Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](Br)=[CH:17][N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(=O)(O)(O)O.[OH-].[Na+].CCOCC>COCCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2c(Br)cn3Cc2cccc(F)c2)CC1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCN3Cc2cccc(F)c2)CC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4-[3-Bromo-1-(3-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (273 mg) was dissolved in 3 mL of 2-methoxyethanol and 85% phosphoric acid (575 mL) was added. The dark solution was heated to 140° C. and stirred for 16 h. The next day the mixture was made basic with 1.0 N NaOH and Et2O was added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After filtering and removing solvent the crude material was taken up in 3 mL of THF and di-tert-butyldicarbonate (218 mg) was added. The mixture was stirred for 24 hours at room temperature, after which the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography to provide 115 mg of 4-[1-(3-fluoro-benzyl)-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester, MS: 326 (M−Boc+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[N:26]1([C:32]2[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>>[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]([N:1]3[CH:5]=[C:4]([C:6]4[C:7]5[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=5[N:9]=[CH:10][N:11]=4)[CH:3]=[N:2]3)[CH2:39][C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#C/C=C/c1cncc(N2CCOCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(N5CCOCC5)c4)c3)ncnc21
Reaction time: 8 h
Yield: 125.6 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (70 mg, 0.0003 mol) (mixture of isomers), DBU (50 μL, 0.0003 mol) was added and the resulting mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (200 mg, 100%) as a crude product; L/MS=531 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([C:9]([OH:11])=O)[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:44][CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1>CN(C)C=O>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([C:9]([NH:44][CH:45]3[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50]3)=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc2ccc(O)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(O)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a stirred mixture of 6-hydroxybenzo[d]thiazole-2-carboxylic acid (0.20 g, 1 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added triethylamine (0.12 g, 1.2 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.2 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.24 g, 1.2 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/1) to afford tert-butyl 4-(6-hydroxybenzo[d]thiazole-2-carboxamido)piperidine-1-carboxylate as a white solid (0.23 g, 62%). 1H-NMR (CDCl3, 300 MHz): δ 7.90 (m, 1H), 7.38 (m, 1H), 7.28 (m, 2H), 7.11 (m, 1H), 4.12 (m, 3H), 2.95 (m, 2H), 2.04 (m, 2H), 1.58 (m, 2H), 1.48 (s, 9H) ppm; MS (ESI): 379.1 (M+1).
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: C1CCNC1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CCN1CCCC1
Reaction time: 24 h

Procedure:
500 mL tetrahydrofuran (THF) was placed in a 1-L suction flask. 35.3 g isovaleraldehyde (0.41 mol) and then 28.4 g pyrrolidine (0.40 mol) were mixed into the THF. 100 g of sodium triacetoxyborohydride (0.47 mol) powder was then added in 5-10 g increments to the solution. During the addition vigorous stirring was used to ensure that the powder did not clump at the bottom of the flask which would prevent the efficient mixing of the suspension. After each addition of the sodium triacetoxyborohydride powder, adequate time was provided to form a uniform slurry before the next addition of the powder. After one day the product was worked up by quenching the suspension with the slow addition of 291 g of a 27% KOH solution. The product was then extracted from the resultant solution with 500 mL pentane. The organic fraction was then collected with a separatory funnel and dried with anhydrous magnesium sulfate. The N-isopentylpyrrolidine product was then isolated by rotary evaporation of the THF and pentane solvents under reduced pressure.
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].S(Cl)([Cl:21])=O>>[C:1]([Cl:21])(=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCCCCCCCCCCCC(=O)O
Product: CC(C)CCCCCCCCCCCCC(=O)Cl

Procedure:
Isohexadecanoic acid (20 g, 0.078 mol) and thionyl chloride (7.2 ml, 0.0984 mol) were refluxed together gently for 1 hour to produce isohexadecanoyl chloride and the reaction was monitored by infra-red spectroscopy. Excess thionyl chloride was distilled away under rotary pump vacuum at reflux temperature. The acyl chloride was dissolved in n-hexane (50 ml) and slowly added to a chilled stirred solution of n-propylamine (7.05 ml, 0.0858 mol, m 0.1 excess). The solution also contained triethylamine (12 ml, 0.0858 mol, 0.1 excess) in n-hexane (200 ml) to ensure base conditions. After the addition was completed the reaction mixture was stirred at room temperature for 3 hours until all the acyl chloride was consumed. This was detected by monitoring the shift in the carbonyl frequency by infra-red spectroscopy. A product mixture was produced which consisted of N-(n-propyl)-isohexadecamide. The produce mixture was washed with water (2×200 ml), 6M hydrochloric acid (4×100 ml), water (100 ml), saturated aqueous sodium bicarbonate (1×100 ml), saturated aqueous sodium chloride (1×100 ml) and dried over MgSO4 before being filtered and rotary evaporated to yield a yellow oil (22.4 g, 96.5%). Infra-red spectroscopy (liquid film) detected absorption peaks at 3280 cm-1 (broad, strong), 3080 cm-1 strong, 1630 cm-1 (strong) and 1540 cm-1 (strong).
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][N:2]=1>CO.[Pd]>[NH:16]1[CH2:15][CH2:14][CH:13]([C:1]2[N:5]3[C:6]4[CH:12]=[CH:11][NH:10][C:7]=4[N:8]=[CH:9][C:4]3=[N:3][N:2]=2)[CH2:18][CH2:17]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Agent: [Pd]
Solvent: CO
Product: c1cc2c(ncc3nnc(C4CCNCC4)n32)[nH]1
Yield: 82.5 %

Procedure:
Benzyl 4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylate (0.34 g, 0.90 mmol, Example #2, Step A) and 10% Pd on carbon (0.10 g, 0.09 mmol) in MeOH (30 mL) was shaken under hydrogen at about 60 psi for about 5 h at ambient temperature. The reaction was filtered through Celite® and concentrated under reduced pressure to constant weight to afford 1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a yellow solid (0.18 g, 77%): LC/MS (Table 2, Method a) Rt=0.70 min; MS m/z: 243 (M+H)+.
Reaction SMILES: [CH2:1]([O-])[CH3:2].[Na+].[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[C:11](O)(=O)C>C(O)C>[C:5]([C:7]1[C:8](=[O:9])[NH:10][CH:11]=[CH:1][CH:2]=1)#[N:6]
Reactant: CC[O-]
Reactant: CC(=O)O
Reactant: N#CCC(N)=O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc[nH]c1=O
Reaction time: 3 h
Yield: 57 %

Procedure:
Sodium ethanolate (9.48 mL; 21 weight 0; 1.0 equiv.) was added to a solution of preceding methylene-dimethylamino (see 1.3.) (10 g; 1.0 equiv.) and cyanoacetamide (2.135 g; 1.0 equiv.) in ethanol (100 mL). The mixture was left under agitation 3 hours at ambient temperature. The medium was then neutralised with the dropwise addition of acetic acid and concentrated under reduced pressure. The reaction medium was diluted in ethyl acetate (200 mL) and the organic phase washed with a brine solution (150 mL). The organic phase was dried over magnesium sulfate, filtered and the solvents evaporated under reduced pressure. The residue was purified on silica gel (CH2Cl2/AcOEt 8:2) to give the pyridone with a global yield of 57%.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH:27]1[CH2:36][O:37][C:38]1[C:46]([CH:47]3[CH2:49][CH2:48]3)=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([F:50])[CH:39]=1)[CH2:33]2.CS(N)(=O)=O.[N:56]1([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:59][CH2:58][CH2:57]1>>[CH:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH:27]1[CH2:36][O:37][C:38]1[C:46]([CH:47]3[CH2:48][CH2:49]3)=[CH:45][C:41]([C:42]([NH:63][S:60]([N:56]3[CH2:59][CH2:58][CH2:57]3)(=[O:62])=[O:61])=[O:43])=[C:40]([F:50])[CH:39]=1)[CH2:33]2
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2C3CC4CC(C3)CC2C4)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained (0.07 g, 26%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.72-8.62 (m, 1H), 7.60-7.54 (m, 1H), 6.67-6.59 (m, 1H), 4.31-4.20 (m, 4H), 4.14-4.07 (m, 2H), 2.36-2.20 (m, 3H), 2.08-1.75 (m, 13H), 1.70-1.60 (m, 2H), 0.97-0.89 (m, 2H), 0.71-0.63 (m, 2H); MS (ES−) m/z 461.3 (M−1).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[CH:5]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[F:11])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1F
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an acetic anhydride (15.5 mL) was added dropwise formic acid (6.1 mL) at 0 degrees under an atmosphere of argon. The mixture was stirred at 50 degrees for 2 hours. After the reaction mixture was cooled to room temperature, it was diluted with tetrahydrofuran (THF; 10 mL). To the diluted solution was added 2-fluoroaniline (5.56 g) in THF (20 mL) at room temperature and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound having the following physical data. The obtained title compound was used to next reaction without further purification.
Reaction SMILES: C[C:2]1[N:7]=[C:6]([C:8]#CC(C2CCNCC2)O)[CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][CH:27]=[C:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:20]=1.Cl[C:35]1C([N+]([O-])=O)=CC=C(C)[N:36]=1>>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([C:35]#[N:36])=[C:2]([N:31]2[CH2:32][CH2:33][C:28](=[CH:27][C:26]#[C:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[N:20]=3)[CH2:29][CH2:30]2)[N:7]=1
Reactant: Brc1cccc(C#CC=C2CCNCC2)n1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Cc1cccc(C#CC(O)C2CCNCC2)n1
Product: Cc1ccc(C#N)c(N2CCC(=CC#Cc3cccc(Br)n3)CC2)n1
Yield: 95 %

Procedure:
The title compound was prepared as described for the compound of Example 237 but starting from Compound 305b instead of compound 237a and 2-chloro-6-methyl-3-nitropyridine instead of 2-bromo-3-nitropyridine. An additional equivalent of TEA was used. After the work-up, the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc gradient from PE:EtAc 95:5 to 6:4 affording the title product. Yellow oil. Yield: 95%.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][CH3:13])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH2:2][CH3:3].Br[CH2:15][C:16]#[N:17]>>[CH2:11]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][CH2:7][N:8]([CH2:15][C:16]#[N:17])[CH2:9][CH2:10]1)[CH2:12][CH3:13]
Reactant: CCCN(CCC)C1CCNCC1
Reactant: N#CCBr
Product: CCCN(CCC)C1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of Dipropyl-piperidin-4-yl-amine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=224.3: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.80-2.75 (m, 2H), 2.40-2.30 (m, 5H), 2.15-2.05 (m, 2H), 1.65-1.60 (m, 2H), 1.50-1.30 (m, 6H), 0.90 (t, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([OH:10])([CH3:9])[CH3:8])[S:5][CH:6]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:18][C:6]1[S:5][C:4]([C:7]([OH:10])([CH3:9])[CH3:8])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1csc(C(C)(C)O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(C(C)(C)O)sc1Br

Procedure:
2-(4-Methylthiazol-2-yl)propan-2-ol (321 mg 2.04 mmol) and NBS (404 mg 2.25 mmol) was stirred in DMF (10 mL) at room temperature for 2 hours under nitrogen. The mixture was diluted with EtOAc (50 mL) and washed with water (2×20 ml), then brine, dried over sodium sulfate and concentrated to give an oil which was purified by ISCO CombiFlash® chromatography eluting with Heptane:EtOAc (100:0 to 0:100 over 20 CV) to the product as a pale yellow oil (296 mg 61%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].C([O-])([O-])=[O:26].[K+].[K+].OO.CCOC(C)=O>CO.CS(C)=O>[C:23]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[N:7][C:2]=1[Cl:1])(=[O:26])[NH2:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C(N)=O)c(Cl)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (300 mg) was dissolved in 20 mL methanol and 10 mL DMSO. To it were added K2CO3 powder (300 mg) and then 3 mL H2O2 (50% solution). The mixture was stirred at 40° C. for 1 h. To it was poured 200 mL EtOAc. The mixture was then washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and pumped to dryness to afford tert-butyl (1S,2R)-2-(5-carbamoyl-6-chloropyrazin-2-ylamino)cyclohexylcarbamate in quantitative yield. Tert-butyl (1S,2R)-2-(5-carbamoyl-6-chloropyrazin-2-ylamino)cyclohexylcarbamate (60 mg, 0.16 mmol) was dissolved in 3 mL NMP. To it were added 4-aminoterahydropyran (100 mg, 0.96 mmol) and DIEA (55 μL, 0.32 mmol). The mixture was stirred at 100° C. for overnight in a sealed tube. It was cooled to RT, diluted with EtOAc, washed with sat. NH4Cl solution, dried over MgSO4, concentrated in vacuo to afford crude tert-butyl (1S,2R)-2-(5-carbamoyl-6-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-ylamino)cyclohexylcarbamate. It was treated with 1:1 DCM and TFA at RT for 1.5 h. It was concentrated and subjected to reverse phase preparative HPLC to isolate the title compound as HCl salt (57 mg). MS found for C16H26N6O2 as (M+H)+ 335.5. UV: λ=282 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:19](=O)[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(O)C.Cl.[OH:30][NH2:31].C([O-])(=O)C.[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:31]/[OH:30])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Reaction time: 3 h

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 48) (150 mg) in tetrahydrofuran (3 mL) and ethanol (3 mL) was added an aqueous solution (2.5 mL) of hydroxyamine hydrochloride (112 mg) and sodium acetate (133 mg), and the mixture was stirred at 70–80° C. for 3 hours. The organic solvent was removed by evaporation, water and ethyl acetate were added for separation/extraction. The organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate; ethyl acetate 10–40%). Among the 2 spots detected by TLC (the solvent system; hexane-ethyl acetate=1:1), the polar fractions (low Rf value on TLC) were collected, and the title compound (116 mg) was obtained as a colorless solid.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][C:11]([NH2:14])=[CH:12][N:13]=2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.B>C1COCC1>[N:1]1([CH2:7][C:9]2[S:10][C:11]([NH2:14])=[CH:12][N:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cnc(C(=O)N2CCOCC2)s1
Agent: B
Solvent: C1CCOC1
Product: Nc1cnc(CN2CCOCC2)s1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
To a solution of 2-(4-morpholinylcarbonyl)-1,3-thiazol-5-amine (Preparation 26, 1.0 g) in THF (10 mL) under nitrogen at ambient temperature is added borane (1.0 M solution in THF, 9.39 mL). The bright yellow mixture is heated to reflux (85° C.) for 1 h. The mixture is cooled to ambient temperature, quenched with aq. NH4Cl, and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed. The residue is purified by column chromatography (eluent 2% MeOH/CH2Cl2) to afford 329 mg (35%) of the title compound as a yellow oil. Physical characteristics: 1H NMR (CDCl3) δ2.49, 3.61, 3.65, 6.84; MS (ESI+) m/z 200 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=S1(=O)CCN(c2nc(Cl)nc3c(NCc4ccccc4)ncnc23)CC1
Product: O=S1(=O)CCN(c2nc(N3CCNCC3)nc3c(NCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 8-benzylamino-2-chloro-4-(1,1-dioxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 213°-215° C.) and piperazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][C@@H:14]([CH2:17][OH:18])[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][C@@H:14]([CH2:17][O:18][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1COc2cc(OCc3ccccc3)ccc2O1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1COc2cc(OCc3ccccc3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of crude ((S)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol (1.65 g, 6.06 mmol) in dry DCM (10 ml), was added triethylamine (0.88 ml). The mixture was cooled to 0° C. and methanesulfonyl chloride (0.49 ml) was added slowly dropwise to reaction mixture. The mixture was stirred at RT for 1 h and then 10 ml of aq 1 M HCl was added. The mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried with Na2SO4 The solvents were removed under reduced pressure and the crude product (2.22 g) was crystallized from IPA (15 ml), which gave a white solid (1.50 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FS(O)(=O)=[O:13].[OH:16]O>S(F)(Cl)(=O)=O.FS(O)=O>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[OH:13].[CH:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[OH:16])[CH:1]=1
Reactant: O=S(=O)(O)F
Reactant: c1ccc2ccccc2c1
Reactant: OO
Agent: O=S(=O)(F)Cl
Agent: O=S(O)F
Product: Oc1ccc2ccccc2c1
Product: Oc1cccc2ccccc12
Reaction time: 0.5 h
Yield: 54.2 %
Yield: 4.4 %

Procedure:
0.1 mol of naphthalene was dissolved at -78° C. in a solution of 50 ml of 1:1 mol/mol FSO3H--SbF5 in 100 ml of sulfuryl chloride fluoride. 0.12 mol of H2O2 (90% solution) was separately dissolved in a solution of 50 ml of 1:1 (m/m) FSO2H--SbF5 and 100 ml of sulfuryl chloride fluoride at the same temperature. The H2O2 superacid solution was carefully added with good stirring at -78° to -70° C. to the superacid solution of naphthalene and the reaction mixture subsequently was stirred for an additional 30 minutes, then quenched with ice water, worked up, and analyzed as in Example 1. 22% naphthalene was recovered unchanged. 54.2% of β-naphthol and 4.4% of naphthol were obtained, together with 6% dihydroxynaphthalenes and only traces of polymeric material.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:29]([CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:22]4[N:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:21]=4[CH:20]=3)[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH:32]1([CH2:31][CH2:30][N:29]2[C:22]3[N:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:21]=3[CH:20]=[C:19]2[CH2:18][N:15]2[CH2:14][CH2:13][C:10]3([CH2:9][NH:8][CH2:12][CH2:11]3)[CH2:17][CH2:16]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3cc4cnc(C#N)nc4n3CCC3CCCCC3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ncc2cc(CN3CCC4(CCNC4)CC3)n(CCC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 8-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (300 mg, 0.59 mmol) in dichloromethane (5 ml), trifluoroacetic acid (3 ml) is added. After stirring for 1.5 h at room temperature, solvent is evaporated down to give 7-(2-cyclohexyl-ethyl)-6-(2,8-diaza-spiro[4.5]dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetic acid salt in quant yield.