Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:20]3=[N:21][C:22]([N:26]4[CH2:32][CH:31]5[O:33][CH:28]([CH2:29][CH2:30]5)[CH2:27]4)=[CH:23][C:24](=[O:25])[N:19]3[CH2:18][C@@:17]2([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:10][CH:9]=1.Cl[CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42].[I-].[Na+]>CN(C=O)C>[CH3:44][N:43]([CH3:45])[C:41](=[O:42])[CH2:40][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:20]3=[N:21][C:22]([N:26]4[CH2:27][CH:28]5[O:33][CH:31]([CH2:30][CH2:29]5)[CH2:32]4)=[CH:23][C:24](=[O:25])[N:19]3[CH2:18][C@@:17]2([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:10][CH:9]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CC4CCC(C3)O4)cc2=O)N1CCc1ccc(O)cc1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1ccc(CCN2c3nc(N4CC5CCC(C4)O5)cc(=O)n3C[C@@]2(C)C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
235 mg (0.72 mmol) of cesium carbonate are added to a solution of 130 mg (0.29 mmol) of (S)-1-[2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 10 mL of DMF. After heating at 80° C. for 20 minutes, 52.60 mg (0.43 mmol) of 2-chloro-N,N-dimethylacetamide and 43.30 mg (0.29 mmol) of sodium iodide are added. The reaction medium is heated at 80° C. overnight. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 25 min 10% B, t 30 min 10% B), 138 mg of N,N-dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenoxy)acetamide were obtained, corresponding to the following characteristics:
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Na+:7].[N+]([O-])(O)=O.[N+]([O-])(O)=O.O=[Zr:17]>>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Zr+4:17].[Na+:7].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: O=[Zr]
Agent: CC(O)C(=O)[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: [Zr+4]

Procedure:
The produced sodium lactate solution was added to 500 gm of zirconium oxynitrate solution which contained 20.0% ZrO2, while mixing. A clear solution product of sodium zirconium lactate was obtained. The product had a pH of 7.5 and it contained 6.0% ZrO. The lactate to zirconium molar ratio in the solution product was 5.0 to 1.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][CH:15]=1)=O.OS(O)(=O)=O.O>C(O)(=O)C>[C:20]([C:18]1[CH:19]=[C:14]([CH:12]=[CH:11][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:7])[CH:15]=[CH:16][CH:17]=1)#[N:21]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: N#Cc1cccc(C=O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cccc(C=CC(=O)c2cccc(C#N)c2)c1

Procedure:
3-Cyanobenzaldehyde (3.0 g, 23.0 mmol) and 3-cyanoacetophenone (3.34 g, 23.0 mmol) in glacial acetic acid (5 mL) and concentrated H2SO4 (3.66 mL, 69 mmol) was stirred at room temperature for 72 hours. Water (200 mL) was added and the reaction filtered. The precipitate was washed with water (2×200 mL) and dried in vacuo to give 3,3′-dicyanochalcone as an off-white solid. MS (APCI) m/z 258 (M+−1, 100%). 13C NMR (50 MHz, d6-DMSO): δ 111.7, 117.8, 118.0, 123.0, 129.7, 131.6, 132.1, 132.4, 133.3, 133.5, 135.3, 136.1, 137.4, 142.1, 187.3.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:29][CH:28]=[N:27][C:26]=1[C:30](O)=[O:31]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccn1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccccn3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-pyridin-2-yl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.56 min; [M+H]+=378.14.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([C:44]2([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=3)[CH2:47][CH2:46][CH2:45]2)=[O:43])=[CH:37][CH:36]=1>O1CCCC1>[Br:1][CH:41]([C:38]1[CH:37]=[CH:36][C:35]([Cl:34])=[CH:40][CH:39]=1)[C:42]([C:44]1([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=2)[CH2:47][CH2:46][CH2:45]1)=[O:43]
Reactant: [Br-]
Reactant: O=C(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C(Br)c1ccc(Cl)cc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.9 %

Procedure:
Phenyltrimethylammonium tribromide (6.59 g) was added in portions at −5° C. to a stirred solution of 2-(4-chlorophenyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (6.2 g) in tetrahydrofuran (150 ml). The mixture was stirred at ambient temperature for 4 hours, allowed to stand at ambient temperature for a further 48 hours, then it was filtered, and the solvent removed in vacuo. The residue was purified via flash chromatography over silica using a 3:97 mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined, and the solvents removed in vacuo. The residue was triturated with petroleum ether (b.p. 60-80° C.) (30 ml) and the resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 2-bromo-2-(4-chlorophenyl)1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone as a colourless solid (4.83 g), m.p. 109-110° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].Cl.[CH3:23]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:21])[C:18](=[CH2:23])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CNC
Reactant: CCCC(=O)c1ccc(OCCCCC(=O)O)c(Cl)c1Cl
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1ccc(OCCCCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-(2,3-Dichloro-4-butyrylphenoxy)valeric acid (9.8 g, 0.029 mole), dimethylamine hydrochloride (15 g, 0.184 mole), paraformaldehyde (2.8 g, 0.09 equivalent) and acetic acid (1 ml) were united and stirred and heated on a steam bath for 3 hours. N,N-dimethylformamide (30 ml) was added and stirring and heating continued for another two hours. The reaction mixture was then poured into ice water and the solid that separated was removed by filtration, washed with water and dried. After recrystallization from butyl chloride the 5-[2,3-dichloro-(2-methylenebutyryl)phenoxy]valeric acid (5.4 g) melted at 107°-109° C.
Reaction SMILES: C(O)C.[CH:4]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:19](=O)[CH2:20][CH:21]([C:27](=O)[CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH2:6][CH2:5]1.C([O-])(=O)C.[NH4+:45]>O>[CH:4]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:19]3[NH:45][C:27]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C(CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1)C(=O)COCc1ccc(OC)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OC(F)F)c(OCC3CC3)c2)[nH]c1COCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To 100 ml of ethanol solution containing 14.0 g (26.8 mmol) of ethyl 2-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-oxoethyl]-4-(4-methoxybenzyloxy)-3-oxobutyrate obtained in Reference example 45-(b) was added 10.3 g (134 mmol) of ammonium acetate, the mixture was stirred at room temperature for 1 hour, and further stirred at 80° C. for 4 hours. After completion of the reaction, to the reaction mixture were added water and a saturated aqueous solution of sodium chloride, and the mixture was extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 10.3 g of the title compound as a beige solid. (Yield: 77%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=2)=[CH:4][CH:3]=1.[N:25]1C2C(=CC=CC=2)C=C[CH:26]=1.Cl>ClCCl>[C:26]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[C:9]2[CH:10]=[C:11]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:12]([OH:19])=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:14]=2)=[CH:4][CH:3]=1)#[N:25]
Reactant: c1ccc2ncccc2c1
Reactant: CC(C)(C)c1cc(C(=O)c2ccc(Br)cc2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)c2ccc(C#N)cc2)cc(C(C)(C)C)c1O
Temperature: 180 °C

Procedure:
A stirred mixture of 52 g (0.13 mole) of 4'-bromo-3,5-di(tertiary-butyl)-4-hydroxybenzophenone, 20 g (0.22 mole) of cuprous cyanide and 150 ml of quinoline was heated at about 180° C. for one day, followed by heating at reflux (235° to 245° C.) for two hours. The cooled solution was mixed with about one liter of 10% aqueous hydrochloric acid, and 400 ml of dichloromethane was added. The solid was separated by filtration, and extracted with additional hydrochloric acid and dichloromethane. The filtrates and washings were combined and the organic layer was separated and evaporated. The residue was recrystallized from a benzene-hexane mixture with treatment with decolorizing charcoal to provide 4'-cyano-3,5-di(tertiary-butyl)-4-hydroxybenzophenone. A further recrystallization from a mixture of ethanol and isopropanol with treatment with decolorizing charcoal provided white needles, m.p. 166.5° to 168° C. Analysis: Calculated for C22H25NO2 : % C, 78.8; %H, 7.5; %N, 4.2; Found; %C, 78.8; %H, 7.5; %N, 4.1.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]1([CH3:13])[CH3:12].[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:22][O:21][C:19]([C:17]1[N:16]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[C:3]2([CH3:13])[CH3:12])[CH:15]=[N:14][CH:18]=1)=[O:20]
Reactant: CC1(C)C(=O)c2ccccc2C1O
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)C1(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-hydroxy-2,2-dimethyl-indan-1-one (2.0 g, 11.3 mmol) in THF (50 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 1.72 g, 13.6 mmol), and triphenylphosphine (3.56 g, 13.6 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (3.13 g, 13.6 mmol) is added. The reaction is placed at room temperature and permitted to stir for three hours. The reaction mixture is cooled to 0° C. and quenched with 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The combined organic layers are dried with Na2SO4 filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 3:7) to furnish 3-(2,2-dimethyl-3-oxo-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; HRMS: (ESI) m/z 285.1246 [(M+H)+: Calcd for C16H16N2O3: 285.1239]; 1H NMR (400 MHz, CDCl3) δ ppm 0.82 (s, 3 H), 1.46 (s, 3 H), 4.02 (s, 3 H), 6.70 (s, 1 H), 7.39 (s, 1 H), 7.47-7.52 (m, 1 H), 7.72 (t, J=7.45 Hz, 1 H), 7.79-7.86 (m, 1 H), 7.93-7.99 (m, 2 H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Ni]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:14][C:15]=1[NH2:16])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1cc(N2CCOCC2)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
A mixture of 4-(3-((tert-butyldimethylsilyloxy)methyl)-4-nitrophenyl)morpholine (4.0 g, 0.11 mol), Raney Ni (1.0 g) in methanol (250 mL) was stirred under an atmosphere of hydrogenated (1.0 atm) at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate was evaporated to give the product 2-((tert-butyldimethylsilyloxy)methyl)-4-morpholinoaniline (3.48 g, yield 95.1%). 1H NMR (400 MHz, CDCl3) δ ppm 6.72-6.76 (m, 2H), 6.62-6.64 (d, 1H, J=8.0 Hz), 4.66 (s, 2H), 3.92 (s, 2H), 3.84-3.86 (t, 4H, J=4.4 Hz), 3.00-3.03 (t, 4H, J=4.8 Hz), 0.90-0.91 (m, 9H), 0.08-0.09 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:12]([NH:13][CH2:14][C:15]([OH:17])=O)=[C:11]([CH3:22])[C:10]=1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:12]([NH:13][CH2:14][C:15]([NH:37][CH:34]2[CH2:35][CH2:36][N:31]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[O:17])=[C:11]([CH3:22])[C:10]=1[CH3:23])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Cc1c(C)c(NC(=O)OC(C)(C)C)c(C)c(C)c1NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C)c(NC(=O)OC(C)(C)C)c(C)c(C)c1NCC(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
A mixture solution of 2.2 g of 2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]acetic acid, 1.67 ml of 1-benzyl-4-aminopiperidine, 10.47 g of 25% propane-phosphonic acid anhydride and 4.76 ml of triethylamine in 40 ml of methylene chloride was stirred over night at room temperature. Then, 20 ml of saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried and concentrated under reduced pressure to give a residue. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to give 2.48 g (73%) of 2-([4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]-N-(1-benzyl-4-piperidinyl)acetamide. Then, a mixture of 438 mg of the compound obtained and 40 mg of 20%-palladium hydroxide on carbon in 4 ml of methanol was stirred for 6 hours under 5 atm of hydrogen. Then, the catalyst was filtered off a Celite (trade name) pad and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=10:1) to give 293 mg (81%) of the above-mentioned compound (21).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=[O:8].I[CH:10]([CH3:12])[CH3:11].O>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH:10]([CH3:12])[CH3:11])[C:6]=1[CH:7]=[O:8]
Reactant: Cc1nc[nH]c1C=O
Reactant: CC(C)I
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncn(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 4-methyl-1H-imidazole-5-carbaldehyde (5.0 g, 45.4 mmol) in anhydrous THF (50 mL) was added diaza(1,3)bicyclo[5.4.0]undecane (DBU, 6.8 mL, 45.4 mmol) and 2-iodopropane (4.5 mL, 45.4 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added. The mixture was extracted with EtOAc (1×50 mL) and 2-butanol (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-2% MeOH/DCM), affording 4-methyl-1-(propan-2-yl)-1H-imidazole-5-carbaldehyde (691 mg, 10% yield).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]([CH:16]1[CH2:21][NH:20][C:19]2[CH:22]=[C:23]([O:26][C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:25][C:18]=2[O:17]1)=[O:15].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]([CH:16]1[O:17][C:18]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:22][C:19]=2[NH:20][CH2:21]1)=[O:15]
Reactant: C#CCO
Reactant: Cc1ccc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(C#CCO)c1
Temperature: 75 °C
Yield: 72.8 %

Procedure:
Prop-2-yn-1-ol (195 mg, 202 μL, 3.48 mmol), N-(2-bromo-4-methyl-phenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (300 mg, 0.69 mmol), PdCl2(PPh3)2 (122 mg, 0.17 mmol), CuI (19.88 mg, 0.10 mmol), and triethylamine (970 μL, 6.96 mmol) were combined in DMF (5 mL) and heated at 75° C. for 18 h. Purification by silica gel chromatography (0-50% ethyl acetate/hexanes) provided N-(2-(3-hydroxyprop-1-ynyl)-4-methylphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (204 mg, 72% yield). LC/MS m/z 407.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1>>[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][C:15]=2[NH2:20])=[O:9])=[CH:5][N:4]=1
Reactant: Nc1ccc(F)cc1N
Reactant: N#Cc1ccc(C(=O)O)cn1
Product: NCc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Yield: 25.9 %

Procedure:
The title compound (135 mg, 52% yield) was prepared as a grey solid from 6-cyano-nicotinic acid (296 mg, 2 mmol) and 4-fluoro-o-phenylenediamine (302 mg, 2.4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 261 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=5)[CH2:32][NH:33]C(OC(C)(C)C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[NH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=1
Reactant: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: NCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(N)CC4)ncc23)n1)c1cccc(Cl)c1

Procedure:
To a solution of crude [4-(3-{2-[2-tert-butoxycarbonylamino-1-(3-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (30 mg, 0.044 mmol) in methanol (40 mL) was bubbled in HCl (gas) for 3 hours at room temperature. Then the mixture was concentrated by evaporation to afford N-(3-{2-[2-amino-1-(3-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-cyclohexane-1,4-diamine; hydrochloride. (Yield 24 mg, 93.3%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[C-:13]#[N:14].[Na+]>C(O)C>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][C:13]#[N:14])=[CH:12][CH:11]=2)[N:6]=[CH:7][CH:8]=1
Reactant: BrCc1ccc2nccnc2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc2nccnc2c1
Temperature: 50 °C
Yield: 28.9 %

Procedure:
To a solution of crude 6-bromomethylquinoxaline (36.0 g) in 95% ethanol (200 mL) was added NaCN (30.9 g, 0.63 mol) at room temperature. The mixture was heated at 50° C. for 3 hours and then concentrated under vacuum. Water (100 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column (Petroleum Ether/EtOAc 10:1) to give 2-(quinoxalin-6-yl)acetonitrile (7.9 g, 23% over two steps). NMR (300 MHz, CDCl3) δ 8.88-8.90 (m, 2H), 8.12-8.18 (m, 2H), 7.74 (dd, J=2.1, 8.7 Hz, 1H), 4.02 (s, 2H). MS (ESI) m/z (M+H)+ 170.0.
Reaction SMILES: C([N:4]1[CH2:26][CH2:25][C:7]2[N:8]([CH2:16][CH:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[OH:18])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.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>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:16][CH:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[OH:18])[C:7]3[CH2:25][CH2:26][NH:4][CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: C=CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2cccnc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cccnc2)CCNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.8 %

Procedure:
2-(2-Allyl-8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-3-yl-ethanol (1.0 g, 2.8 mmol) was dissolved in DCM and the solution was purged with nitrogen for 5 min. 1,3-Dimethylbarbituric acid (1.34 g, 8.6 mmol) and Pd(PPh3)4 (66.5 mg, 0.056 mmol) were added and the reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was basified with saturated aqueous potassium carbonate, and extracted with EtOAc (3×50 mL). The combined organic layer was washed with saturated aqueous potassium carbonate (6×20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse phase chromatography to obtain 50 mg of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-3-yl-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.47 (s, 1H), 8.41 (d, 1H), 7.59 (d, 1H), 7.19 (m, 3H), 7.10 (s, 1H), 7.00 (d, 1H), 5.0 (t, 1H), 4.10 q (d, 2H), 3.92 q (d, 2H), 3.10 (m, 2H), 2.90 (m, 2H), 2.47 (m, 1H), 2.42 (s, 3H). This racemate was separated by chiral semi-preparative HPLC to obtain enantiomers 9a and 9b.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.O.[H][H]>C(O)(=O)C.CN(C=O)C.[Pd]>[NH2:8][C@@H:9]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: N[C@H](/C=C/c1ccc(S(=O)(=O)O)cc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N[C@H](CCc1ccc(S(=O)(=O)O)cc1)Cc1ccccc1

Procedure:
100 mg (0.25 mmol) of 4-[(1E,3S)-3-amino-4-phenylbut-1-en-1-yl]benzenesulphonic acid trifluoroacetate were suspended in 10 ml of acetic acid and a few drops of DMF and water, admixed with 70 mg (0.07 mmol) of palladium on charcoal (10%) and hydrogenated at hydrogen pressure 2.2 bar for 24 h. The solution was filtered and the filtrate purified by prep. HPLC.