Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][C:32]=3[CH3:37])[N:29]=[CH:30][C:23]=12>C1COCC1>[CH:3]1([O:7][CH2:8][C@H:9]([O:20][C:22]2[C:23]3[CH:30]=[N:29][N:28]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][C:32]=4[CH3:37])[C:24]=3[N:25]=[CH:26][N:27]=2)[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Reactant: Cc1cnccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ccncc2C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (205 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate M1) (200 mg, 0.81 mmol) as suspension in dry THF (4 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric combined organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 10% MeOH in ethyl acetate to give the product (360 mg, 96%). 1H NMR (400 (2H, m), 2.35 (3H, s), 2.54 (3H, s), 3.97-4.10 (3H, m), 6.05 (1H, t), 7.49 (1H, d), 8.12 (1H, d), 8.44 (1H, s), 8.61 (1H, s), 8.62-8.65 (2H, m), 8.69 (1H, s), 9.44 (1H, d); m/z (ESI+) (M+H)+=461; HPLC tR=1.67 min.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl.N1CCCNCC1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: C1CNCCNC1
Agent: Cl
Solvent: CCO
Product: c1ccc(CN2CCCNCC2)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 101 mg of homopiperazine, 175 mg of homopiperazine dihydrochloride, 3 mL of ethanol was heated to 70° C. into a solution. 0.115 mL of benzyl chloride was added and the mixture was stirred at 70° C. for 3 hours. After cooling to room temperature, ethanol was removed under reduced pressure, and 20 mL of aqueous 2N sodium hydroxide solution was added to the solution, which was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1-benzyihomopiperazine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)=[O:9]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:18]=[CH:17][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
Prepared from N-methylpiperazine and 4-formylbenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:4][C:3]=1[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(O)ccc1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-tert-butylphenol (Intermediate 104, 1.17 g, 5.10 mmols) and imidazole (520.0 mg, 7.65 mmols) in 10 mL DMF was added chloro-triisopropylsilane (1.18 g, 6.10 mmols). After stirring overnight at room temperature the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 1.80 g (92%), was isolated by column chromatography (0-1.5% EtOAc—hexanes) as a colorless oil.
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[N:16]3[CH:17]=[C:18]([O:21][C@H:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C@@H:25]([NH2:32])[CH2:24][CH2:23]4)[CH:19]=[CH:20][C:15]3=[N:14][N:13]=2)[CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:32][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([N:9]5[CH2:8][CH2:7][CH:6]([O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[C@@H:10]5[CH3:11])=[N:13][N:14]=4)[CH:17]=3)[CH2:23][CH2:24]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(O[Si](C(C)C)(C(C)C)C(C)C)[C@@H]5C)n4c3)c3ccccc32)cc1
Yield: 79 %

Procedure:
A solution of Intermediate 92c (210 mg, 0.39 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 159 mg, 0.390 mmol) in 1,4-dioxane (4 mL) and DIPEA (105 μL, 0.600 mmol) was stirred at 65° C. for 15.5 h and at 90° C. for 1.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a pale brown solid (242 mg, 79%). LCMS (Method 3): Rt 5.18 min, m/z 791 [MH+].
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:35]([O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:35]([O:37][C:38]1[CH:43]=[C:42]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:22])[CH3:23])[CH:41]=[CH:40][CH:39]=1)[CH3:36]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCOc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Yield: 81.6 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 3-ethoxy-phenylboronic acid (2.51 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (420 mg, 0.60 mmol) in 1,4-dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15.4 mL) was heated in a microwave at 100° C. for 2 h under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×40 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (40 g, 11% ethyl acetate/petroleum ether) afforded 2-(1-(3-ethoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.2 g, 81%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (d, 1H, J=4.5 Hz), 7.87 (d, 1H, J=8.4 Hz), 7.67 (d, 2H, J=4.8 Hz), 7.41 (t, 1H, J=7.5 Hz), 7.27-7.10 (m, 4H), 6.79 ((t, 2H, J=6.3 Hz), 6.52 (s, 1H), 6.14 (d, 1H, J=6.6 Hz), 3.94-3.85 (m, 2H), 2.71-2.64 (m, 1H), 1.33 (t, 3H, J=7.2 Hz), 1.14 (t, 6H, J=7.5 Hz).
Reaction SMILES: [C:1]([CH:3]=[C:4]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:5]1([C:4]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:3][C:1]#[N:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=CC#N)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC=C(c1ccccc1)N1CCNCC1
Reaction time: 1 h

Procedure:
tert-Butyl 4-(2-cyano-1-phenylvinyl)piperazine-1-carboxylate (600 mg) was dissolved in a 10% solution of TFA in methylene chloride (11 ml). After 1 hour at room temperature, the reaction mixture was partitioned between saturated NaHCO3 (20 ml) and EtOAc (20 ml), and the aqueous phase was extracted with EtOAc (3×20 ml). Then the combined organic layer was dried over MgSO4 and concentrated to offer a residue which was purified using silica gel chromatography to give 3-phenyl-3-(piperazin-1-yl)acrylonitrile. MS m/z: (M+H)+ calcd for C13H16N3 214.13, found 214.15. Retention time 0.91 min (column E).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][OH:53]>CN(C)C=O>[OH:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][NH:47][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:10]
Reactant: NCCOCCO
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: COC(=O)c1cccc(C(=O)NCCOCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (20 g, 111.11 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), HATU (63.2 g, 166.32 mmol, 1.50 equiv), N,N-diisopropylethylamine (21.5 g, 166.67 mmol, 1.50 equiv), and 2-(2-aminoethoxy)ethanol (23.3 g, 221.90 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was dissolved in 200 mL of ethyl acetate. The resulting mixture was washed with 10×200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (100:1). This resulted in 15 g (51%) of methyl 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoate as red oil.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:22][C:23](N(OC)C)=[O:24])=[CH:17][CH:16]=1.[NH4+].[Cl-]>C1COCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:22][C:23]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=2)=[O:24])=[CH:19][CH:20]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1cc(Br)ccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Temperature: -70 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of n-BuLi (12.9 mL 1.6 M in hexane) was added dropwise a solution of 4-bromo-2-methylpyridine (3.56 g) in THF (170 mL) at −70° C. over a period of 20 min. The reaction mixture was stirred at −70° C. for 5 min, before a solution of 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (2.5 g) in THF (100 mL) was added dropwise. After the addition was complete, the mixture was stirred at −70° C. for 3 hours. A saturated solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:1) to give the title compound as an yellow oil (1.49 g, 55%), MS (ESI+): m/z=394.0797 ([M+H]+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6].C1C(=O)N([Cl:25])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cnc(N)c1Cl
Temperature: 50 °C
Yield: 86.8 %

Procedure:
A mixture of 2-amino-5-(2,4-dichloro-phenyl)-isonicotinonitrile (300 mg, 1.14 mmol, prepared according to Example 15, Step 6.1) and NCS (159 mg, 1.19 mmol) in DMF (4 mL) was stirred and heated at 50° C. for 3 h. The reaction mixture was cooled to RT, poured into AcOEt (40 mL) and washed with water (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/TBME 95:5→100% TBME) to yield the title compound (310 mg, 0.99 mmol, 87%) as a yellow solid. MS: 296 [M−1]+; HPLC: AtRet=2.43; TLC: RF 0.33 (hexane/TBME 1:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]2=[O:30])[CH2:15][CH2:14]1>C(O)(C)C>[OH:12][CH:10]([CH2:9][O:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][N:6]=1)[CH2:11][N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:20]2=[O:30])[CH2:17][CH2:18]1
Reactant: O=C1N(c2ccccc2)CCN1C1CCNCC1
Reactant: Clc1nccnc1OCC1CO1
Solvent: CC(C)O
Product: O=C1N(c2ccccc2)CCN1C1CCN(CC(O)COc2nccnc2Cl)CC1

Procedure:
7.27 g of 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine and 7.35 g of 1-(4-piperidyl)-3-phenyl-2-imidazolidinone in 120 ml of isopropanol are stirred for 24 hours at approx. 20° C. The reaction mixture is then concentrated in a water jet vacuum. The residue crystallises from ether and yields 1-{1-[2-hydroxy-3-(3-chloro-pyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenylimidazolidin-2-one with a melting point of 122°-124° C. The starting material can be prepared as follows: 9.8 g of N-phenylethylenediamine and 13.9 g of 1-benzyl-4-piperidone are dissolved in 200 ml of methanol and, with the addition of 0.7 g of a 5% platinum on charcoal catalyst, hydrogenated at room temperature and under normal pressure. The calculated amount of hydrogen is taken up after approx. 3 hours. The reaction mixture is filtered to remove the catalyst and concentrated in a water jet vacuum. The residue crystallises from methanol/water to yield 21.4 g of 1-benzyl-4-(2-phenylamino-ethylamino)-piperidino with a melting point of 78°-81° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:35])=[C:23]([C:25]4[O:26][C:27]5[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=5[C:29]=4[Cl:30])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:37].Cl.CCOCC>>[ClH:30].[ClH:37].[Cl:30][C:29]1[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[O:26][C:25]=1[C:23]1[C:22]([NH2:35])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:18]=2)[CH:24]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4oc5ccccc5c4Cl)c3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1oc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
To a solution of 4-{4-[6-Amino-5-(3-chlorobenzofuran-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (78.0 mg, 0.158 mmol) in DCM (2.5 mL, 39 mmol) was added 1.0 M of HCl in Et2O (1.5 mL; 1.5 mmol), and the mixture was stirred at ambient temperature for 8.5 h. The solid formed was filtered off, washed with DCM, and dried in vacuo overnight, yielding the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.20-9.09 (brm, 1H), 9.02-8.91 (brm, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.96 (very brs, 2H), 7.76 (d, J=8.4 Hz, 1H), 7.74 (dd, J=8.4, 0.8 Hz, 1H), 7.55 (ddd, J=1.2, 7.2, 8.4 Hz, 1H), 7.48 (ddd, J=0.8, 7.2, 8.4 Hz, 1H), 4.55-4.46 (mc, 1H), 3.38 (brd, J=12.8 Hz, 2H), 3.08 (q, J=12.2 Hz, 2H), 2.26-2.08 (m, 4H). MS(ES+): m/z=394.10/396.09 (65/21) [MH+], 311.04/313.07 (100/34) [MH+-piperidine]. HPLC: tR=2.28 min (polar—5 min, ZQ3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[N:6]1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:29][C:15]([F:14])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[CH:7]=[N:6]3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCCCn1ncc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(N2CCN(CCCn3ncc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
1-(3-chloropropyl)-1H-benzopyrazole (6.98 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoromethyl phenyl piperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 7.6 g compound (I-59) with a yield of 63.1%. ESI-MS [M+H]+: m/z 389.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=3[CH3:21])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=4)[CH:17]=[CH:16][C:15]=3[CH3:21])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(N)cc1NC(=O)c1csc2c(N)ncnc12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
4-Amino-N-(5-amino-2-methylphenyl)thieno[3,2-d]pyrimidine-7-carboxamide (30 mg, 0.1 mmol) was dissolved in THF (1 mL) and TEA (42 μL, 0.30 mmol) was added thereto. 3-(trifluoromethyl)benzoyl chloride (19 μL, 0.13 mmol) was added to reaction mixture at 0° C. and stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography (3/97 MeOH/DCM) to obtain the title compound (35 mg, 74% yield).
Reaction SMILES: [I:1][C:2]1[C:3]([Cl:18])=[C:4]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:19][S:20]([C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])=[C:3]([Cl:18])[C:2]=1[I:1])(=[O:22])=[O:21]
Reactant: C[C@@](O)(C(=O)Nc1cccc(I)c1Cl)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(I)c1Cl)C(F)(F)F
Temperature: 80 °C

Procedure:
(R)-N-[3-Iodo-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 31) (4.92 g) was added in portions to chlorosulphonic acid (18 ml) at 0° C. The reaction mixture was heated to 80° C. for 4 hours, allowed to cool to ambient temperature and poured onto ice-water (200 g). The mixture was extracted into DCM (2×250 ml), the organic phase was washed with brine (300 ml) and dried. Volatile material was removed by evaporation to give the title compound (4.8 g) as a brown gum. NMR (CDCl3) 1.78 (s, 3H), 3.59 (s, 1H), 8.23 (d, 1H), 8.74 (d, 1H), 9.53 (s, 1H); m/z: 490.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[F:26][C:27]([F:33])([F:32])[CH2:28][C:29](=O)[CH3:30].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:29]([CH2:28][C:27]([F:33])([F:32])[F:26])[CH3:30])[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CC(=O)CC(F)(F)F
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(CC(F)(F)F)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C

Procedure:
A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (0.37 g, 1 mmol) in 11 mL of 95:5 methanol-acetic acid was treated with excess of 4,4,4-trifluorobutan-2-one (1 g, 7.9 mmol), followed by sodium cyanoborohydride (0.25 g, 4 mmol). The reaction mixture was heated at 70° C. overnight, after which a small trace of the desired product was detected by LC-MS analysis. The crude reaction mixture was directly submitted to silica gel chromatography; elution with 9:1 dichloromethane-2 M ammonia in methanol provided a small amount of impure product. Further purification by preparative thin layer chromatography afforded 10 mg of the title compound, identified by LC-MS (Method A).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:11]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(C)C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:6][CH2:7][CH:8]([O:10][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:33][CH:32]=1)[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCCC(=O)OCC(C)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)OC(C)COC(=O)CCC)cc2)cc1

Procedure:
0,75 g of optically active 1-butyryloxy-2-propanol [obtainable by esterification of (S)-1,2-propanediol], 1,7 g of p-(p-n-octylphenyl)-benzoic acid chloride, 20 ml of toluene and 2,1 ml of pyridine are boiled under reflux for 6 hours. The pyridinium chloride is filtered off hot with suction and the filtrate is worked up in the customary manner. Optically active 1-butyryloxy-2-[p-(p-n-octylphenyl)-benzoyloxy]-propane is obtained.