Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][C:12]([CH3:16])([CH3:15])[S:11]1.[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[N:14]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:13][C:12]([CH3:16])([CH3:15])[S:11]1
Reactant: CC1(C)CNC(=Nc2cccc(Cl)c2Cl)S1
Reactant: CC(C)CBr
Product: CC(C)CN1CC(C)(C)SC1=Nc1cccc(Cl)c1Cl

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C1a to afford 2-(2,3-dichlorophenylimino)-5,5dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2-(2,3-dichlorophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][P:17]([O-:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[P:17]([Cl:1])([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Temperature: 40 °C

Procedure:
Dibenzyl chlorophosphate was prepared by adding N-chlorosuccinimide (2.2 g) to a solution of dibenzylphosphite (4.4 g) in dry toluene (70 ml) at room temperature with stirring. The resulting solid was filtered off and the filtrate concentrated to ca. 10 ml. and added to a solution of 4′-methoxyphenyl 2,3,4-tri-O-acetylmannoside (3.86 g) in pyridine (30 ml) at 0° C. and the mixture allowed to stand over night. The mixture was warmed to 40° C. for 1 h and the solvent evaporated under reduced pressure. The residue was chromatographed on a silica gel 60 chromatography column (2.5×55 cm). The column was first eluted with CHCl3 and this fraction discarded. Subsequent elution with 20% acetone/CHCl3 gave 4′-methoxyphenyl 2,3,4-tri-O-acetylmannoside dibenzylphosphate (2.9 g). (1Hnmr, CDCl3: 2.06, s, 3H; 2.09, s, 3H; 2.13, s, 3H; 3.53, t, 1H; 3.6, s, 3H; 3.88, t, 1H; 3.97, m, 1H; 4.8, d, 1H; 5.12, m, 1H; 5.3, m, 2H; 6.81, d, 2H; 6.97, d, 2H; 7.3, m, 10H.) Starting material (1.46 g) was recovered from the column by elution with 10% EtOH/CHCl3.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: OCc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Reactant: CNC
Agent: Cl
Product: CN(C)c1cc2c(cn1)-c1nc(-c3nc(CO)nn3CC(F)(F)F)cn1CCO2

Procedure:
(5-(9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol 387 was reacted with dimethylamine-HCl to give 394 (11 mg) as a colorless solid. LCMS: 410.1. 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 7.94 (s, 1H), 6.13 (s, 1H), 5.84 (q, J=8.9 Hz, 2H), 5.32 (t, J=6.1 Hz, 1H), 4.50 (m, 4H), 4.45 (d, J=6.0 Hz, 2H), 3.05 (s, 6H)
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl>C1COCC1>[O:4]=[C:3]([CH2:5][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=1)[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClCc1cccc(Cl)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1cccc(Cl)c1
Yield: 63.7 %

Procedure:
Ethyl acetoacetate (78.6 g, 0.6 mole) was added to a slurry of sodium hydride (20.8 g of 75% dispersion in oil, 0.65 mole) in dry THF at 0° C. under nitrogen followed by addition of n-butyl lithium (390 ml, 1.6 M in hexane, 0.63 mole) by the method given in Description 1(a). 3-Chlorobenzyl chloride (100 g, 0.62 mole) was added and after work-up and purification by vacuum distillation the required product was obtained as a very pale yellowish green oil (97.3 g, 64%), δ(CDCl3) 7.3-6.9 (4H, m), 4.18 (2H, q, J=7 Hz), 3.42 (2H, s), 2.88 (4H, s), and 1.27 (3H, t, J=7 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C-:20]#[N:21].[Na+].[Na+].[I-].Cl>O.CS(C)=O>[C:20]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])#[N:21]
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Reactant: [C-]#N
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCCCCCCCCCCCCC(=O)O
Temperature: 120 °C
Reaction time: 20 h
Yield: 72.5 %

Procedure:
A mixture of 16-bromohexadecanoic acid (16.61 g, 49.5 mmol), DMSO (150 ml), NaCN (12.5 g, 255 mmol), and NaI (1.92 g, 12.8 mmol) was stirred at 120° C. for 20 h. The mixture was allowed to cool to room temperature, and was then poured into a stirred mixture of water (1.7 l) and concentrated HCl (30 ml). Rinsing with water (100 ml). The resulting suspension was stirred at room temperature overnight. The product was filtered and washed with water (2×100 ml), and the solid was recrystallized twice from MeCN (90 ml and 50 ml). 10.1 g (72%) of 16-cyanohexadecanoic acid was obtained.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([CH:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3].[CH:33](OCC)=[O:34]>>[CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])=[CH:30][CH:31]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH:33]=[O:34])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(N)c2)C[C@H]1C
Reactant: CCOC=O
Product: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NC=O)c2)C[C@H]1C
Yield: 51 %

Procedure:
(±)-4-(α-(trans-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-aminobenzyl)-N,N-diethylbenzamide (0.42 g, 0.97 mmol) (Example 32, infra) was dissolved in 15 mL of ethyl formate and heated at reflux overnight under nitrogen. The reaction was concentrated to dryness and purified by chromatography on silica gel with ethanol (0-10%) in dichloromethane to give 0.23 g (51%) of (±)-trans-4-(α-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-formamidobenzyl)-N,N-diethylbenzamide. NMR (300 MHz, CDCl3): δ 1.0 (m, 3H) ; 1.2 (d, m, 9H); 1.8-2.2 (m, 3H); 2.4-2.9 (m, 5H); 3.2-3.6 (m, 5H); 5.1-5.3 (m, 3H) 5.8 (m, 1H); 6.7-7.8 (m, 8H); 7.9-8.1 (m, 1H), 8.6-8.9 (m, 1H). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration with ethanolic hydrogen chloride. The solution was concentrated to dryness. The resulting foam was dissolved in a minimal amount of ethanol and precipitated with diethyl ether to give 0.96 g of the hydrated monohydrochloride salt as an off-white solid. Calc. for C28H38N4O2HCl 1.5 H2O: C, 63.92; H, 8.05; N, 10.65; Cl, 6.74. Found: C, 64.21; H, 7.96; N, 10.77; Cl, 6.92.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C>C(O)C>[F:26][C:25]([F:28])([F:27])[C:24]([NH:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:23]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: CCO
Product: O=C(NCCCC[C@H](NC(=O)C(F)(F)F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-L-lysine is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl ether.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2.C(N(CC)CC)C.[C:23]([O:27][C:28](ON=C(C1C=CC=CC=1)C#N)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:28]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2)([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29]
Reactant: NCc1cccc2ccc(C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Part D--A solution of 8-aminomethyl-2-naphthoic acid (0.50 g, 0.00025 mol) and triethylamine (0.038 mL, 0.028 g, 0.000275 mol) in aqueous tetrahydrofuran (50%, 5 mL) was added, portionwise as a solid, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.068 g, 0.000275 mol). All was stirred at ambient temperature over 5 hours. The solution was concentrated to half volume and extracted with diethylether. The aqueous layer was then acidified to a pH of 1.0 using hydrochloric acid (1N) and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give the title compound, N-(BOC)-8-aminomethyl-2-naphthoic acid (0.050 g, 0.00017 mol) as a white solid. mp=190°-191° C.; 1H NMR (DMSO) d 13.1 (bs, 1H), 8.8 (s, 1H), 8.0 (q, 2H, J=7.9 Hz), 7.9 (d, 1H, J=8.1 Hz), 7.6 (t, 1H, J=7.5 Hz), 7.65-7.55 (m, 2H), 4.6 (d, 2H, J=5.5 Hz), 1.4 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1.[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:29][CH:30]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][N:6]1[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]2[N:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:2](=[O:1])[CH2:7]1
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Reactant: N#Cc1ccc(CCN2CCNCC2=O)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(CCN2CCN(CCc3ccc(C#N)cn3)C(=O)C2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-[2-(2-Oxopiperazin-1-yl)ethyl]pyridine-3-carbonitrile [I-14](1 eq), (4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (1 eq) and NaBH(OAc)3 in 10 mL of DCM was stirred overnight at RT. The mixture was diluted with 50 mL of DCM and washed with brine, concentrated and the residue was purified by prep-TLC (DCM:MeOH=15:1) to afford the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 8.73 (s, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 5.18 (s, 2H), 3.71 (t, J=7.2 Hz, 2H), 3.26 (s, 2H), 3.08-3.14 (m, 4H), 2.85 (t, J=7.6 Hz, 2H), 2.65 (s, 2H), 2.54 (t, J=7.6 Hz, 2H), 2.21 (s, 3H).
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:89])[C@@H:83]([CH2:85][C:86]([OH:88])=[O:87])O>CC(C)=O>[CH3:35][CH:34]([CH3:36])[CH2:33][C@@H:32]([B:4]1[O:5][C@H:83]([CH2:85][C:86]([OH:88])=[O:87])[C:82](=[O:89])[O:3]1)[NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1)=[O:49])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)C[C@@H](O)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.305 g, 0.278 mmol) and D-malic acid (130.3 mg, 0.33 mmol) were mixed in acetone (3 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. White solid precipitated out and the resultant slurry was agitated at ambient temperature for 3 h. The slurry was filtered to collect solid 2-((R)-2((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.410 g, 100%). [M+H] calculated for C23H28BN4O7, 483.2051. found, 483.2.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]([NH:11][C:12]1[S:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[C:15]([CH3:17])[N:16]=1)(=[O:10])[CH3:9].C(N(CC)CC)C>O1CCOCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:18]([C:14]1[S:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[N:16][C:15]=1[CH3:17])(=[O:19])=[O:20]
Reactant: OCCNCCO
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N(CCO)CCO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.2 %

Procedure:
To a stirred solution of diethanolamine (1.24 g, 11.8 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methyl-thiazole-5-sulfonyl chloride (1.0 g, 3.93 mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid bis-(2-hydroxy-ethyl)-amide (0.74 g, 58%) as a white solid. MS (ISP) 324.0 [(M+H)+]; mp 204° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.CN(C1CCCCC1)C1CCCCC1.[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])[N:9]=2)[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1
Reactant: Cc1cc(C=O)cc2cn[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(C=O)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 5 h

Procedure:
To a solution of 7-methyl-1H-indazole-5-carbaldehyde (5.0 g, 31.25 mmol) and N-methyl-dicyclohexylamine (13.5 mL, 62.35 mmol) in dry tetrahydrofuran (120 mL) at 0° C., was added 2-(trimethylsilyl)ethoxymethyl chloride (6.65 mL, 39.5 mmol). The ice-bath was removed and stirring continued for 5 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated in vacuo. Column chromatography afforded 8.5 g (93%). 1H-NMR (400 MHz, CDCl3) δ 12.3 (br., 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.42 (s, 1H), 6.12 (d, J=7.0 Hz, 1H), 5.31 (d, J=7.0 Hz, 1H), 3.80 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH:25]([C:27]1[CH:32]=[CH:31]C(B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:1]3[CH:31]=[CH:32][C:27]([CH:25]=[O:26])=[CH:28][CH:29]=3)[C:10]=12
Reactant: Cc1nn([C@H]2CC[C@@H](N3CCN(C)CC3)CC2)c2ncnc(N)c12
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN(C2CCC(n3nc(-c4ccc(C=O)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 54.3 %

Procedure:
cis-3-Methyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.0 g, 6.80 mmol), 4-formylphenylboronic acid (1.22 g, 8.16 mmol), palladium tetrakistriphenyphosphine (0.47 g, 0.41 mmol) and sodium carbonate (1.73 g, 16.31 mmol) were mixed with ethylene glycol dimethyl ether (70 mL) and water (35 mL). The reaction mixture was heated at reflux overnight under nitrogen. Organic solvent was removed under reduced pressure and the aqueous layer was filtered and washed with water. After drying on the lyophilizer, the residue was purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase to give 4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde (1.55 g, 54%). 1H NMR (DMSO-d6) δ 1.60 (m, 2H), 1.72 (m, 2H). 2.07 (m, 2H), 2.15 (s, 3H), 2.22-2.46 (m, 1H), 4.83 (m, 1H), 7.88 (d, J=8.13 Hz, 2H), 8.07 (d, J=8.10 Hz, 2H), 8.21 (s, 1H), 10.11 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=420.2, Rt=0.70 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:20](/[CH:30]=[CH:31]\[CH3:32])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:33][CH2:34][C:35](Br)=[O:36]>ClCCl>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:35](=[O:36])[CH2:34][Br:33])[CH2:26][CH2:25]2)=[C:20](/[CH:30]=[CH:31]\[CH3:32])[CH:19]=1)([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCNCC1
Solvent: ClCCl
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
(Z)-1-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazine (38 mg, 0.0595 mmol) was dissolved in dichloromethane (1.0 mL). Under ice-cold conditions, N,N′-dimethylaniline (9.0 μL, 0.0714 mmol) and bromoacetylbromide (5.5 μL, 0.0625 mmol) were added, and the mixture was stirred under ice-cold conditions for 0.5 hours. Then, under ice-cold conditions, N,N′-dimethylaniline (9.0 μL, 0.0714 mmol) and bromoacetylbromide (5.5 μL, 0.0625 mmol) were added, and the mixture was stirred under ice-cold conditions for 0.5 hours. The reaction solution was concentrated in vacuo, and the obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (16 mg (yield 47%)) was obtained as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]([O:12]C)=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>C(O)C.O>[C:1]([C:4]1[C:5]([C:10]([OH:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ncccc1C(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cccnc1C(=O)O
Reaction time: 1 h

Procedure:
To methyl 3-acetyl-2-pyridinecarboxylate (1.86 g) in 20 ml of ethanol is added lithium hydroxide monohydrate (10 mmol) in 20 ml of hot water. After 1 hour, conc. hydrochloric acid (1 ml) is added, and the mixture is reduced under vacuum. The resulting solid is extracted with hot methylene chloride, and the residue is stirred with 15 ml of THF for 1 hour at 60°, then filtered and dried to give 3-acetyl-2-pyridinecarboxylic acid.
Reaction SMILES: [CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][C:3](=[O:12])[CH:2]=1.[H][H]>O1CCCC1.[C].[Pd]>[CH2:5]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:1][CH2:2][C:3](=[O:12])[CH2:4]1
Reactant: [H][H]
Reactant: O=C1C=CC2(CCCCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1CCC2(CCCCC2)CC1
Yield: 103.2 %

Procedure:
To a solution of spiro[5.5]undec-1-en-3-one (8.9 g) obtained in Step 1 in tetrahydrofuran (360 mL) was added 5% palladium carbon (0.89 g), followed by stirring the reaction mixture at room temperature in an atmosphere of hydrogen under normal pressure for 2 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated to obtain spiro[5.5]undecan-3-one (9.3 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH2:45][C:46]5[CH2:51][CH2:50][C:49]([CH3:53])([CH3:52])[CH2:48][C:47]=5[C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=5)[CH2:41][CH2:40]4)[CH:36]=[CH:35][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[O:61]1[CH2:64][C:63](=O)[CH2:62]1.C([BH3-])#N>O1CCCC1.C(O)(=O)C>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([C:47]2[CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][CH2:51][C:46]=2[CH2:45][N:42]2[CH2:41][CH2:40][N:39]([C:37]3[CH:36]=[CH:35][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH:26]5[CH2:31][CH2:30][N:29]([CH:63]6[CH2:64][O:61][CH2:62]6)[CH2:28][CH2:27]5)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:38]=3)[CH2:44][CH2:43]2)=[CH:59][CH:58]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(C6COC6)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 139B (120 mg) in tetrahydrofuran (3 mL) and acetic acid (1 mL) was added oxetan-3-one (50.8 mg) and MP-cyanoborohydride (2.15 mmol/g, 150 mg). The mixture was stirred at room temperature overnight. The mixture was filtered. The filtrate was concentrated and the residue was loaded on a silica gel cartridge and eluted with 5-10% 7N NH3 in methanol in dichloromethane to give the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.62 (s, 1H), 8.51 (d, 1H), 8.20 (d, 1H), 7.99 (d, 1H), 7.74 (m, 1H), 7.48 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.36 (dd, 1H), 6.20 (d, 1H), 4.54 (t, 2H), 4.43 (t, 2H), 3.66 (m, 1H), 3.44 (m, 3H), 3.04 (m, 5H), 2.73 (s, 2H), 2.61 (m, 2H), 2.12 (m, 11H), 1.61 (m, 2H), 1.38 (t, 2H), 0.93 (m, 6H).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][O:5][C:6]([O:11][CH3:12])([CH3:10])[CH:7]([NH2:9])[CH3:8]>O.CO>[CH3:4][O:5][C:6]([O:11][CH3:12])([CH3:10])[CH:7]([NH:9][C:2]#[N:1])[CH3:8]
Reactant: N#CBr
Reactant: COC(C)(OC)C(C)N
Solvent: CO
Solvent: O
Product: COC(C)(OC)C(C)NC#N

Procedure:
Cyanogen bromide (424 mg., 4 m moles) was added to a solution of 2,2-dimethoxy-1-methylpropylamine (266 mg., 2 m moles) and KHCO3 (400 mg., 4 m moles) in a mixture of water (2 ml.) and methanol (4 ml.). After 15 minutes the mixture was poured in to water (150 ml.) and the mixture extracted with CH2Cl2. The extract was washed with water and brine, dried (MgSO4) and evaporated to dryness to give 2,2-dimethoxy-1-methylpropylcyanamide as a pale yellow oil (280 mg., 88%) having the following n.m.r. spectrum in CDCl3 : 1.15 (s, 3H); 1.18 (d, 3H); 3.15 (s, 6H); 3.0-3.6 (m, 1H); 4.0 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH3:39]>>[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH3:39])[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCN(C)c1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-mopholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-(2-methoxyethyl)-methylamine. ES-MS m/e (%): 458 (M+H+, 100).