Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:18]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:35]1([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:44]3[CH2:43][CH2:42][C:41]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:25])[CH3:26])[CH:18]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)Oc1cccc(C(=O)CN2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: CC(C)Oc1cccc(C(=O)CN2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.24 g, 0.5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.24 g, 0.98 mmol). Chromatograph on silica gel to give the title compound: Rf =0.45 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCC=C1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)CCc3ccccc32)CC1
Reaction time: 20 h
Yield: 66.8 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.169 g, 0.51 mmol) and 4-butylidenepiperidine (0.200 g, 1.4 mmol) in MeCN (2 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 4:1) to give the title compound (107LH53) (0.116 g, 67%). 1H NMR (CD3OD) δ 7.23-7.18 (m, 3H), 7.02-6.98 (m, 1H), 5.11 (t, J=7.4 Hz, 1H), 3.98 (d, J=6.8 Hz, 2H), 2.89-2.85 (m, 2H), 2.61-2.56 (m, 2H), 2.40-2.35 (m, 2H), 3.32-2.04 (m, 11H), 1.98-1.92 (m, 2H), 1.36-1.29 (m, 2H), 0.90-0.85 (m, 2 CH3); 13C NMR (CD3OD) δ 173.0, 140.3, 137.1, 129.1, 128.4, 128.4, 124.3, 123.7, 116.9, 64.6, 57.4, 56.6, 46.5, 37.0, 32.9, 30.2, 30.1, 29.1, 26.3, 24.2, 17.2, 14.1.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1>C(O)C>[F:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCF)CC2)cn1
Solvent: CCO
Product: Nc1ccc(N2CCN(CCF)CC2)cn1
Reaction time: 3 h
Yield: 105.9 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 75 mg dry weight) and a solution of 217b (455 mg, 1.79 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 3 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (3.50 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×50 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a quantitative yield of 217c (425 mg) as a yellow semi-solid: 1H NMR (500 MHz, CDCl3) d 7.75 (d, J=3.0 Hz, 1H), 7.20 (dd, J=9.0, 3.0 Hz, 1H), 6.51 (d, J=8.5 Hz, 1H), 4.66 (t, J=5.0 Hz, 1H), 4.56 (t, J=5.0 Hz, 1H), 4.35-4.15 (br s, 2H), 3.08 (t, J=5.0 Hz, 4H), 2.79 (t, J=5.0 Hz, 1H), 2.74 (t, J=4.5 Hz, 1H), 2.71 (t, J=5.0 Hz, 4H); MS (ESI+) m/z 225.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[CH3:27][C:28]([O:31][C:32]([NH:34][C@H:35]([C:39](O)=[O:40])[CH2:36][C:37]#[CH:38])=[O:33])([CH3:30])[CH3:29].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:28]([O:31][C:32]([NH:34][C@@H:35]([CH2:36][C:37]#[CH:38])[C:39]([NH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[O:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1)=[O:40])=[O:33])([CH3:30])([CH3:29])[CH3:27]
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#CCCCN)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC#Cc1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of tert-butyl 4-(3-(5-aminopent-1-ynyl)phenoxy)piperidine-1-carboxylate (0.59 g, 1.6 mmol), Boc-L-propargylglycine (0.35 g, 1.6 mmol), N-ethyldiisopropylamine (0.73 ml, 4.1 mmol) in DMF (20 ml) was added HBTU (0.81 g, 2.1 mmol). The resulting solution was stirred at room temperature overnight. (S)-tert-Butyl 4-(3-(5-(2-(tert-butoxycarbonylamino)pent-4-ynamido)pent-1-ynyl)phenoxy)piperidine-1-carboxylate was isolated and purified over Gilson HPLC as a colorless oil. MH+ 554.44
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[N:25]1([CH2:31][CH2:32][C:33](O)=[O:34])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:33](=[O:34])[CH2:32][CH2:31][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CCN1CCOCC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)CCN2CCOCC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(3-morpholin-4-yl-propionyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 3-morpholin-4-yl-propionic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a white solid. MS m/e: 490.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CO>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)=[CH:26][CH:25]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Fc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a mixture of 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (4.2 mg, 0.016 mmol) described in Manufacturing Example 5-1-1 and methanol (0.4 mL) was added 1 N aqueous sodium hydroxide solution (16 μL, 0.016 mmol), which was then concentrated under a reduced pressure. To a mixture of the residue and N,N-dimethylformamide (0.5 mL) was added 4-fluorobenzyl bromide (2.3 μL, 0.019 mmol), which was stirred for 1 hour at room temperature. The reaction mixture was purified as is by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3.1 mg, 39%) as a trifluoroacetic acid salt.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[SH:11][CH2:12][C:13]([OH:15])=[O:14]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].[OH-].[K+].O>[Cl:10][C:6]1[C:3]2[CH:4]=[C:12]([C:13]([OH:15])=[O:14])[S:11][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)CS
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc2c(Cl)cccc2s1
Temperature: 123.88888888888889 °C
Yield: 85.2 %

Procedure:
In a glass pressure bottle, 2,6-dichlorobenzaldehyde (13.5 g, 0.075 mol) and TBAB (0.4 g) was added to a solution of 2-mercaptoacetic acid (7 ml) in potassium hydroxide (12.5 g) and water (100 ml). The bottle was then sealed and heated in a hot oil bath at 255° F. and 20 psi for 1 hour The bottle was then removed from the hot oil bath and cooled. A pale yellow precipitate was obtained in the bottle. At ambient temperature, the bottle was opened and sufficient water was added to dissolve the precipitate. The resultant aqueous material was washed with ether and then acidified with hydrochloric acid to produce a pale yellow solid. The pale yellow solid was collected on a filter, washed with water and dried, to produce 18.1 g of 4-chloro-2-benzo[b]thiophenecarboxylic acid (85.2% yield, mp 227-231° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[Br:12]N1C(=O)CCC1=O>>[Br:12][C:7]1[C:8]([CH3:9])=[C:3]([C:1]#[N:2])[C:4]([OH:11])=[N:5][C:6]=1[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c(C#N)c(O)n1
Product: Cc1nc(O)c(C#N)c(C)c1Br

Procedure:
In a method to prepare 5,6,7-tri-substituted-5-deazapteridines, for example, 3-cyano-2-hydroxy-4,6-dimethylpyridine (commercially available) may be brominated with N-bromosuccinimide, affording the corresponding 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine. The bromo compound was in turn may be treated with phosphorus oxychloride in the presence of N,N -dimethylformamide, yielding 2-chloro-5-bromo-3-cyano-4,6-dimethylpyridine. The so-prepared pyridine was cyclized with quanidine carbonate in N,N-dimethylacetamide, yielding the targeted 5,6,7-trisubstituted-5-deazapteridines, for example, 2,4-diamino-6-bromo-5,7-dimethylformamide. Example 19 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1C(OC(C)(C)C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.Cl>O1CCOCC1>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][N:2]([CH3:1])[CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:9][CH:8]=2)=[CH:16][CH:15]=1
Reactant: CN(Cc1ccc(Oc2ccc(Br)cc2)cc1)C[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(Cc1ccc(Oc2ccc(Br)cc2)cc1)C[C@H]1CCCN1
Yield: 128.8 %

Procedure:
A solution of 1,1-dimethylethyl (R)-2-[[methyl[[4-(4-bromophenoxy)phenyl]methyl]amino]methyl]-1-pyrrolidinecarboxylate (670 mg, 1.8 mmol) in a solution of 4 N hydrochloric acid in dioxane (6 mL) was stirred overnight. Solvent was removed under reduced pressure and 870 mg of (R)—N-[[4-(4-bromophenoxy)phenyl]methyl]-N-methyl-2-pyrrolidinemethanamine was isolated as the hydrochloride salt.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)=[O:16]>>[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: O=Cc1ccccc1B(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccccc1C=O

Procedure:
Methyl 2-bromo-5-nitrobenzoate was coupled to 2-formylphenylboronic acid using the procedure described for Example 4, Part A to provide methyl 2-(2′-formylphenyl)-5-nitrobenzoate. 1HNMR (300 MHz, CDCl3) δ 8.91 (s, 1H); 8.42 (d, 1H, J=8.5 Hz); 8.00 (d, 1H, J=8.5 Hz); 7.64 (m, 2H); 7.47 d, 1H, J=8.5 Hz); 7.22 (d, 1H, J=8.5 Hz); 3.71 (s, 3H).
Reaction SMILES: [CH:1]1([C:4](=O)/[CH:5]=[C:6](\O)/[CH:7]([F:9])[F:8])[CH2:3][CH2:2]1.O.[NH2:13][NH2:14].Cl>C(O)C>[CH:1]1([C:4]2[NH:14][N:13]=[C:6]([CH:7]([F:9])[F:8])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(/C=C(\O)C(F)F)C1CC1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: FC(F)c1cc(C2CC2)[nH]n1
Reaction time: 3 h
Yield: 76.4 %

Procedure:
Intermediate 62 (390 mg, 2.4 mmol) dissolved in ethanol (2 ml), added hydrazine hydrate (0.13 ml, 2.65 mmol) and HCl (0.18 ml). This mixture was refluxed for 3 h. After 3 h, ethanol was removed on rotavapour and work up (H2O/AcOEt) afforded the title compound (290 mg) which was used in the next step without further purification. 1H-NMR (δ ppm, CDCl3, 400 MHz): 12.96 (s, 1H), 6.84 (t, J 54.8, 1H), 6.15 (s, 1H), 1.95-1.87 (m, 1H), 0.99-0.91 (m, 2H), 0.74-0.66 (m, 2H).
Reaction SMILES: [H+].[CH3:2][C@H:3]([NH2:12])[C@H:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[I:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>C(Cl)Cl.[OH-].[Na+]>[I:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:12][CH:3]([CH3:2])[CH:4]([OH:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [Cl-]
Agent: [H+]
Agent: [Na+]
Solvent: ClCCl
Product: CC(NC(=O)c1ccc(I)cc1)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a ice-cooled mixture of norephedrine hydrochloride (1) (7.02 g, 37.5 mmol) in CH2Cl2 (180 mL) and 5% NaOH aqueous solution (60 mL) was added dropwise a solution of 4-Iodobenzoyl chloride (2c, 10.1 g, 37.9 mmol) in CH2Cl2 (100 mL). After the addition had completed, the resulting mixture was stirred at 0° C. for 4 h. The solvent was removed in vacuo. The residue was washed with H2O, dried, the recrystallized from EtOH to provide a white solid (12.8 g, 90%). mp 209-210° C. 1H NMR (DMSO-d6) d 1.03 (d, J=6.6 Hz, 3 H, CH3), 4.05-4.12 (m, 1 H, --CHCH3), 4.65 (s, 1 H, --CHOH), 5.46 (d, J=3.6 Hz, 1 H, NH), 7.14 (t, J=7.2 Hz, 1 H, aromatic), 7.23 (t, J=7.5 Hz, 2 H, aromatic), 7.32 (d, J=7.2 Hz, 2 H, aromatic), 7.53 (d, J=8.4 Hz, 2 H, aromatic), 7.75 (d, J=8.1 Hz, 2 H, aromatic), 8.30 (d, J=8.4 Hz, 1 H, aromatic). 13C NMR (DMSO-d6) d 14.70 (q, CH3), 51.30 (d, --CHCH3), 74.41 (d, --CHOH), 98.48 (s, =CI--, aromatic), 126.23 (d, aromatic), 126.73 (d, aromatic), 127.75 (d, aromatic), 129.29 (d, aromatic), 134.19 (s, aromatic), 137.03 (d, aromatic), 143.59 (s, aromatic), 164.70 (s, aromatic). Anal. Calcd. for C16H16INO2 : C, 50.41; H, 4.23; N, 3.67. Found: C, 50.35; H, 4.24; N, 3.65.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[N:4]=[C:5](SC)[NH:6][CH:7]=1.[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=2)=[CH:14][C:13]=1[C:28]([F:31])([F:30])[F:29]>C(O)C>[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][C:5]3[NH:6][CH:7]=[C:2]([CH3:1])[C:3](=[O:10])[N:4]=3)=[CH:19][CH:18]=2)=[CH:14][C:13]=1[C:28]([F:29])([F:30])[F:31]
Reactant: CSc1nc(=O)c(C)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CCO
Product: Cc1c[nH]c(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Yield: 35.4 %

Procedure:
5-Methyl-2-methylsulfanyl-1H-pyrimidin-4-one (25 mg, 0.16 mmol, 1 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (60 mg, 0.192 mmol, 1.2 eq) were stirred in 300 μl of absolute ethanol for 50 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 11 g normal phase silica KP-NH column and DCM/MeOH solvent system (gradient 0-7% of MeOH in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the crude was triturated with cyclohexane to obtain 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-methyl-1H-pyrimidin-4-one (24 mg, yield=33.9%, purity=96%) in form of white powder. MS: [M+H]+=424.31. 1H NMR (300 MHz; CDCl3) δ/ppm 1.79 (s, 3H), 2.90 (t, J=6.24 Hz, 2H), 3.52 (s, 2H), 3.56-3.67 (m, 2H), 6.23 (br.s., 1H), 6.92 (d, J=7.56 Hz, 2H), 7.00 (d, J=7.95 Hz, 1H), 7.21 (d, J=7.56 Hz, 2H), 7.28 (s, 1H) 7.38 (d, J=8.32 Hz, 1H), 7.63 (s, 1H), 11.62 (br.s., 1H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8](S(C)(=O)=O)[N:7]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][NH:25][C:24]1=[O:28].C(N(CC)CC)C>COC(O)C>[S:1]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][NH:25][C:24]3=[O:28])[N:7]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: NCCN1CCNC1=O
Reactant: CS(=O)(=O)c1nccc(-c2cc3ccccc3s2)n1
Agent: COC(C)O
Solvent: CCN(CC)CC
Product: O=C1NCCN1CCNc1nccc(-c2cc3ccccc3s2)n1
Temperature: 100 °C

Procedure:
A mixture of 4-(benzo[b]thiophen-2-yl)-2-(methylsulfonyl)pyrimidine (75 mg, 0.26 mmol)), 1-(2-aminoethyl)imidazolidin-2-one (33 mg, 0.26 mmol) and triethylamine (32 mg, 0.31 mmol) in methoxyethanol (3 mL) was heated at 100° C. overnight. After cooling to rt the solvent was removed in vacuo and the product was purified by chromatography eluting with methanol/dichloromethane (1:20) to give the title compound as a slightly yellow solid (56 mg, 64%). MS (M+H)+ 340.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)=[CH:6][CH:5]=1)(=[O:37])[CH3:36]
Reactant: Nc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To a stirred solution of 0.38 g (1 mmol) of N-(4-amino-phenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-acetamide dihydrochloride (Example 181) and 0.28 ml (2 mmol) of triethylamine in 10 ml of dichloromethane 0.1 ml (1 mmol) of acetic anhydride in 2 ml of dichloromethane is added dropwise below 10° C., and the reaction mixture is stirred at room temperature for 3 hours. The solvent is evaporated and the residue is treated with water and the crystals are filtered off to yield 0.15 g (39%) of the title compound. Melting Point: 173-180° C. (water)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH2:31][CH3:32]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:30][CH2:31][CH3:32])[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.4 %

Procedure:
To a solution of 0.600 gm (2.05 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 35 mL acetonitrile were added 0.283 gm (2.05 mMol) potassium carbonate followed by 240 μL (2.46 mMol) iodopropane and the reaction mixture was stirred at room temperature for 2.5 days. Additional iodopropane was added and the reaction stirred at room temperature until all of the starting material had been consumed. The reaction mixture was then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane and the combined organic phases were then dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 96.5:3:0.5 dichloromethane: isopropanol:ammonium hydroxide. Fractions shown to contain the desired compound were concentrated under reduced pressure to give 0.270 gm (39%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=O)=[O:10].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[S:9]([CH3:12])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of (2,4-dichloro-phenyl)-methyl sulfone (Ono Mitsunori, Nakamura Yoshisada, Sato Shingo, Itoh Isamu, Chem. Lett, 1988, 395–398.; 3.33 g, 16 mmol) and sulfuric acid (conc, 14 ml) was added a mixture of sulfuric acid (4 ml) and nitric acid (fuming, 2 ml) dropwise under ice-water bath. The mixture was stirred at 55° C. for 1 h. The mixture was poured onto ice-water and neutralized with 6N aqueous NaOH and then extracted with dichloromethane. The organic layer was washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with hexane/ethyl acetate (2:1/1:1) to give 3 g (74%) of the title compound as white solids.
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=O.[NH4+:30].[Cl-]>C(O)C>[F:27][C:26]([F:29])([F:28])[C:22]1[CH:21]=[C:20]([C:2]2[N:30]=[C:5]([CH:7]3[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3)[NH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: [Cl-]
Solvent: CCO
Product: FC(F)(F)c1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Temperature: 25 °C
Yield: 189.1 %

Procedure:
Microwave heat a mixture of tert-butyl 4-(2-oxo-2-(3-(trifluoromethyl)phenyl)-ethylcarbamoyl)piperidine-1-carboxylate (2.5 g, 6.09 mmol) and NH4Cl (1.68 g, 31.4 mmol) in ethanol (20 mL) at 300 W, 120° C., and 200 PSI for 16 h in a CEM Discover microwave apparatus. Cool the mixture to room temperature. Repeat the procedure with a second portion of tert-butyl 4-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethylcarbamoyl)-piperidine-1-carboxylate (2.35 g, 5.67 mmol) and NH4Cl (1.8 g, 33.6 mmol) in ethanol (20 mL) utilizing the same microwave and heating program. Cool the mixture to room temperature. Repeat the above procedure with a third portion of tert-butyl 4-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (2.0 g, 4.82 mmol) and NH4Cl (1.34 mg, 25.0 mmol) in ethanol (15 mL) at 300 W, 160° C., and 200 PSI for 12 h in a microwave apparatus. Cool the mixture to room temperature. Combine the batches, adsorb onto silica gel, and concentrate in vacuo. Purify the residue by silica gel chromatography (120 g RediSep column, eluting with a gradient of 0% through 100% CMA:methylene chloride, 3 L) to provide 4-(4-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine (3.40 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[CH:3]=1.C(O)(=[O:13])C.C1N2CN3CN(C2)CN1C3.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:3]=1)[CH:9]=[O:13]
Reactant: CC(=O)O
Reactant: Fc1ccc(Br)cc1CBr
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1cc(Br)ccc1F
Temperature: 90 °C

Procedure:
A mixture of 79.5 g (0.296 mol) of 4-bromo-2-bromomethyl-1-fluorobenzene (prepared according to G. E. Stokker, A. W. Alberts et al., J. Med. Chem., 1986, 29, 170), 126 ml of acetic acid, 82.7 g (0.59 mol) of hexamethylenetetramine and 126 ml of water is heated for 2 hours at reflux. The mixture is cooled to 90° C., 99.5 ml of concentrated hydrochloric acid are added and the mixture is heated for 30 min at reflux. Cooling, extraction with ether, washing with water, washing with an aqueous NaHCO3 solution, washing with water, drying over Na2SO4, filtration and evaporation under vacuum are carried out. The residue is purified by chromatography on silica (eluent: 10/1 hexane/ethyl acetate). Yd.: 23.6 g (39%)