Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:18])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][N:33]([C:37]([O:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[O:38])[CH2:34]3)=[CH:29][CH:28]=2)[CH:24]=[C:23]([N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)[N:22]=1>>[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][N:33]([C:37]([O:39][CH:40]4[CH2:45][CH2:44][N:43]([C:1]([O:2][CH:3]5[CH2:4][CH2:5][CH2:6][CH2:7]5)=[O:18])[CH2:42][CH2:41]4)=[O:38])[CH2:34]3)=[CH:29][CH:28]=2)[CH:24]=[C:23]([N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)[N:22]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)OC5CCCC5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from cyclopentyl 4-nitrophenyl carbonate and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=564.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+].C(O)C>O>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reaction time: 2 h

Procedure:
6-Hydroxynaphthalene-2-carboxylic acid (39.8 g), 1-bromooctane (61.3 g), potassium hydroxide (23.7 g), ethanol (900 ml) and water (120 ml) were stirred and refluxed for 16 hours. 10% Aqueous potassium hydroxide (200 ml) was added and refluxing was continued for a further 2 hours, when the solution was poured into water (5 liter) and acidified to ph 1. The solid was filtered, washed with water, dried and recrystallised from acetic acid to give the product (49.0 g, 77.2% theory) as a white crystalline solid, mpt 150°-153° C. (98.2% pure by hplc).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:17]3[N:34]=[CH:33][S:32][C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=[O:26])[N:21]=2)[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+].[ClH:37]>O1CCOCC1.O>[ClH:37].[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:17]3[N:34]=[CH:33][S:32][C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([OH:27])=[O:26])[N:21]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COCC1CCCN1c1cccc(Nc2nc(-c3cccc(C(=O)OC)c3)nc3scnc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCC1CCCN1c1cccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)c1
Reaction time: 0.15 h
Yield: 31 %

Procedure:
Methyl 3-(7-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (100 mg, 0.21 mmol) and NaOH (100 mg, 2.5 mmol) in 3 mL of 1,4-dioxane and 3 mL of H2O was stirred at room temperature for 3 hours and then treated by conc. HCl until pH=3-4. The solvent was removed under reduce pressure the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 50% acetonitrile/50% water (0.1% TFA V/V) initially, and then proceed to 80% acetonitrile/20% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid hydrochloride (30 mg, 31%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.28 (s, 1H), 9.41 (s, 1H), 8.98 (s, 1H), 6.62 (d, 1H, J=7.5 Hz), 8.08 (d, 1H, J=7.5 Hz), 7.66-7.62 (m, 2H), 7.47 (brs, 1H), 7.28 (brs, 1H), 3.95 (brs, 1H), 3.54-3.51 (m, 2H), 3.32-3.27 (m, 2H), 3.19 (s, 3H), 2.03-1.19 (m, 4H). LC-MS: 462 [M+H]+, tR=1.66 min. HPLC: 96.12% at 214 nm, 96.76% at 254 nm, tR=6.84 min.
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([O:28]CC)=O)[C:8]1=[O:31])(=[O:3])[CH3:2].[CH3:33][NH2:34]>C(O)C>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:34][CH3:33])=[O:28])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Solvent: CCO
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine in ethanol using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d6 (90° C.) δ ppm 1.80-1.87 (m, 3 H), 2.95 (d, J=4.94 Hz, 6 H), 3.53 (t, J=6.79 Hz, 2 H), 4.18 (s, 2 H), 4.36 (s, 2 H), 7.12 (t, J=8.44 Hz, 2 H), 7.35-7.40 (m, 2 H), 8.05 (s, 1 H), 8.54 (s, 1 H), 10.07 (s, 1 H), 17.05 (br. s., 1 H); ES+ MS: 427 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11]N(C)C.[OH-].[Na+].[N+:17]([CH:20]([CH3:22])[CH3:21])([O-:19])=[O:18]>C(O)(=O)C>[CH3:21][C:20]([CH3:22])([N+:17]([O-:19])=[O:18])[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2ccc(Cl)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(Cc1c[nH]c2ccc(Cl)cc12)[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 20 h
Yield: 105.1 %

Procedure:
5-Chloro-3-(dimethylaminomethyl)-1H-indole (10.6 g, 50.5 mmol), prepared as in Example 2, Step (a) and powdered sodium hydroxide (3.0 g, 75.0 mmol) were combined in 2-nitropropane (80 mL, 890.8 mmol) and the mixture was stirred at 120° C. and under nitrogen for 20 hours. The mixture was cooled, acidified with 10% acetic acid (80 mL), stirred at room temperature for 1 hour, and then extracted into ether. The organic phase was separated, washed with water and then brine, dried over magnesium sulfate, and evaporated. Filtration of the residue through a short column of silica gel gave 3-(2,2-dimethyl-2-nitroethyl)-5-chloro-1H-indole (13.5 g, 53.1 mmol) as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[N:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])[O-].[K+].[K+]>CCOCC.O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][NH2:10]
Reactant: N#CCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCOC1CCCCO1
Yield: 93.3 %

Procedure:
A solution of 35 g of tetrahydropyran-2-yloxy acetonitrile in 100 ml of ether is added dropwise to a slurry of 10 g of lithium aluminum hydride in 300 ml of ether and 100 ml of tetrahydrofuran. The slurry is refluxed for 210 minutes, cooled, and 25 ml of sat. potassium carbonate solution is added at a rate that maintains gentle reflux. After 90 minutes the slurry is filtered and the solid is washed with ether. The filtrate is evaporated in vacuo and distilled to give 33.6 g of 2-(tetrahydropyran-2-yloxy)ethylamine, boiling point 41.5°-46°C at 0.5-0.8 mm.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[N+:19]([O-])([O-:21])=[O:20].[K+].[OH-].[Na+]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:11])=[CH:12][C:13]=2[N+:19]([O-:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: Nc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
4-cyclohexylaniline (15 g, 85.58 mmol) was added portionwise to conc. sulfuric acid (85 mL, 1.6 mol) to generate a homogeneous solution. The solution was then cooled to 0° C. and KNO3 (13 g, 128.6 mmol) was added portionwise maintaining the internal temperature below 5° C. The reaction was stirred for 5 minutes at −10° C. and then poured on ice water, basified with 6N NaOH solution and the aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and concentrated to obtain 4-cyclohexyl-3-nitroaniline (17 g, 921%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J=8.5 Hz, 1H), 6.97 (d, J=2.5 Hz, 1H), 6.82 (dd, J=8.4, 2.5 Hz, 1H), 2.85 (ddd, J=11.4, 8.3, 3.2 Hz, 1H), 1.89-1.69 (m, 6H), 1.49-1.29 (m, 4H).
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:52][O:51][CH2:50][CH2:49]1>>[O:22]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH2:20][N:16]1[C:14]1[CH:13]=[CH:12][C:11]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=3)[CH2:27][CH2:26]2)=[O:24])=[C:10]([C:9]([N:8]2[CH2:49][CH2:50][O:51][CH2:52][CH2:6]2)=[O:40])[CH:15]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C1COCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N3CCOCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzamide (249 mg) described in Example 785 and morpholine (39 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (58 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:18]=[CH:19][CH:20]=1)/[CH:12]=[CH:13]/[C:14](=[N:16]O)[NH2:15].N1C=CC=CC=1.Cl.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:18]=[CH:19][CH:20]=1)/[CH:12]=[CH:13]/[C:14]1[N:16]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[O:4][N:15]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: NC(/C=C/c1cccc(Cl)c1F)=NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Fc1c(Cl)cccc1/C=C/c1noc(C(Cl)(Cl)Cl)n1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
12.7 g (0.07 mol) of trichloroacetyl chloride are added dropwise to a suspension of 6.4 g (0.03 mol) of (E)-3-chloro-2-fluoro-cinnamamide oxime in 90 ml of chloroform and 6 ml (0.07 mol) of dry pyridine. During this process the temperature of the reaction mixture rises slightly. Stirring is subsequently continued for 1 hour, and the pyridine hydrochloride which separates out in this process is filtered off and washed with chloroform. The filtrate is concentrated in vacuo and the solid which remains is recrystallised. 5.0 g (48.7% of theory) of (E)-3-(3-chloro-2-fluoro-styryl)-5-tri-chloromethyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C@H:12]4[CH2:17][N:16]([CH2:18][CH2:19][CH2:20][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)=[O:22])[CH2:15][CH2:14][C@H:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C@@H:12]4[CH2:17][N:16]([CH2:18][CH2:19][CH2:20][C:21]([C:23]5[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=5)=[O:22])[CH2:15][CH2:14][C@@H:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1
Reactant: CN1CCN2c3c(cccc31)[C@H]1CN(CCCC(=O)c3ccc(F)cc3)CC[C@H]12
Solvent: ClC(Cl)Cl
Product: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(=O)c3ccc(F)cc3)CC[C@@H]12

Procedure:
The above compound was resolved into its enantiomers on chiral HPLC column. 4-((6bS,10aR)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone. Viscous tan liquid. [a]D=−36.8° (c=0.886, CHCl3). MS (CI): 394 (M+H+).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20]I>CC(C)=O.C(Cl)Cl>[CH2:3]([C:10]1[N:14]([CH3:20])[C:13]2[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:12]=2[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Brc1ccc2[nH]c(Cc3ccccc3)nc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cn1c(Cc2ccccc2)nc2cc(Br)ccc21
Reaction time: 1 h
Yield: 36.8 %

Procedure:
Powdered KOH (5.25 g, 93.50 mmol) was added to a stirred solution of 2-benzyl-5-bromo-1H-benzimidazole (5.37 g, 18.70 mmol) in acetone (100 mL), after 10 min, methyl iodide (1.28 mL, 20.57 mmol) was added and the mixture was stirred for 1 h and diluted with DCM. The mixture was washed with water and brine, then dried over Na2SO4 and concentrated. The residue was taken up in DCM and hexanes and the resulting suspension filtered. The filter cake was washed with hexanes and dried on a high vacuum pump to give an off-white solid (2.07 g, 37%). LC-MS [M+H]+=302.1, RT=2.47 min
Reaction SMILES: Br[C:2]1[N:3]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH3:31])[CH:28]=2)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=[C:6]([Cl:23])[CH:5]=2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C[C:75]([N:77](C)C)=O>O.[Zn].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]>[Cl:23][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([S:11][C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([C:75]#[N:77])[N:3]2[C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH3:31])[CH:28]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: CCCn1cc(-n2c(Br)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCCn1cc(-n2c(C#N)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Temperature: 120 °C
Yield: 33 %

Procedure:
To a stirred solution of compound 4 (200 mg, 0.38 mmol) in DMA (20 mL) under inert atmosphere were added zinc powder (5.02 mg, 0.07 mmol), ZnCN2 (67.8 mg, 0.58 mmol), xantphos (89.5 mg, 0.15 mmol), Pd2(dba)3 (70.85 mg, 0.07 mmol) at RT; heated to 120° C. under microwave for 30 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 10-15% EtOAc/Hexanes to afford compound 5 (60 mg, 33%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.99 (s, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.78 (s, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.42-7.27 (m, 3H), 7.24-7.22 (m, 1H), 4.36 (q, J=7.0 Hz, 2H), 4.21 (t, J=7.5 Hz, 2H), 2.02-1.98 (m, 2H), 1.36 (t, J=7.0 Hz, 3H), 1.01 (t, J=7.5 Hz, 3H); LC-MS (ESI): 92.5%; m/z 465 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.92 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]O)=[CH:5][N:6]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]2)[C:21]1=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3([C:32]4=[CH:33][C:34]5[O:38][CH2:37][O:36][C:35]=5[CH:39]=[C:31]4[O:30][CH2:29]3)[C:21]2=[O:40])=[CH:5][N:6]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: OCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1N(Cc2cnc(Cl)s2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 0 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a solution of (2-chloro-1,3-thiazol-5-yl)methanol (0.30 g, 2.00 mmol) in anhydrous CH2Cl2 (20.0 mL) was added thionyl chloride (0.50 g, 4.20 mmol) followed by triethylamine (0.40 g, 4.00 mmol) at 0° C. After stirring at 0° C. for one hour and ambient temperature for one hour, the reaction mixture was diluted with CH2Cl2 (50.0 mL) and extracted with water (2×20 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in methyl-ethyl ketone (10.0 mL) followed by the additions of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.36 g, 2.00 mmol) and cesium carbonate (1.95 g, 6.00 mmol). The reaction mixture was heated at 70° C. overnight, cooled, filtered and the filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to yield the title compound (0.032 g, 3.4%) as a colorless solid: mp 195-198° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.39-6.93 (m, 5H), 6.66 (s, 1H), 6.15-6.12 (m, 1H), 5.89 (d, 2H), 5.10 (s, 2H), 4.70 (dd, 2H); MS (ES+) m/z 413.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1.[OH-].[Na+]>O>[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]3[N:8]=2)=[CH:16][CH:15]=1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Reactant: CSc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Reaction time: 15 h

Procedure:
1.0 g 2,3-diamino-5-nitropyridine and 1.125 g 4-methylsulfanylbenzoic acid in 20 ml polyphosphoric acid were heated to 160° C. with stirring for 15 hrs. The mixture was cooled and poured into water. The pH was adjusted to 4-5 by addition of sodium hydroxide and the precipitate collected by filtration. The filtration residue was stirred in 50 ml pyridine at 60° C., cooled and insoluble components removed by filtration. The filtrate was evaporated and the residue used without further purification in the next steps. Yield 0.656 g of 30% purity
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]=[N+]=[N-])=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>CO.Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1C
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1-c1ccccc1C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
To a flask at ambient temperature under N2 containing 10% palladium on carbon catalyst (1.0 g) was added a solution of 4-azidomethyl-2-(2-methylphenyl)benzoic acid methyl ester (5.00 g, 17.8 mmol), prepared as in Example 1191A, in MeOH (75 mL). Two drops of conc. HCl added, and reaction stirred vigorously overnight under an atmosphere of H2. Catalyst filtered off through celite and washed with MeOH. Filtrate concentrated in vacuo, and residue taken up in an aqueous 4N NaOH solution. Aqueous solution extracted with CHCl3 (3×), and extracts dried with Na2SO4, filtered, and concentrated in vacuo to afford the desired product (1.37 g, 30%). m/e (DCI) 256 (MH+)
Reaction SMILES: [CH3:1][CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[NH2:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=1>C(O)(=O)C>[CH3:15][C:13]1[CH:14]=[C:10]2[N:9]=[C:3]([CH3:4])[C:2]([CH3:1])=[C:6]([CH3:7])[N:11]2[N:12]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(=O)C(C)C(C)=O
Solvent: CC(=O)O
Product: Cc1cc2nc(C)c(C)c(C)n2n1
Yield: 86.6 %

Procedure:
12.6 g of 3-methyl-2,4-pentanedione, 30 cc of acetic acid and 9.6 g of 3-amino-5-methylpyrazole were introduced into a 100 ml three-necked round-bottomed flask fitted with a magnetic stirrer, a condenser and a thermometer. The medium was refluxed for 1 hour. The acetic acid was evaporated off and the product was taken up in 50 cc of petroleum ether. The solid was filtered off and washed with petroleum ether. Drying under vacuum and over phosphoric anhydride yielded 15 g of 2,5,6,7-tetramethylpyrazolo[1,5-a]pyrimidine (yield=85.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([Li])CCC>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]=[C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: [Li]CCCC
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 152 %

Procedure:
7-Nitro-1-tetralone (1.00 g, 5.23 mmol) was dissolved in dry THF (5 mL) and added to a solution of methyltriphenylphosphonium bromide (2.00 g, 5.60 mmol) and n-butyllithium (2.5 M in hexanes, 2.2 mL, 5.5 mmol) in THF (10 mL) cooled by an ice water bath. The mixture was allowed to warm to room temperature and stirred overnight. It was poured into ice water (45 mL) and extracted with EtOAc (3×20 mL). The extract was washed with NaCl solution, dried (MgSO4), filtered and concentrated to give a black solid (1.504 g). It was dissolved in CHCl3 and flash chromatographed over silica gel (65 g) eluting with EtOAc/hexane (1:20) to afford a white solid (263 mg, 27% yield): mp 45-47° C.
Reaction SMILES: [ClH:1].Cl.CN[C@H]1CCCN([CH2:11][CH:12]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)C1.OC1(C(C2C=CC=C(OC(F)(F)F)C=2)C([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH:47][C:48](=O)OC(C)(C)C)[CH2:42]2)=O)CCCCC1>>[ClH:1].[ClH:1].[CH3:48][NH:47][C@H:43]1[CH2:44][CH2:45][CH2:46][N:41]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:24]2([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=2)[CH3:11])[OH:30])[CH2:42]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)C(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: CN[C@H]1CCCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CN[C@H]1CCCN(C2CCCCC2(O)C(C)c2cccc(OC(F)(F)F)c2)C1

Procedure:
In an analogous manner to Example 13, step 2, 1-(2-[(3S)-3-(methylamino)piperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl ((3S)-1-{(1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetyl}piperidin-3-yl)carbamate. MS m/z 401; HRMS: calcd for C21H31F3N2O2+H, 401.24159; found (ESI, [M+H]+), 401.2419.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:30])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: CN1CCN(C(=O)CCl)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)CC1

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which have been described in example 69) with commercially available 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone as electrophile, the title compound was obtained as a white solid.