Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([NH2:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH3:12][C:8]([CH3:13])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([NH2:11])=[O:10]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C(N)=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-hydroxy-α,α-dimethyl-benzeneacetamide (Example 198b, 15.34 g) dissolved in DMF (150 mL) was treated with potassium carbonate (11.83 g) and benzyl bromide (10.18 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water (500 mL) and stirred for 30 min. The solid was filtered off and washed with water and dried in vacuo to afford the subtitle compound (19.45 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[C:7](=[O:20])[CH2:6][CH2:5]2.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:20])=[CH:3][C:2]=1[N:1]([S:22]([CH3:21])(=[O:24])=[O:23])[S:22]([CH3:21])(=[O:24])=[O:23].[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:20])=[CH:3][C:2]=1[NH:1][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: Nc1cc2c(cc1Oc1ccc(F)cc1F)C(=O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)N(c1cc2c(cc1Oc1ccc(F)cc1F)C(=O)CC2)S(C)(=O)=O
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)C(=O)CC2
Reaction time: 3 h

Procedure:
12.8 g of 5-amino-6-(2,4-difluorophenoxy)-1-indanone in 95 ml of pyridine was combined at 0° C. with 8.3 ml of methanesulfonyl chloride. After 3 hours at 0° C. and 16 hours at 20° C., the mixture was concentrated, the residue taken up in chloroform, the solution washed with 1 N hydrochloric acid, and concentrated. Chromatography of the residue over silica gel with dichloromethane-ethyl acetate yielded 1.2 g of 6-(2,4-difluorophenoxy)-5-bis(methylsulfonyl)amino-1-indanone, mp 190° C. (from toluene) and subsequently 8.9 g of 6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone, mp 153° C. (from ethanol).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[CH:24]=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[CH:12][C:11]=1[F:34])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:34][C:11]1[CH:12]=[C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1ccc(O[C@H]2CCCC[C@@H]2c2cn[nH]c2)cc1F
Yield: 84.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide (0.12 g, 0.171 mmol) prepared in Example 108a, triethylsilane (0.15 mL), trifluoroacetic acid (1.5 mL), dichloromethane (1.5 mL) and methanol (1.5 mL), to yield the title compound (60 mg, 76%) as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C>CN(C=O)C.O>[N+:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:2][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:7][C:6]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc2oc(CCl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2oc(CN3CCCC3)nc2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A reaction mixture of 3 g (14.11 mmol) of 2-chloromethyl-5-nitrobenzoxazole, 1.5 mL (17.97 mmol) of pyrrolidine, and 3.9 g (28.22 mmol) of potassium carbonate in 30 mL of DMF is stirred for 4 hours at 50° C. Then the reaction mixture is diluted with water and covered with diisopropyl ether, The precipitated yellow solid is suction filtered, washed again, and dried in the circulating air dryer at 60° C. Yield: 1.8 g (52% of theory); C12H13N3O3 (M=247.25); calc.: molecular ion peak (M+H)+: 248; found: molecular ion peak (M+H)+: 248; Rf value: 0.4 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [O:1]=[C:2]([C:8]([O-:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:13].N1C=CC=[CH:30][CH:29]=1>>[OH:1][C:2]([CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:13])([C:8]([O:10][CH2:29][CH3:30])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(=O)C(=O)[O-]
Reactant: c1ccncc1
Product: CCOC(=O)C(O)(CC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)OCC

Procedure:
19 cm3 of ethyl ketomalonate and 2.5 cm3 of pyridine were added to 23.1 g of 4-benzyloxyacetophenone. The reaction medium was heated and maintained at reflux for 12 hours. After cooling, the reaction medium was purified by chromatography on silica gel (particle size 40-63 μm, under an argon pressure of 150 kPa), eluting with a mixture of dichloromethane and methanol (99/1 by volume). The fractions containing the product were combined and then concentrated under reduced pressure (45° C.; 5 kPa). The product obtained was triturated in 150 cm3 of ethanol, filtered through a sinter funnel, washed with twice 50 cm3 of ethanol and 50 cm3 of isopropyl ether to give, after drying under reduced pressure (2 kPa; 55° C.), 5.6 g of diethyl hydroxy[2-(4-benzyloxyphenyl)-2-oxoethyl]malonate melting at 80° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1)=O.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[NH:15][C:14](=[O:19])[C:13]4[NH:20][CH:21]=[CH:22][C:12]=4[C:11]=3[CH:10]=2)[N:4]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: NC(N)=S
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 16.9 %

Procedure:
17 mg (1.5 mmol) of thiourea is added to a suspension of 57 mg (0.15 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 mL of ethanol. The mixture is stirred at 90° C. for 3 hours then the mixture is cooled to room temperature. Triethylamine (2 mmol) is added then the solvent is evaporated and the product is purified by chromatography on silica (chloroform/methanol/triethylamine 8/2/1). After drying, 9 mg (17%) of 8-(2-amino-thiazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(P(CCCC)CCCC)CCC.[C:25]1([C:31](O)([CH3:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:31]([CH3:33])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:32])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CC(C)(O)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 34.1 %

Procedure:
To a solution of 4-chloro-3-nitrophenol (0.5 g), tri(n-butyl)phosphine (0.72 mL) and 2-phenyl-2-propanol (0.26 g) in tetrahydrofuran (5 mL) was added 1, 1′-azobis (N,N-dimethyl -formamide) (0.5 g), and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was diluted with diethyl ether, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=10/1) to give 2-chloro-5-(1-methyl-1-phenylethoxy)-1-nitrobenzene (0.19 g). This material was dissolved in tetrahydrofuran (3.5 mL). To the solution were added methanol (3.5 mL), nickel(II) bromide (11 mg) and sodium borohydride (0.12 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =3/1) to give the title compound (0.14 g).
Reaction SMILES: [Na].O=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH:5]=O.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH:21][C:22]([NH2:24])=[NH:23].[OH-].[K+]>C(O)CCC.C(O)(=O)C>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH:21][C:22]1[N:24]=[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:23]=1
Reactant: Cc1ccc(N)cc1NC(=N)N
Reactant: O=CCC(=O)c1cccnc1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCCO
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C

Procedure:
Under inert atmosphere, 16 g sodium salt of β-oxo-3-pyridinepropanal, with HPLC purity of 99% (A %) and 25% salt content (residue by calcination), and 11.7 g (2-methyl-5-aminophenyl)guanidine in 115 mL n-butanol is suspended. 9 mL acetic acid is added, and the mixture is stirred at room temperature for an hour. 6 g potassium hydroxide is added portionwise, and the mixture is refluxed for 18 hours, removing the water with a Dean Stark apparatus. Once completed the conversion, the suspension is cooled and the organic layer is washed with water. The organic layer is concentrated to a small volume, and toluene is added. The precipitate is filtrated, yielding, upon drying, 15.5 g of product with HPLC purity of 99.2% (A %), identified through LC-MS and
Reaction SMILES: [OH:1][CH2:2]C(CO)OCN1C=C(C=C)C(=O)NC1=O.ClN1C(=O)CCC1=O.[OH:26][CH2:27][CH2:28][O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Cl:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]>ClCCl.CO>[OH:26][CH2:27][CH:28]([CH2:2][OH:1])[O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Cl:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]
Reactant: C=Cc1cn(COC(CO)CO)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=NC(CCl)c1cn(COCCO)c(=O)[nH]c1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: ClCCl
Product: [N-]=[N+]=NC(CCl)c1cn(COC(CO)CO)c(=O)[nH]c1=O
Yield: 57 %

Procedure:
Reaction of 9a with N-chlorosuccinimide, using the procedure outlined for the preparation of 2b, and purification of the product by silica gel column chromatography using dichloromethane-methanol (90:10, v/v) as eluent yielded 10b as a syrup (75 mg, 57%).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].CCN(C(C)C)C(C)C.CO[CH:16]=[N:17][C:18]1[C:19]([CH3:32])=[N:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:22]([Br:24])[CH:23]=1>ClCCl>[Br:24][C:22]1[CH:23]=[C:18]([NH:17][CH:16]=[N:4][CH2:2][CH3:3])[C:19]([CH3:32])=[N:20][C:21]=1[O:25][CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CCN
Reactant: COC=Nc1cc(Br)c(OCCCC(C)C)nc1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN=CNc1cc(Br)c(OCCCC(C)C)nc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
In a 50 ml single-necked round-bottomed flask, 540 mg of N-[5-Bromo-2-methyl-6-(4-methyl-pentyloxy)-pyridin-3-yl]-formimidic acid methyl ester is dissolved in 6.60 ml of dry dichloromethane. Under stirring at an ambient temperature, 214 mg of ethylamine hydrochloride along with 0.45 ml of Hünig's base are added. Stirring is continued at room temperature for 20 hours. Then, the volatiles are removed in vacuo at 50° C. After purification on silica gel (eluent: heptane/ethyl acetate 8:1 (v:v) with 5% triethylamine) to give 530 mg of the title compound in the form of a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[OH:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1C(C(C2C=CC=CN=2)O)=CN=C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(O)c2cccnc2)cc1OC
Agent: Cn1cncc1C(O)c1ccccn1
Product: COc1ccc(C(=O)c2cccnc2)cc1OC

Procedure:
The title compound was prepared analogously to the method in Intermediate 25: step b using (3,4-dimethoxyphenyl)(pyridin-3-yl)methanol (Intermediate 27: step a) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[NH:14][C:13](=O)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:18])=O>>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([Cl:18])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@H](C)c1nccc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reaction time: 3 h

Procedure:
(R)-2-(1-Butyryloxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 3.00 g, 16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature and stirred for 3 h. Excess phosphorus oxychloride was removed under vacuum and the resulting oil was partitioned between dichloromethane and saturated aqueous sodium carbonate. The layers were separated and the organic layer was washed once with water, once with saturated aqueous sodium chloride and dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an orange oil, 3.19 g (85%). 1H NMR (CDCl3, 300 MHz) δ0.98 (t, 3H), 1.54 (d, 3H), 1.67 (m, 2H), 2.48 (t, 2H), 5.68 (q, 1H), 6.36 (d, 1H), 8.21 (d, 1H); [α]D +27.6 (c 1.0, MeOH).
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[CH2:5]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[OH:18])[C:11](=[N:13][OH:14])[NH2:12])[CH:6]=[CH2:7]>N1C=CC=CC=1>[CH2:5]([C:8]1[CH:9]=[C:10]([C:11]2[N:12]=[C:1]([CH3:2])[O:14][N:13]=2)[CH:15]=[CH:16][C:17]=1[OH:18])[CH:6]=[CH2:7]
Reactant: CC(=O)Cl
Reactant: C=CCc1cc(C(N)=NO)ccc1O
Solvent: c1ccncc1
Product: C=CCc1cc(-c2noc(C)n2)ccc1O
Temperature: 25 °C

Procedure:
Acetyl chloride (2.28 ml) was added dropwise to a solution of 3-allyl-4-hydroxybenzamidoxime (5.4 g) in pyridine (48 ml). The solution was heated at reflux for 16 hours, cooled to ambient temperature and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with saturated aqueous sodium carbonate solution, dried (MgSO4) and evaporated, to give 2-allyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenol as a low-melting solid (3.8 g), m/z 217 (M+H).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9]C([O-])(C)C.[K+].IC.C(OC(N[C@H](C1(C)CCCCC1)C(O)=O)=O)(C)(C)C>C(Cl)Cl>[CH3:9][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: O=CC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1(C)CCCCC1
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: CC1(C=O)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A flame-dried 500-mL round-bottomed flask capped with a rubber septum was charged with anhydrous CH2Cl2 (150 mL) via cannula and cyclohexanecarboxaldehyde (12) (9.09 mL, 75 mmol, 1.0 equiv) via syringe under N2. The flask was cooled in an ice bath for 10 min, the septum was removed, and t-BuOK (10.9 g, 97.5 mmol, 1.3 equiv) was added in one portion with rapid stirring. The septum was replaced, and iodomethane (14.0 mL, 225 mmol, 3.0 equiv) was added in one portion via syringe. The mixture was stirred at 0° C. under N2 for 30 min. The mixture was then allowed to warm to room temperature and stirred an additional 2 h. The resulting pale yellow, heterogeneous mixture was filtered through a 10-cm diameter medium porosity fritted disk funnel, and the cake was washed with CH2Cl2 (3×15 mL). The filtrate was washed with brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was distilled under reduced pressure (1 torr) while maintaining the receiving flask between −20 to −40° C. (bp <30° C.). The distillate was a clear, colorless oil that contained (1-methyl)cyclohexanecarboxaldehyde (13) and 1.25 equiv CH2Cl2, as determined by 1H-NMR analysis: 13.2 g total, ˜7.2 g (1-methyl)cyclohexanecarboxaldehyde (57 mmol, 76% yield). The product was used in the next step without further purification.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[N:6]=1)=[NH:4].N[CH2:17][CH2:18][SH:19]>C(Cl)(Cl)Cl>[S:19]1[CH2:18][CH2:17][N:4]=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[O:12][CH2:13][CH2:14][O:15]2)[N:6]=1
Reactant: COC(=N)c1cccc(C2OCCO2)n1
Reactant: NCCS
Solvent: ClC(Cl)Cl
Product: c1cc(C2=NCCS2)nc(C2OCCO2)c1
Temperature: 130 °C
Yield: 97 %

Procedure:
1 g of 6-[1,3]dioxolan-2-yl-pyridine-2-carboximidic acid methyl ester (4.80 mmol) and 0.47 g of 2-aminoethanethiol (2.16 mmol) are mixed. The mixture is heated at 130° C. for 1 hour 30 minutes. The reaction mixture is taken up in chloroform, washed with water and then dried over magnesium sulfate. After filtration and evaporation of the solvent, the title product is isolated by chromatography on a silica column (eluent: chloroform/methanol; 98:2). 1.10 g of solid are recovered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:24][CH2:25][CH2:26][C:27]4[NH:31][CH:30]=[N:29][CH:28]=4)[CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccnc(F)c2)cc1
Reactant: NCCc1c[nH]cn1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nn3ccccc3c2-c2ccnc(NCCc3cnc[nH]3)c2)cc1
Temperature: 140 °C

Procedure:
In a sealed-tube was combined 2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 27. 30 mg, 0.10 mmol) and histamine (40 mg, 0.36 mmol), and the reaction was placed in a pre-heated oil bath at 140° C. The reaction was stirred at 140° C. until consumption of starting material was indicated by TLC analysis (50% ethyl acetate in hexanes). The contents of the sealed-tube were transferred to a flask and concentrated to dryness at 50° C. under high vacuum. The residue was purified by silica gel chromatography to yield the title compound, 23 mg (0.06 mmol, 60%). 1H NMR (d6-DMSO) δ 11.8 (brs, 1H), 8.73 (d, 1H, J=6.8 Hz), 7.94 (d, 1H, J=5.3 Hz), 7.63 (d, 1H, J=9.3 Hz), 7.57 (dd, 2H, J=5.3, 8.6 Hz), 7.48 (s, 1H), 7.30 (t, 1H, J=7.6 Hz), 7.23 (t, 2H, J=9.0 Hz), 6.97 (t, 1H, J=6.8 Hz), 6.75 (brs, 1H), 6.57 (br t, 1H, J=5.3 Hz), 6.44 (s, 1H), 6.33 (d, 1H, J=5.3 Hz), 3.41 (q, 2H, J=6.6 Hz), 2.7 (t, 2H, J=6.6 Hz). MS (ES+ve): 399.1 (50, M+), 305.3 (90), 169.4 (100).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([CH2:22][N:23]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39]([C@H:41]4[CH2:45][CH2:44][CH2:43][N:42]4[C:46]([O:48][CH2:49][CH:50]4[C:62]5[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=5[C:56]5[C:51]4=[CH:52][CH:53]=[CH:54][CH:55]=5)=[O:47])=[O:40])=[CH:34][CH:33]=3)[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:38][C:39]([C@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46]([O:48][CH2:49][CH:50]3[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][C:56]=4[C:57]4[C:62]3=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:47])=[O:40])=[CH:36][CH:37]=2)[CH2:22][C:20]2[CH:19]=[CH:18][C:16]3[NH:17][C:13]([C@@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)=[N:14][C:15]=3[CH:21]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc(NC(=O)[C@H]4CCCN4C(=O)OCC4c5ccccc5-c5ccccc54)cc3)c3ccc(F)cc3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(CN(Cc2ccc3[nH]c([C@@H]4CCCN4)nc3c2)c2ccc(F)cc2)cc1)[C@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 27.5 %

Procedure:
The product from Example 99E (0.38 g, 0.455 mmol) was dissolved in dichloromethane (4 mL) and treated with trifluoroacetic acid (3 mL) at ambient temperature for 3 hours, then concentrated to dryness, taken up in ethyl acetate and washed with sodium bicarbonate solution. The organic was dried over sodium sulfate, filtered, and concentrated to give 0.092 g (28%) of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:14]1[C:27]2[CH:26]([C:28]([Cl:30])=[O:29])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>>[ClH:30].[ClH:30].[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:28]([CH:26]2[C:27]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[O:19][C:20]3[C:25]2=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:29])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(CCCO)CC1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: C=CCN1CCN(CCCOC(=O)C2c3ccccc3Oc3ccccc32)CC1
Product: Cl
Yield: 76 %

Procedure:
3-(4-Allyl-piperazin-1-yl)-1-hydroxy-propane, prepared as described in Example 2, Step A, is reacted with xanthene-9-carbonyl chloride as described in Example 1, Step B. 3-(4-Allyl-piperazin-1-yl)-1-(xanthene-9-carbonyloxy)-propane dihydrochloride is obtained with a yield of 76%; m.p.: 209°-211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.ClC(Cl)C.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:32][CH:29]3[CH2:31][CH2:30]3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=CC1CC1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a small sample of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034 g, 0.1 mmol) weighed out in a 1 mL sealable vial, dichloroethane was added (300 μL), followed by excess of cyclopropanecarboxaldehyde (20 μL, >0.15 mmol) and sodium triacetoxyborohydride (200 μL of a 1.5 M solution in N-methylpyrrolidinone). The vial was capped and placed in a shaker at 70° C. overnight. After an additional 24 heat room temperature, methanol was added (400 μL) and the vial was shaken for a few minutes. The reaction mixture was then applied to a 2 g SCX column, washed with methanol (30 mL) and gravity-eluted with 1 N ammonia in methanol (20 mL). The yellow fractions were combined and concentrated in vacuo to a dry residue (0.040 g, >100%), which was identified as the title compound by LC-MS (Method A).