Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(=S)=S>[C:1]([C:12]1[CH:13]=[C:8]([CH:5]([CH3:6])[CH3:7])[CH:9]=[CH:10][C:11]=1[CH:14]([CH3:16])[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(C)c1ccc(C(C)C)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1cc(C(C)C)ccc1C(C)C
Temperature: -10 °C
Yield: 88.5 %

Procedure:
A solution of 142 ml (157 g, 2.0 mol) of acetyl chloride in 362 ml (310 g, 1.91 mol) of 1,4-diisopropylbenzene was added dropwise during the course of 2 hours to a suspension of 200 g (1.5 mol) of aluminum trichloride in 260 ml of carbon disulfide cooled to -10° C. The mixture was stirred for a further 1.5 hours at -100° C., in the course of which the evolution of hydrogen chloride greatly decreased, and a further 100 g (0.75 mol) of aluminum trichloride were then added in portions and the mixture was stirred for a further hour. The reaction mixture was cautiously poured onto I kg of ice/100 ml of 2N hydrochloric acid (strongly exothermic? ). The oily organic phase was separated off and the aqueous phase was extracted twice using ether. The combined organic phases were washed with dilute sodium carbonate solution, then with water and dried over calcium chloride. The solvents were stripped off and the residue was distilled through a 30 cm Vigreux column in a pump vacuum. After a forerun (b.p. 70°-91° C./ 0.6 torr, colorless oil, 10.9 g), the title compound (b.p. 92°-95° C./0.6 torr, colorless oil, 344.3 g, 1.69 mol), was obtained, yield 88.4%. The afterrun (b.p. 97°-104° C./1.0 torr, 10.25 g) is a colorless oil which immediately solidifies.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[F:8][C:7]1[C:2]([N:18]2[CH2:19][CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17]2)=[N:3][CH:4]=[N:5][C:6]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14]
Reactant: CCC#CCOc1ncnc(Cl)c1F
Reactant: CC1CCCNC1
Product: CCC#CCOc1ncnc(N2CCCC(C)C2)c1F
Reaction time: 3 h
Yield: 89 %

Procedure:
0.2 g of 4-chloro-5-fluoro-6-(2-pentynyloxy)pyrimidine and 0.29 g of 3-methylpiperidine were mixed and left for 3 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.23 g of 5-fluoro-4-(3-methylpiperidino)-6-(2-pentynyloxy)pyrimidine (hereinafter, referred to as Compound (10)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg+].[Br-]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]([OH:19])[CH3:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg+]
Reactant: CC(C)(C)OC(=O)NC1CCCc2cc(C=O)ccc21
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)CCCC2NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid tert-butyl ester (Step c, 2.80 g, 10.2 mmol, 1.0 eq) in THF (100 mL) at −78° C. was added a solution of MeMgBr (Aldrich, 1.4 M in toluene/THF (3:1), 29 mL, 40.7 mmol, 4.0 eq) slowly. The reaction was stirred at −78° C. for 20 min, warmed to RT and stirred at RT for 2 h. The reaction was quenched with saturated NaHCO3 (120 mL), and the crude was extracted with EtOAc (100 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The title compound was obtained as a white solid. MS (ESI, pos. ion) m/z: 292 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([CH3:9])[O:4][N:3]=1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:9])[O:4][N:3]=1
Reactant: Cc1noc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1noc(C)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a 0° C. solution of 3,5-dimethyl-1,2-oxazole-4-carbaldehyde (1.0 g, 8.0 mmol) in anhydrous methanol (60 mL) was added sodium borohydride (450 mg, 12.0 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added and methanol was evaporated. The resultant mixture was extracted with EtOAc (1×50 mL) and CH2Cl2 (3×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (3,5-dimethyl-1,2-oxazol-4-yl)methanol (805 mg, 79% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([C:13]4[CH:18]=[C:17]([C:19]#[C:20][Si](C)(C)C)[CH:16]=[C:15]([C:25]#[C:26][Si](C)(C)C)[CH:14]=4)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:31]45[CH2:58][C:35]6([CH3:59])[CH2:36][C:37]([C:40]7[CH:45]=[C:44]([C:46]#[C:47][Si](C)(C)C)[CH:43]=[C:42]([C:52]#[C:53][Si](C)(C)C)[CH:41]=7)([CH2:39][C:33]([CH3:60])([CH2:34]6)[CH2:32]4)[CH2:38]5)([CH2:5]3)[CH2:3]1)[CH2:9]2.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.Cl>CO>[CH3:60][C:33]12[CH2:39][C:37]3([C:40]4[CH:45]=[C:44]([C:46]#[CH:47])[CH:43]=[C:42]([C:52]#[CH:53])[CH:41]=4)[CH2:36][C:35]([CH3:59])([CH2:58][C:31]([C:4]45[CH2:10][C:8]6([CH3:11])[CH2:7][C:6]([C:13]7[CH:18]=[C:17]([C:19]#[CH:20])[CH:16]=[C:15]([C:25]#[CH:26])[CH:14]=7)([CH2:12][C:2]([CH3:1])([CH2:9]6)[CH2:3]4)[CH2:5]5)([CH2:38]3)[CH2:32]1)[CH2:34]2
Reactant: CC12CC3(C)CC(c4cc(C#C[Si](C)(C)C)cc(C#C[Si](C)(C)C)c4)(C1)CC(C14CC5(C)CC(C)(CC(c6cc(C#C[Si](C)(C)C)cc(C#C[Si](C)(C)C)c6)(C5)C1)C4)(C2)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cc(C#C)cc(C23CC4(C)CC(C)(C2)CC(C25CC6(C)CC(C)(CC(c7cc(C#C)cc(C#C)c7)(C6)C2)C5)(C4)C3)c1
Reaction time: 4 h

Procedure:
Next, 39.8 g (53.5 mmol) of the previously obtained 3,3′,5,5′-tetramethyl-7,7′-bis[3,5-bis(trimethylsilylethynyl)phenyl]-1,1′-biadamantane and 1.46 g (10.6 mmol) of potassium carbonate were stirred in a mixed solvent comprising 600 ml of tetrahydrofuran and 300 ml of methanol, for 4 hours under a nitrogen atmosphere at room temperature. This was added to 1000 ml of a 10% hydrochloric acid aqueous solution, and the precipitate was filtered and washed with 1000 ml of water and then with 1000 ml of acetone, after which it was dried to obtain 21.2 g of 3,3′,5,5′-tetramethyl-7,7′-bis(3,5-diethynylphenyl)-1,1′-biadamantane.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH3:32].C([BH3-])#N.[Na+]>CO>[CH2:31]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH3:32]
Reactant: CC=O
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, acetaldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)=[O:3].Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:16][CH:15]=1>>[NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(N)=O)cc3)cc2)CC1
Yield: 18.9 %

Procedure:
The title compound (15 mg, 15%) was prepared from [4-(aminocarbonyl)phenyl]boronic acid (33 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3 and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.86 (d, 2H, J=8.1 Hz), 7.63 (d, 2H, J=8.1 Hz), 7.55 (d, 2H, J=8.8 Hz), 6.97 (d, 2H, J=8.9 Hz), 6.09 (s, 2H), 4.99-4.86 (m, 1H), 4.28-4.14 (m, 2H), 3.85 (d, 2H, J=6.4 Hz), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.34-1.18 (m, 8H); LRMS (ESI), m/z 419 (M+Na).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH2:22]>C(O)(C)C>[ClH:2].[OH:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:22][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1ccc2c(Nc3ccc(C)c(O)c3)ncnc2c1
Yield: 73.9 %

Procedure:
A mixture of 4-chloro-7-(2-methoxyethoxy)quinazoline hydrochloride (450 mg, 1.6 mmol), (prepared as described for the starting material in Example 1), and 3-hydroxy4-methylaniline (280 mg, 2.27 mmol) in isopropanol (20 ml) was heated at reflux for 30 minutes. The solvent was removed by evaporation and the residue was triturated with isopropanol. The resulting solid was collected by filtration, washed with isopropanol and dried under vacuum to give 4-(3-hydroxy4-methylanilino)-7-(2-methoxyethoxy)quinazoline hydrochloride (428 mg, 74%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:10])[CH2:3][CH2:2]1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a stirred solution of 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid (0.36 g, 1.00 mmol) in dichloromethane (20 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.50 mmol) and 4-dimethylaminopyridine (0.28 g, 2.30 mmol). The reaction was stirred at ambient temperature for 10 minutes, methanesulfonamide (0.15 g, 1.56 mmol) was added and the stirring was continued at ambient temperature for 17 hours. 5% aqueous hydrochloric acid solution (10 mL) were added and diluted with ethyl acetate (100 mL), washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (30% ethyl acetate in hexanes) afforded the title compound (0.27 g, 62%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (br s, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.59 (d, J=14.1 Hz, 1H), 4.12 (s, 2H), 3.39 (s, 3H), 2.03-1.88 (m, 3H), 1.76-1.63 (m, 5H), 1.48-1.23 (m, 3H), 0.94-0.87 (m, 2H), 0.64-0.58 (m, 2H); MS (ES−) m/z 436.2 (M−1).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:33]([O:35][CH2:36]C)=[O:34])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]1[CH:44]=[C:43](I)[C:42]([CH3:46])=[CH:41][N:40]=1.[F-].[Cs+]>C(COC)OC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:38][C:39]1[CH:44]=[C:43]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[NH:17][C:16]([C:33]([O:35][CH3:36])=[O:34])=[C:15]3[CH2:14][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:42]([CH3:46])=[CH:41][N:40]=1
Reactant: CCOC(=O)c1[nH]c2c(B3OC(C)(C)C(C)(C)O3)cccc2c1CCCOc1cccc2ccccc12
Reactant: Cc1cnc(F)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1[nH]c2c(-c3cc(F)ncc3C)cccc2c1CCCOc1cccc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 43A (0.40 g), 2-fluoro-4-iodo-5-methylpyridine (0.209 g), tetrakis(triphenylphosphine)palladium (46 mg) and cesium fluoride (0.365 g) in dimethoxyethane (3 mL) and methanol (1.5 mL) was heated at 120° C. for 20 minutes under microwave conditions (CEM Discovery). After cooling to room temperature, the reaction mixture was loaded onto a silica gel cartridge. The cartridge was dried in vacuum oven for 1 hour and eluted with 1:4 ethyl acetate/hexanes to give the desired product. 1H NMR (500 MHz, DMSO-d6): 11.33 (s, 1H), 8.23-8.25 (m, 1H), 8.17 (s, 1H), 7.86-7.88 (m, 1H), 7.79-7.81 (m, 1H), 7.45-7.56 (m, 3H), 7.39 (t, J=7.93 Hz, 1H), 7.12-7.14 (m, 2H), 7.04 (d, J=2.14 Hz, 1H), 6.91 (d, J=7.32 Hz, 1H), 4.20 (t, J=5.95 Hz, 2H), 3.78 (s, 3H), 3.37 (t, J=7.48 Hz, 2H), 2.20-2.26 (m, 2H), 2.00 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][C:8]#[N:9]
Reactant: Brc1ccccn1
Reactant: N#CCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCc1ccccc1-c1ccccn1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzylcyanide (12.33 g) in tetrahydrofuran (85 ml) was added dropwise, at -70° C. in argon streams, a hexane solution (65 ml) of n-butyl lithium. The mixture was then stirred for 30 minutes at -50° C., to which was then added dropwise 2-bromopyridine (9.7 ml). The reaction temperature was gradually raised up to 0° C. Fifteen minutes later, a saturated ammonium chloride solution was added to the reaction mixture, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The concentrate was purified by means of a silica gel column chromatography to give the title compound (6.59 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:13](=[O:17])[CH2:12]2)[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(CCOC1CCCCO1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a suspension of 1,3-dioxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.0 g, 3.7 mmol) in DMF (12 ml), 2-(2-bromoethoxy)-tetrahydro-2H-pyrane (0.62 ml, 4.1 mmol) and potassium carbonate (0.62 g, 4.5 mmol) are added at ambient temperature and the mixture is stirred for overnight at room temperature. The reaction mixture is quenched with water and extracted with ethyl acetate. The combined extracts are washed with brine and dried over sodium sulfate, filtrated. The solvent is evaporated down to give 1.6 g of crude 1,3-dioxo-2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1.Cl[CH2:29][C:30]([NH2:32])=[O:31].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:24][CH2:25]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1
Reactant: NC(=O)CCl
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)CN1CCC(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one (20 mg, 0.047 mmol) in N-methylpyrrolidinone (0.5 mL) is added 2-chloroacetamide (9 mg, 0.094 mmole) and diisopropylethylamine (0.016 mL, 0.094 mmole) and heated at 120° C. for 16 h. The reaction is concentrated and purified by column chromatography (silica, 5% methanol/dichloromethane) to provide 2-{4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-piperidin-1-yl}-acetamide. 1H NMR (300 MHz, CDCl3) d 7.88-7.83 (m, 3H), 7.47 (dd, 1H), 6.98 (bs, 1H), 5.30 (bs, 1H), 3.86 (s, 2H), 3.46 (s, 4H), 3.28 (d, 2H), 2.95 (s, 2H), 2.82 (d, 2H), 2.06 (t, 2H), 1.69-1.50 (m, 3H), 1.33-1.25 (m, 2H); MS (Ion spray) 485 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:29])[CH3:28]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (33 mg, 48%), MS (ISP) m/z=371.4 [(M+H)+], mp 183° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (75 mg, 0.19 mmol) and acetic acid.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#N)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1CC(O)=[O:37].O>[Ni]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=[O:37])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccccn1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Agent: [Ni]
Solvent: O
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Yield: 45 %

Procedure:
(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl) ethylamino)nicotinonitrile (Example 1, 0.4 g, 1.1 mmol) was dissolved in the mixture pyridine-acetic acid-water (1:1:1, 18 ml total volume) at room temperature, to which was added Raney nickel (0.09 g, 1.1 mmol). The reaction was purged with nitrogen, evacuated, and then placed under hydrogen filled balloon for 18 hours. The reaction mixture was flushed with nitrogen, and filtered to remove the catalyst, which was washed with MeOH (30 ml). The filtrate was then extracted with DCM (5×50 ml), washed with aq. NaHCO3, and purified by reverse phase column chromatography (5-30% ACN) to give the title compound (0.18 g, 45%). 1H NMR (400 MHz, CD3OD) δ 9.40 (s, 1H), 7.45 (d, J=10.4 Hz, 1H), 7.34-7.31 (m, 2H), 7.05-7.01 (m, 2H), 6.11 (s, 1H), 5.26 (s, 1H), 1.92-1.86 (m, 1H), 1.55 (d, J=7.0 Hz, 3H), 1.00-0.98 (m, 2H), 0.71-0.64 (m, 2H). MS: Calcd.: 383. Found: [M+H]+ 384.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:16][Si](Cl)(C)C>CO>[CH3:16][O:14][C:13](=[O:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)CCc1c[nH]c2ccc(Br)cc12
Solvent: CO
Product: COC(=O)CCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The 5-bromoindole-3-propionic acid 87 (4.0 g, 14.91 mmol) was dissolved in methanol (MeOH, 100 mL) and Trimethylsilyl chloride (TMSCl, 33.0 mL, 32.8 mmol, 1.0 M in CH2Cl2) was added dropwise The mixture was stirred for 24 hours, followed by refluxing for 1 hour. The reaction was allowed to cool to room temperature and the solvent was evaporated to ester as a white solid, (M+1=284).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2].CCO>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To ((3R,5R)-1-benzyl-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (prepared as described in WO2004014893) (4.6 g, 15.11 mmol) Pd(OH)2 on carbon (0.46 g) and EtOH (80 ml) were added and the reaction mixture stirred at RT under 1 atm of H2. After 3 hours the palladium was filtered off and the solvent was evaporated. The remaining oil was dried under high vacuum to give 2.9 g of ((3R,5R)-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester as an off-white crystalline solid (89% yield).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH:5]([CH3:32])[CH:6]([NH:19][C:20]([CH:22]1[CH2:26][CH:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][NH:23]1)=[O:21])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([CH2:16][CH2:17][CH3:18])[O:8]1>CO.CCOCC>[CH3:32][CH:5]([CH3:4])[CH:6]([NH:19][C:20]([CH:22]1[CH2:26][CH:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][N:23]1[CH2:1][CH2:2][OH:3])=[O:21])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([CH2:16][CH2:17][CH3:18])[O:8]1
Reactant: C1CO1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(CCC)C(O)C(O)C2O)C1
Solvent: CCOCC
Solvent: CO
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(CCC)C(O)C(O)C2O)N(CCO)C1
Reaction time: 48 h
Yield: 34 %

Procedure:
The title compound was prepared according to the process illustrated in Scheme 19. Ethylene oxide was used as the alkylating agent. To a stirred solution of 4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide (example 103) (12.0 mg 0.029 mmol, 1 equiv) and TEA (100 μL) in MeOH (2 mL) at 0° C. was added condensed ethylene oxide (200 μL) was added and the reaction mixture stirred 48 h. The reaction mixture evaporated to dryness, and the resulting residue was purified by column chromatography on silica 20% 0.25M NH3 in MeOH/DCM to give the crude N alkylated product. The crude product was taken up in Et2O, filtered and the filtrate treated with 2M HCl in Et2O, the precipetated HCl salt was collected washed with Et2O and lyophylized to give the title compound as a colorless powder (4.4 mg 34%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:22]([O:24]CC)=O)=[N:3]1.[OH-].[NH4+:28]>CO>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:22]([NH2:28])=[O:24])=[N:3]1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccn3)nc1-2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(N)=O)c2c1-c1nc(Nc3ccccn3)ncc1CC2
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-methyl-8-(pyridin-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (220 mg, 0.63 mmol) in methanol (250 mL), 33% aqueous ammonium hydroxide (100 mL) was added and the solution was stirred at 65° C. for 8 hours.