Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]([CH3:20])[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:13]([NH:12][CH:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH:8]1[CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CCC(NCc2ccccc2)C(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CC(CO)CCC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A cooled (0° C.) mixture comprising 4-benzylamino-3-methyl-cyclohexanecarboxylic acid ethyl ester (0.90 g, 3.27 mmol) in THF (50 mL) is treated with LiAlH4 (4.09 mL, 8.08 mmol of a 2M solution in THF) and the reaction mixture is stirred at RT for 2 hours. The reaction is quenched with water (5 mL), NaOH (5 mL) followed by water (20 mL). The resulting precipitate is removed by filtration and washed with EtOAc. The organic phase is washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford the title compound which is used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (4H, m), 7.19 (1H, m) 4.31 (1H, t), 3.68 (2H, m), 3.29 (0.4H, t), 3.15 (1.6H, t), 2.45 (1H, m), 2.18 (0.2H, m), 2.06 (0.8H, m), 1.69 (2H, m), 1.52 (3H, m), 1.27 (2H, m), 1.03 (1H, m), 0.90 (0.6H, d), 0.88 (2.4H, d), 0.80 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=1.[Cl:16]N1C(=O)CCC1=O.[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[C:5]([Cl:16])=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=1
Reactant: CCCNc1cc(N(C)C)nc(N)[n+]1[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCNc1c(Cl)c(N(C)C)nc(N)[n+]1[O-]
Reaction time: 4 h
Yield: 60.2 %

Procedure:
1 g of 2-amino-4-propylamino-6-dimethylamino-pyrimidine 3-oxide of Example 1 is dissolved in 15 ml of ethanol. 0.75 g of N-chlorosuccinimide are added as solution in 35 ml of ethanol, dropwise at room temperature. After 4 hours' stirring the reaction mixture is evaporated to dryness. The oil obtained is taken up in 10 ml of water. The pH is adjusted to 8 by adding sodium hydroxide and the mixture is then extracted with 3×20 ml of butanol. The butanol phase is evaporated to dryness. The residue is recrystallized from 5 ml of acetonitrile. 0.7 g of 2-amino-4-propylamino-5-chloro-6-dimethylaminopyrimidine 3-oxide are obtained.
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[Br:36]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[Br:36][C:19]1[C:20]([CH3:35])=[CH:21][C:22]([NH:24][C:25]2[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=2)=[CH:23][C:18]=1[C:15]1[S:14][C:13]([C@@:2]2([OH:1])[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]2)=[N:17][CH:16]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.4 %

Procedure:
To a suspension of (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (example 42(1), 50 mg, 0.099 mmol) in chloroform (800 μL) was added N-bromosuccinamide (21 mg, 0.12 mmol). The mixture was stirred at room temperature for 15 minutes, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage 10 G, eluting with 1:99 to 10:90 methanol:dichloromethane) to give (1S,4R)-4-[5-(2-bromo-3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid (22 mg, 0.038 mmol, 38% yield) as a pale yellow solid. ESI: [M+H]+ m/z 587.1. 1H NMR (500 MHz, CD3OD) δ 8.70 (d, J=4.9, 1H), 7.86 (d, J=2.6, 1H), 7.78-7.64 (m, 2H), 7.13 (d, J=4.9, 1H), 2.46 (s, 3H), 2.35 (dd, J=2.9, 12.8, 1H), 2.22 (ddd, J=6.1, 13.2, 24.2, 1H), 2.01 (dd, J=6.7, 14.5, 3H), 1.79 (d, J=14.4, 1H), 1.72 (dd, J=3.2, 13.5, 1H), 1.22 (s, 3H), 1.11 (s, 3H). rhSYK activity=+++
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].ClCCC[Si](C)(C)C.Cl>CN(C)C(=O)C.CS(C)=O>[C:10](#[N:11])[C:3]1[C:4](=[CH:7][CH:8]=[CH:9][CH:2]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1C#N
Agent: C[Si](C)(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 143.4 %

Procedure:
In 150 ml of an N,N-dimethylacetamide/dimethylsulfoxide (=5/1 volume ratio) mixed solvent were dissolved 20 g of 3-hydroxyphthalonitrile and 10.55 g of potassium carbonate, to which 31.4 g of 3-chloropropyltrimethylsilane were added dropwise at 45° C. Immediately after the addition, the mixture was stirred for 24 hours while maintaining the reaction temperature at 90°-110° C. The reaction mixture was then cooled to room temperature and 180 ml of dilute hydrochloric acid was added. The mixture was extracted with 1.2 liters of toluene. The organic layer was washed well with water, followed by the removal of water with magnesium sulfate and the purification with a toluene/silica gel column, thereby to obtain 25.5 g (yield: 71.2%) of a compound having the following formula (XIX). The compound is in the form of white crystals and has a melting point of 145° C. The IR spectrum of the compound is shown in FIG. 5. ##STR41##
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.BrC1C2C([N:30]3[CH2:35][CH2:34][CH2:33][C@H:32]([CH3:36])[CH2:31]3)=NC=NC=2N(S(C2C=CC(C)=CC=2)(=O)=O)C=1>>[I:11][C:10]1[C:3]2[C:2]([N:30]3[CH2:35][CH2:34][CH2:33][C@H:32]([CH3:36])[CH2:31]3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(N4CCC[C@H](C)C4)ncnc32)cc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Product: C[C@H]1CCCN(c2ncnc3c2c(I)cn3COCC[Si](C)(C)C)C1

Procedure:
4-Chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) was converted to the product using the method described for synthesis of 5-bromo-7-[(4-methylphenyl)sulfonyl]-4-[(3S)-3-methylpiperidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine (C15) in Example 7. Yield: 7.38 g, 15.6 mmol, 80%. LCMS m/z 473.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.34 (s, 1H), 5.55 (s, 2H), 4.06-4.17 (m, 2H), 3.50-3.57 (m, 2H), 2.91 (ddd, J=12.6, 11.5, 3.5 Hz, 1H), 2.58 (dd, J=12.6, 10.8 Hz, 1H), 1.95-2.07 (m, 1H), 1.76-1.95 (m, 3H), 1.11-1.23 (m, 1H), 0.96 (d, J=6.8 Hz, 3H), 0.88-0.94 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5]1)([OH:3])=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](OC(=O)C2CCCN2C(OCC2C=CC=CC=2)=O)=[CH:24][CH:23]=1)([O-])=O>>[CH2:22]([NH:19][C:1]([CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)=[O:3])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Product: CCCCCCNC(=O)C1CCNC1

Procedure:
By substituting the 3-carboxy-1-phenylmethyloxycarbonylpyrrolidine obtained in Example 10 for the N-carbobenzoxy-DL-proline p-nitrophenyl ester in the procedure of Example 2, 3-[(hexylamino)carbonyl]pyrrolidine is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.[CH:9]1([CH:12]([CH:14]2[CH2:16][CH2:15]2)O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH:9]1([CH:12]([CH:14]2[CH2:16][CH2:15]2)[N:6]2[CH:5]=[C:4]([NH2:1])[CH:8]=[N:7]2)[CH2:11][CH2:10]1
Reactant: OC(C1CC1)C1CC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1cnn(C(C2CC2)C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (500 mg), dicyclopropylmethanol (0.92 g) and triphenylphosphine (2.3 g) in THF (10 mL) was added diisopropyl azodicarboxylate toluene (1.9M, 4.6 mL) solution at room temperature. The reaction mixture was stirred at room temperature for 2 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A suspension of the obtained residue and palladium on carbon (1 g) in methanol (30 mL) was stirred at room temperature for 12 hr under a hydrogen atmosphere, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (140 mg).
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:24]([NH2:27])([CH3:26])[CH3:25]>CS(C)=O.O>[CH:24]([NH:27][C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1NC(C)C
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 27.8 mg, 0.090 mmol) and isopropylamine (0.023 mL, 0.269 mmol) in DMSO (0.8 mL) was heated under argon in a sealed flask at 60° C. for 1 h. The reaction was cooled to 25° C. and diluted with water (10 mL). The precipitated solid was collected by vacuum filtration, washed with water (2×5 mL), and dried in vacuo to provide rac-2-(3-(isopropylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (19.6 mg, 0.056 mmol, 63% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (1H, br. s.), 7.90 (1H, d, J=7.2 Hz), 7.56 (1H, d, J=7.4 Hz), 7.31 (1H, t, J=7.8 Hz), 7.03 (1H, d, J=1.8 Hz), 6.97 (1H, br. s.), 6.89 (1H, d, J=7.2 Hz), 4.35 (1H, dq, J=13.3, 6.4 Hz), 3.46 (1H, dt, J=10.0, 3.4 Hz), 3.05-3.19 (2H, m), 2.54 (3H, s), 1.36 (3H, d, J=6.5 Hz), 1.32 (3H, d, J=6.5 Hz), 1.29 (3H, d, J=6.3 Hz). m/z (ESI, +ve) 350.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([C:22]([F:25])([F:24])[F:23])=[N:16][N:17]([CH3:21])[C:18]=2[O:19][CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(C2C(OC)=NN(C)C=2C(F)(F)F)CC1)=O)(C)(C)C>N1CCCCC1>[CH3:20][O:19][C:18]1[N:17]([CH3:21])[N:16]=[C:15]([C:22]([F:25])([F:23])[F:24])[C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1c(C2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)nn1C
Agent: COc1nn(C)c(C(F)(F)F)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCNCC1
Product: COc1c(C2CCNCC2)c(C(F)(F)F)nn1C

Procedure:
The title compound was prepared using conditions similar to those described in Piperidine 35, Step E, substituting 1-(tert-butoxycarbonyl-4-(5-methoxy-1-methyl-3-(trifluoromethyl)-(1H)-pyrazol-4-yl)piperidine (from Piperidine 35, Step D) for 1-(tert-butoxycarbonyl-4-(3-methoxy-1-methyl-5-(trifluoromethyl)-(1H)-pyrazol-4-yl)piperidine. For the title compound: 1H NMR (500 MHz, CD3OD) δ 3.94 (s, 3H), 3.72 (s, 3H), 3.10 (d, J=13, 2), 2.70 (tt, J=13, 4, 1H), 2.64 (td, J=13, 3, 2H), 1.84 (qd, J=13, 4, 2H), 1.71 (d, J=13, 2H); ESI-MS 264.1 (M+H); HPLC A: 1.1 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=3)\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1ccc(F)c(F)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)c(F)c1
Temperature: 80 °C

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (79 mg, 0.36 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (8 mg, 0.036 mmol), L-proline (9 mg, 0.086 mmol) and potassium phosphate (183 mg, 0.86 mmol) were added and the reaction mixture was stirred for min. at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.43 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 39 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.60 (m, 1H), 7.56 (s, 1H), 7.45 (m, 1H), 7.36 (m, 1H), 7.20 (s, 2H), 7.02 (s, 1H), 4.50 (m, 2H), 3.70 (m, 2H), 3.18 (m, 2H), 3.10 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][NH:9][C:10]([C:23]2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=[O:39]>ClCCl>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:39])[CH3:23])[N:3]=1
Reactant: Brc1ccn(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CC(=O)NCCn1ccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(3-bromo-1H-pyrazol-1-yl)-N-tritylethanamine obtained in Step B (100 mg) and triethylsilane (38.8 μL) in dichloromethane (1.2 mL) was slowly added trifluoroacetic acid (1.2 mL) under ice-cooling. The reaction mixture was warmed to room temperature, stirred for 3 hr, and concentrated under reduced pressure. To a solution of the obtained residue and acetic anhydride (32.7 μL) in dichloromethane (2.0 mL) was added triethylamine (97.0 μL) under ice-cooling, and the mixture was stirred for 2 hr. To the reaction mixture was added dichloromethane, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (40.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3.S(OC)(O[CH3:24])(=O)=O>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17]([O:19][CH3:24])=[O:18])=[CH:5][CH:4]=1)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(C(=O)O)c2c1OC1(CCOCC1)O2
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC)c2c1OC1(CCOCC1)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.9 %

Procedure:
A suspension of the crude 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-carboxylic acid (2.17 g, 8.15 mmol), KHCO3 (2.58 g, 26.0 mmol) and dimethyl sulphate (1.58 mL, 16.7 mmol) in acetone (62 mL) was stirred at room temperature for two days before it was evaporated to dryness under reduced pressure. Ethyl acetate (100 mL) was added. The organic phase was washed with 0.5 M aqueous NaOH (6×30 mL) and evaporated to dryness under reduced pressure. The crude product was redissolved in dichloromethane (75 mL), dried over MgSO4 and evaporated to dryness under reduced pressure. Standard silica gel column chromatography afforded methyl 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-carboxylate (1.87 g, 79%). 13C NMR (CDCl3) δ 164.9, 149.1, 147.2, 135.2, 124.0, 117.5, 107.1, 106.5, 65.2, 56.4, 51.8, 35.9.
Reaction SMILES: COC(=O)[C@H:4]([NH:12][CH2:13][CH2:14][NH:15][C:16]([O:18]C(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:5]([C@H:4]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:14][NH:15][C:16]1=[O:18])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCNC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCCN(Cc2ccccc2)[C@@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
(3R)-3-Benzylpiperazin-2-one (4.1 g; 21.6 mmol, prepared as described in Example 1) was dissolved in methanol (40 ml). Benzaldehyde (2.3 g; 21.6 mmol) was added followed by 4 Å molsieves (2 g) and the mixture was stirred under an atmosphere of nitrogen for 1/2 h. Acetic acid (1.2 ml) was added and sodium cyanoborohydride (2.0 g; 32.4 mmol) was added portion wise during 20 minutes. The reaction mixture was stirred overnight and the filtered. From the filtrate the solvent was evaporated and the residue was dissolved into ethyl acetate (15 ml) and purified on silica gel using ethyl acetate as eluent. This afforded 2.6 g of (3R)-3,4-dibenzylpiperazin-2-one.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([F:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][CH:16]([F:19])[CH2:17][OH:18].[H-].[Na+]>>[F:15][CH:16]([F:19])[CH2:17][O:18][C:2]1[C:7]([C:8]2([F:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: OCC(F)F
Reactant: N#Cc1cc(Cl)c(C2(F)CCC2)cn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(OCC(F)F)c(C2(F)CCC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-(1-fluorocyclobutyl)-pyridine-2-carbonitrile (example 305c) and 2,2-Difluoro-ethanol (CAN 359-13-7) as starting materials and sodium hydride as reagent. The title was isolated (1 g, 83%) as a yellow oil; MS (ESI, m/z): 257.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11]C=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:8][CH2:9][CH2:14][CH2:13][CH:12]([C:15]([F:16])([F:17])[F:18])[CH3:11])=[O:26]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)CCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CCCNC(=O)CCCCCBr)C(F)(F)F
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.30 mL) and 4-aminobenzotrifluoride (1.21 g) were stirred in dichloromethane (35 mL) at 0° C. under nitrogen and treated with 6-bromohexanoyl chloride (1.15 mL). After 20 minutes, the reaction was allowed to warm to 20° C. and stirred an additional 40 minutes. The reaction was treated with aqueous saturated sodium bicarbonate (40 mL), and extracted with dichloromethane. The extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to a solid. This solid was dissolved ethyl acetate and the title compound was precipitated out as fine white needles by addition of hexanes (2.35 g). M.p. 96°-98° C. Anal. Calc. for C13H15BrF3NO: C, 46.17;H, 4.47;N, 4.14. Found: C, 46.25;H, 4.59;N, 4.12.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([C@@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@@H:31]([NH:33][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: C[C@H](NC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1)c1ccccc1

Procedure:
The product from Example 33B and (S)-1-phenylethanamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 437 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([Si:10]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:11][C:12]1[CH:22]=[CH:21][C:15]([C:16](OCC)=[O:17])=[CH:14][CH:13]=1)[CH3:9].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH3:25][CH:23]([Si:10]([CH:26]([CH3:28])[CH3:27])([CH:8]([CH3:9])[CH3:7])[O:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc(CO)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 75 mL of dry diethyl ether was added a solution of lithium aluminium hydride (4M in diethyl ether, 14 mL, 55.8 mmol), and the solution was cooled to 0° C. A solution of ethyl 4-{[tris(1-methylethyl)silyl]oxy}benzoate (Step 1, 9.0 g, 27.9 mmol) in dry diethyl ether (90 mL) was added dropwise, maintaining the temperature below 5-10° C. After the addition was completed, stirring of the reaction mixture was continued for 1 h at 0° C. Then, still at the same temperature, a saturated aqueous solution of sodium sulfate (60 mL) was added with caution. After warming to rt, the precipitate which had formed was removed by filtration, and the residue was washed with diethyl ether. The organic layer was separated from the filtrate, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo. The crude product thus obtained was purified by MPLC (silica, cyclohexane/ethyl acetate 5:1→1:1) to afford the title compound in pure form (7.38 g, 94%): 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.87 (d, 2H), 4.60 (d, 2H), 1.56 (t, 1H), 1.23 (m, 1H), 1.10 (d, 18H); EI-MS m/z 280 (M)+; HPLC RT (Method H) 5.33 min.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]#[N:35])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]#[N:35])=[CH:28][CH:27]=1
Reactant: CC1(C)OB(c2ccc(CCC#N)cc2)OC1(C)C
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCC#N)cc1
Yield: 68.3 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (400 mg, 1.3 mmol) was reacted with 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanenitrile (600 mg, 1.9 mmol) to afford the desired product (320 mg, 69%) as a brown solid: ESI MS m/z 361 [C21H16N2O2S+H]+.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]3[N:16]=[C:17]4[N:21]([CH:22]=3)[C:20]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:19][S:18]4)=[CH:13][CH:12]=[CH:11][N:10]=2)=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:24]1([CH2:23][C:20]2[N:21]3[CH:22]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[N:16]=[C:17]3[S:18][CH:19]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: COc1ccc(CNc2ncccc2-c2cn3c(CN4CCOCC4)csc3n2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1-c1cn2c(CN3CCOCC3)csc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-Methoxy-benzyl)-[3-(3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazol-6-yl)-pyridin-2-yl]-amine (100 mg, 0.23 mmol) was mixed with 2 mL of CH2Cl2 along with triethylsilane (0.11 mL, 2 eq). Trifluoroacetic acid (1 mL) was added and the reaction mixture was stirred at room temperature for 18 hours. The following day, the reaction mixture was concentrated. The resulting residue was triturated with Et2O to afford essentially quantitative yield of 3-(3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazol-6-yl)-pyridin-2-ylamine as the TFA salt.