cccc(OC)c1C
Reactant: ClCCl
Agent: BrB(Br)Br
Product: CCCCCCCCCCCCNc1cc(O)ccc1C
Temperature: 0 °C
Yield: 70 %

Procedure:
As a general methyl group de-protection procedure, 4 methyl-3-dodecylamino-1-methoxy benzene 120 was suspended in dry CH2Cl2, cooled to 0° C. and 5 equivalents of a solution of BBr3 (1M CH2Cl2, Aldrich Chem. Co.) were added and the reaction maintained at 0° C. for 16 hours. The reaction was quenched at 0° C. by slow addition of MeOH and then careful addition of solid NaHCO3 (10 Equiv.) until foaming stops. The mixture was filtered, the filtrate was concentrated to an oil, and the product was isolated by normal phase chromatography eluting with methanol/CH2Cl2. The solvent was removed from the pure fractions to give 3-dodecylamino-1-hydroxy-4 methylbenzene 120 (R═H, R′═R′″═H, R″=Me) as a waxy solid in 70-80% yield (1HNMR (CDCl3) δ 6.91 (d, 1H), 6.17 (d, 1H), 6.14 (dd, 1H) 4.62 (bs, OH), 3.53 (bs, NH), 3.14 (t, 2H), 2.09 (s, 3H), 1.70 (p, 2H), 1.46 (m, 18H), 0.93 (t, 3H))
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.Cl[CH2:21][CH:22]=O.C([O-])(O)=O.[Na+].CCOC(C)=O>CO>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:21]=[CH:22][N:12]=[C:7]3[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: CC[C@@H]1C(N)=Nc2cnc(Cl)nc2N1C1CCCC1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC[C@@H]1c2nccn2-c2cnc(Cl)nc2N1C1CCCC1
Temperature: 68 °C

Procedure:
(R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydropteridin-6-amine (177 mg, 0.64 mmol) in MeOH (1.5 mL) treated with 50% aqueous chloroacetaldehyde (131 μL, 1.3 Eq.) and the reaction mixture heated to reflux for 6 hours. A further portion of 50% aq. chloroacetaldehyde (400 μL, 3.0 Eq.) was added, and the reaction mixture heated to 68° C. overnight. NaHCO3 (aq. sat.) and EtOAc was added, and the aqueous was further extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:20][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:12][C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][O:2]1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(c2ccccc2)OCC(C(=O)c2ccccc2)(c2ccccc2)O1
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 12.1 grams (50 millimoles) of α-methylol benzoin, 6.0 grams (50 millimoles) of acetophenone, 1.0 gram of p-toluenesulfonic acid and 100 ml. of benzene was refluxed under a Dean-Stark trap for 2 hours, the mixture allowed to stand overnight at room temperature, then saturated with ammonia gas and filtered. The resulting oil was distilled at 135°-165° C at 20μ vacuum pressure to yield 10.5 grams of an only partially pure product. 7.2 grams of this product were chromatographed on silica gel with 5% diethyl ether-hexane elution to yield 6.2 grams of a product that was still not entirely pure, which was subjected to NMR and infrared examination as follows:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:4]=2[S:5](=[O:9])(=[O:8])[C:6]=1[CH3:7].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O>[Cl:14][C:11]1[CH:12]=[CH:13][C:3]2[CH:2]=[C:6]([CH2:7][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[S:5](=[O:9])(=[O:8])[C:4]=2[CH:10]=1
Reactant: CC1=C(Cl)c2ccc(Cl)cc2S1(=O)=O
Reactant: C1CCNCC1
Solvent: O
Product: O=S1(=O)C(CN2CCCCC2)=Cc2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3.75 g 3,6-dichloro-2-methyl-benzo[b]-thiophene-1,1-dioxide and 35 ml piperidine is stirred for 4 hours at 80° C., water is subsequently added and it is extracted with ethyl acetate. The extract is concentrated by evaporation and it is ground with ethyl acetate. 1.6 g of the title compound (36% of the theoretical yield) of melting point 154°-156° C. is isolated.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[N:22]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:33][CH:30]2[CH2:29][CH2:28][N:27]([C:23]3[N:22]=[C:21]([C:20]([F:35])([F:34])[F:19])[CH:26]=[CH:25][N:24]=3)[CH2:32][CH2:31]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: NC1CCN(c2nccc(C(F)(F)F)n2)CC1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(NC2CCN(c3nccc(C(F)(F)F)n3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 80.7 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.70 mmol), 1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-ylamine (0.190 g, 0.77 mmol) and TEA (0.078 g, 0.77 mmol) was dissolved in dry MeCN (3 ml) and heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was purified by silica gel column chromatography using a 65:35 mixture of heptane and EtOAc as eluant, to give the title compound (0.280 g, 81%). 1H NMR (500 MHz, CDCl3): δ 8.45-8.41 (m, 1H), 7.58-7.52 (m, 2H), 7.49-7.42 (m, 3H), 6.74-6.70 (m, 1H), 5.26-5.19 (m, 1H), 4.59-4.51 (m, 2H), 4.41 (hep, 1H), 3.26-3.16 (m, 1H), 2.58-2.49 (m, 2H), 1.78-1.71 (m, 2H), 1.57 (d, 6H), 1.35-1.24 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 161.2, 160.3, 158.7, 156.6, 156.3, 134.5, 131.9, 130.2, 129.0, 125.3, 121.8, 119.6, 107.2, 104.9, 50.7, 47.9, 42.4, 32.2, 20.4; Mass Spectrum: M−H+ 496.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:7]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[CH:20][C:8]=2[S:9][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1)=[O:12]>ClCCl.C(OCC)(=O)C>[Cl:5][C:6]1[C:7]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[C:20]([N+:1]([O-:4])=[O:2])[C:8]=2[S:9][C:10]=1[C:11]([N:13]1[CH2:14][CH2:15][CH:16]([OH:19])[CH2:17][CH2:18]1)=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1sc2cc(O)c(O)cc2c1Cl)N1CCC(O)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl)N1CCC(O)CC1
Reaction time: 3 h

Procedure:
A solution of 1 M HNO3 in dichloromethane (0.67 ml) was added to a solution of (3-chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidin-1-yl)-methanone (0.17 g) in ethyl acetate (10 ml). Stirring was continued at 60° C. for 3 hours and then at room temperature overnight. The mixture was concentrated to smaller volume and the precipitate filtered and washed with water. The crude product was recrystallized from N,N-dimethylformamide/ethanol (25:75).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1F)[CH3:2].C(N(C(C)C)CC)(C)C.C[N:26]1C(=O)[CH2:29][CH2:28][CH2:27]1>>[N+:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:26]3[C@H:2]([CH2:1][O:3][C:4](=[O:15])[C:5]=2[CH:10]=1)[CH2:29][CH2:28][CH2:27]3)([O-:13])=[O:12]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC[C@@H]2CCCN2c2ccc([N+](=O)[O-])cc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
By adopting a similar procedure as described in “Mueller, W; Stauss, U.; Forschungsinst, W.; Bern, S. Helvetica Chimica Acta 1982, 65, 2118.” (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one was prepared as follows. A mixture of 2-fluoro-5-nitro-benzoic acid ethyl ester (1.16 g, 5.44 mmol.), S-prolinol (638 mg, 6.31 mmol) and diisopropylethylamine (1.5 mL, 8.62 mmol) in dry NMP (20 mL) was stirred at 100° C. for 3 h. Solvent was removed and the mixture was partition between EtOAc and water. Organic layer was extracted two more times with EtOAc. Combined organic was washed successively with water (twice) and brine. After drying over magnesium sulfate, solvent was evaporated. The product, (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one was obtained as a solid (1.08 g, 80%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[N:13]([CH3:24])[C:12]=2[CH:11]=[CH:10][C:9]=1[O:25][CH3:26])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:34](N1CCCCC1)=[O:35].COC1C=C(C=O)C2N(C)C3C(SC=2C=1C(C(C)(C)C)O[SiH](C)C)=CC(OC)=CC=3.[BH4-].[Li+]>C(OCC)C.O1CCCC1.O1CCCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[C:9]([O:25][CH3:26])=[CH:10][CH:11]=[C:12]2[C:21]=1[S:20][C:19]1[C:18]([CH2:34][OH:35])=[C:17]([O:22][CH3:23])[CH:16]=[CH:15][C:14]=1[N:13]2[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)Sc1c(ccc(OC)c1C(C)(C)O[SiH2]C(C)(C)C)N2C
Reactant: O=CN1CCCCC1
Agent: COc1ccc2c(c1)Sc1c(C(O[SiH](C)C)C(C)(C)C)c(OC)cc(C=O)c1N2C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1CO)Sc1c(ccc(OC)c1C(C)(C)O[SiH2]C(C)(C)C)N2C
Temperature: 0 °C
Yield: 67.6 %

Procedure:
A solution of 4.56 g (10.9 mmol) of 4-(tert.-butyl-dimethyl-silanyloxymethyl)-3,7-dimethoxy-10-methyl-phenothiazine in 50 ml of diethyl ether/tetrahydrofuran (4:1) was reacted with 7.5 ml of n-butyllithium solution (1.6M in hexane) and 1.89 g (16.84 mmol) of N-formylpiperidine analogously to that described in Example 4.1.1c. The resulting 3,7-dimethoxy-4-(tert.butyldimethylsilanyloxymethyl)-10-methylphenothiazine-carbaldehyde was dissolved in 50 ml of tetrahydrofuran and reduced with 12.0 ml of lithium borohydride solution (1M in tetrahydrofuran) analogously to that described in Example 4.1.8.b. The reaction mixture was poured into ice/1M sodium dihydrogen phosphate solution, whereupon the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:1), whereupon, after recrystallization from ethyl acetate/hexane and drying, 3.30 g (67.6%) of [6-(tert.-butyl-dimethyl-silanyloxymethyl)-3,7-dimethoxy-10-methyl-phenothiazine4-yl]methanol were obtained as a white solid of m.p. 46°-47°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)=[CH:16][N:17]=3)[N:14]=2)[CH2:3][CH2:2]1.[OH:29][C:30]([CH3:35])([CH3:34])[C:31](O)=[O:32].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[OH:29][C:30]([CH3:35])([CH3:34])[C:31]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:28])[F:27])[CH:19]=4)=[CH:16][N:17]=3)[N:14]=2)[CH2:3][CH2:2]1)=[O:32]
Reactant: CC(C)(O)C(=O)O
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(NCC4CCNCC4)nn23)c1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(O)C(=O)N1CCC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound N-(piperidin-4-ylmethyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (200 mg, 0.47 mmol) was combined with 2-hydroxy-2-methylpropanoic acid (49 mg, 0.47 mmol), EDC (99 mg, 0.51 mmol) and HOAT (64 mg, 0.47 mmol). The mixture was then taken up in DMF (2 mL) and NMM (257 uL, 2.34 mmol) was added. The mixture was then stirred overnight at room temperature. The DMF solution was then poured into an excess of water (20 mL) causing a precipitate to form. The precipitate was collected by filtration and purified via column chromatography (DCM/MeOH 0-15%) to give Compound 2-hydroxy-2-methyl-1-(4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl)piperidin-1-yl)propan-1-one.
Reaction SMILES: [CH:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[C:25]([C:32](=[O:34])[CH3:33])=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:1]([CH:4]1[N:9]([C:22]2[N:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[C:25]([C:32](=[O:34])[CH3:33])=[CH:24][N:23]=2)[CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CC(C)C1NCCn2c1nc1ccc(S(C)(=O)=O)cc12
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cnc(N2CCn3c(nc4ccc(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (7.50 mg, 0.03 mmol) in DMSO (1 mL) were added 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (11.5 mg, 0.05 mmol) and DIEA (9.90 mg, 0.08 mmol) under N2. The mixture was stirred at 100° C. for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and then purified by preparative HPLC to afford a racemic mixture of 1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (2.40 mg, 20% yield) as a white solid. LC-MS m/z 482.1 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 8.76 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.84-7.83 (m, 1H), 6.15 (d, J=8.0 Hz, 1H), 5.45 (d, J=13.6 Hz, 1H), 4.42-4.36 (m, 1H), 4.20 (brs, 1H), 3.91-3.80 (m, 1H), 3.09 (s, 3H), 2.60-2.46 (m, 4H), 1.34 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.0 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: COc1ccc(N=C=O)cc1
Solvent: CCO
Product: COc1ccc(NC(=O)NCCCOc2cccc(CN3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.3 %

Procedure:
To the mixture of 3-(3-piperidinomethylphenoxy)propylamine (3.1 g) in ethanol (31 ml) was added 4-methoxyphenylisocyanate (1.9 g) dropwise slowly under cooling on an ice-water bath. The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (50 ml), washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the crude product (3.3 g) was obtained (yield 66.0 %). This crude product was recrystallized from ethanol to give the title compound (2.1 g), mp 111°-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(OCC)(=O)C>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-aminoindan (100 g), acetic anhydride (84 g), pyridine (65 g) and ethyl acetate (500 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under diethyl ether (800 ml). The solid was filtered off, washed with diethyl ether (500 ml) and with hexane (500 ml) and dried. There was thus obtained 5-acetamidoindan (104.5 g), m.p. 107° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:24])=[C:16]([CH3:23])[C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1.Cl>CN(C)C=O.O>[CH3:24][C:15]1[C:14]([O:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])=[N:19][N:18]2[N:20]=[CH:21][N:22]=[C:17]2[C:16]=1[CH3:23]
Reactant: Cc1c(Cl)nn2ncnc2c1C
Reactant: CC(C)(CO)CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCC(C)(C)CS(N)(=O)=O)nn2ncnc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
In 30 ml of dimethylformamide was suspended 1.38 g of 60% sodium hydride in oil, followed by addition of 2.51 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperature for 1 hour. To this was added 2.56 g of 6-chloro-7,8-dimethyl[1,2,4]triazolo[1,5-b]pyridazine and the mixture was stirred at room temperature for 3 hours. Following addition of 100 ml of iced water, the reaction mixture was adjusted to pH 6 with 5N-hydrochloric acid and extracted with 3 portions of ethyl acetate-tetrahydrofuran (2:1). The extract was washed with 20 ml of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethane-methanol (30:1). The fractions containing the desired product were pooled and concentrated to provide 0.63 g of the title compound. m.p. 175°-177° C.