Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][PH:6](=[O:9])[O:7]C)(=[O:3])[CH3:2].[I-].[Na+:11]>CC(CC)=O>[C:1]([CH2:4][CH2:5][PH:6](=[O:7])[O-:9])(=[O:3])[CH3:2].[Na+:11]
Reactant: CO[PH](=O)CCC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)CC[PH](=O)[O-]

Procedure:
Methyl acetylethylphosphinate (6 g)was reacted with sodium iodide (6.0 g) in ethyl methyl ketone (50 ml) in the same manner as in Example 12. The solution was stirred and refluxed 1.25 hours, cooled and the product filtered off and washed with a little ethyl methyl ketone and dried in vacuo (5.3 g). Decomposes 192°-4°.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].O.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N>[F:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[C:12]#[N:13]
Reactant: CN(C)C=O
Reactant: OCc1ccc(Br)c(F)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc(CO)cc1F
Temperature: 95 °C
Reaction time: 0.25 h

Procedure:
4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol) was dissolved in DMF (100 mL) and then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95° C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([Li])CCC.Cl[CH2:13][C:14]1[CH:30]=[CH:29][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[O:19])=[CH:16][CH:15]=1.C1COCC1>CCOCC.O>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:30][CH:29]=1
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reactant: C1COCCN1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.2 %

Procedure:
In an atmosphere of argon, morpholine (192 mg, 2.2 mmol) was dissolved in ether (5 ml) to which, with cooling in an ice bath, was subsequently added n-butyl lithium (1.45 ml, 1.52M, 2.2 mmol). After 5 minutes of stirring at room temperature, to this was added 4-chloromethyl-N-(2-methoxyphenyl)benzamide (276 mg, 1.0 mmol) at the same temperature. After adding THF (5 ml) and stirring for 2.5 hours at 60° C., the reaction solution was mixed with water (20 ml) and extracted with ethyl acetate. After removing insoluble materials by filtration, the organic layer was washed with water and saturated brine and then dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by subjecting it to a silica gel column chromatography (ether) to obtain 128 mg (39.2%) of the title compound in the form of light yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](=[C:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](=[C:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(C(=C2CCNCC2)c2cccs2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(=C(c2ccccc2)c2cccs2)CC1
Yield: 84 %

Procedure:
The title compound was prepared in a yield of 84% in a similar manner to that described in Preparation 1' by reacting N-(3-bromopropyl)phthalimide and 4-[α-(2-thienyl)benzylidene]piperidine.
Reaction SMILES: C([C:8]1[C:9]([OH:30])=[C:10]([C:14]([C:16]2[CH:21]=CC=[C:18]([CH2:22][C:23]3[CH:28]=[CH:27]C=CC=3)[C:17]=2O)=[O:15])[CH:11]=[CH:12][CH:13]=1)C1C=CC=CC=1.C(N)=O>O>[O:30]1[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:8]=2)[C:14](=[O:15])[C:16]([C:17]2[CH:18]=[CH:22][CH:23]=[CH:28][CH:27]=2)=[CH:21]1
Reactant: O=C(c1cccc(Cc2ccccc2)c1O)c1cccc(Cc2ccccc2)c1O
Solvent: O
Solvent: NC=O
Product: O=c1c(-c2ccccc2)coc2ccccc12
Yield: 21.7 %

Procedure:
Benzyl-2-hydroxyphenyl ketone (29.0 g) and formamide (29.0 g). were heated together at 208° for 1 hr. The reaction mixture was cooled and diluted with water. The oily product was extracted into chloroform and the solution washed with water, dried and evaporated. The residue was chromatographed on alumina, eluting with toluene, and the product recrystallised once from petroleum ether (80°-100°) and once from toluene to yield isoflavone (3.55 g), m.pt. 132°-134°
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1>>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:33]5[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnc(N)nc4)cc2OCC3)n(C(C)C)n1

Procedure:
8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine to give 257. MS (ESI+) 403.2
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[N:16]=[CH:15][C:14]4[N:20]([CH3:31])[C:21](=[O:30])[N:22]([C:23]5[C:24]([Cl:29])=[N:25][N:26]([CH3:28])[CH:27]=5)[C:13]=4[C:12]=3[CH:11]=2)[CH:7]=[N:6][C:5]=1[O:32][CH3:33].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:29][C:24]1[C:23]([N:22]2[C:13]3[C:12]4[CH:11]=[C:10]([C:8]5[CH:7]=[N:6][C:5]([O:32][CH3:33])=[C:4]([CH2:3][OH:2])[CH:9]=5)[CH:19]=[CH:18][C:17]=4[N:16]=[CH:15][C:14]=3[N:20]([CH3:31])[C:21]2=[O:30])=[CH:27][N:26]([CH3:28])[N:25]=1
Reactant: COC(=O)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cnc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cc1CO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-[1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinic acid methyl ester (stage 200.1, 0.176 mmol) in THF (2 ml) cooled with an ice-bath was added dropwise a 1 M solution of LiAlH4 in THF (0.150 mmol). The reaction mixture was stirred for 1 h 15 min at rt, then quenched with water, diluted with EtOAc and filtered over Celite. The filtrate was washed with saturated aqueous NaHCO3, with water, with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in MeOH/TFA and purified by preparative HPLC. The fractions containing pure product were basified with NaHCO3 and concentrated. The precipitate was filtered, washed with water (2×) and dried under vacuum to give the title compound as a white solid. (HPLC: tR 2.53 min (Method A); M+H=451 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.41 (s, 1H), 8.30-8.27 (m, 1H), 8.14-8.10 (m, 1H), 7.98-7.93 (m, 1H), 7.84-7.81 (m, 1H), 7.53-7.50 (m, 1H), 5.32 (t, 1H), 4.51 (d, 2H), 4.01 (s, 3H), 3.92 (s, 3H), 3.59 (s, 3H))
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[NH:2]2.[H-].[Na+].Cl[C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=2)[N:14]=1>C1COCC1.CN(C=O)C>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:25][CH3:26])[N:14]=[C:13]([N:2]1[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][CH:1]1[CH2:6][CH2:5]3)[CH:22]=[N:21]2
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: O=C1NC2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncc(N3C(=O)C4CCC3CC4)nc2cc1OC
Temperature: 80 °C
Yield: 34.9 %

Procedure:
2-Azabicyclo[2.2.2]octan-3-one (228 mg, 2.3 mmole) is dissolved in a mixture of THF/DMF (5 mL/3 mL) and treated with NaH (60%, 184 mg, 4.6 mmole). The resulting mixture is heated at 60° C. for 0.5 hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (344 mg, 1.5 mmole). After being heated at 80° C. overnight, the reaction mixture is concentrated. The residue is chromatographed on silica gel (50% ethyl acetate/hexane) to give 164 mg (23%) of a yellow solid (m.p. 158-159° C.).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH:31]([CH3:34])[CH:32]=O)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH:31]([CH3:34])[CH2:32][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:4]3[C:3]([CH3:2])=[C:11]4[C:7](=[CH:6][CH:5]=3)[C:8](=[O:12])[O:9][CH2:10]4)[CH2:16][CH2:17]2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: COc1cc(C(C)C=O)ccc1C#N
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: COc1cc(C(C)CN2CCN(CCc3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
2-Methoxy-4-[1-methyl-2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(1-oxopropan-2-yl)benzonitrile. LC-MS (IE, m/z): 434.5 [M+1]+. (0.15 μM)
Reaction SMILES: [Cl-].[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Zn+].Cl[C:9]1[N:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH:12]=[N:11][C:10]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C1COCC1.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>[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:9]1[N:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH:12]=[N:11][C:10]=1[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1
Reactant: [Zn+]c1ncco1
Reactant: O=C(Nc1cnc(-c2ccncc2)c(Cl)n1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(Nc1cnc(-c2ccncc2)c(-c2ncco2)n1)C1CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
(1,3-Oxazol-2-yl)zinc chloride (0.33M in THF, 9.3 mL, 3.06 mmol) was added to a solution of N-(6-chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide (Preparation 8, 280 mg, 1.02 mmol) in THF (2 mL) and the mixture was degassed Pd(PPh3)4 (118 mg, 0.102 mmol, 10 mol %) was added and degassing was repeated. The reaction mixture was heated to 90° C. in a sealed tube and stirred overnight. The mixture was cooled and more (1,3-oxazol-2-yl)zinc chloride (0.33M, 5.0 mL, 1.65 mmol) and Pd(PPh3)4 (90 mg, 8 mol %) were added and the mixture was degassed and heated to 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was purified by flash silica gel chromatography (dichloromethane/methanol 98:2) to give the title compound (80 mg, 26%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=3)[N:23]=2)[CH:15]=1)[OH:13].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=3)[N:23]=2)[CH:15]=1)=[O:13]
Reactant: COC(=O)c1ccccc1SCC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1SCC(=O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a stirred solution of hydroxy compound 46 (10.0 g, 0.021 mol) in dichloromethane (100 ml) was added in single lot pyridinium chlorochromate (13.44 g, 0.035 mol) and allowed to stir at ambient temperature for 2 hours. The resulting mixture was filtered through a bed of highflow. The residue was washed with dichloromethane (500 ml). The combined filtrate layer was evaporated and subjected to FC to give pale yellow solid 47 (8.0 g, 80%).
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:25][CH:24]=2)[N:13]=1.[H][H]>CN(C=O)C.[OH-].[OH-].[Pd+2].CCOC(C)=O>[NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:27][CH:28]=2)[N:13]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.5 %

Procedure:
tert-Butyl 2-(4-((4-((2-(2-amino-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I40) (0.120 g, 0.207 mmol) was dissolved in dry DMF (5 mL) under an atmosphere of nitrogen. 20% Pearlman's catalyst (0.060 g) in EtOAc (5 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 20 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a pale yellow gum which was purified by silica gel chromatography (Biotage, Isolera 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I41) (0.090 g, 74% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1H), 8.67 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.43 (s, 1H), 7.26-7.21 (m, 1H), 7.20-7.09 (m, 5H), 6.89 (s, 1H), 5.31-5.19 (m, 1H), 3.92 (d, J=13.2 Hz, 1H), 3.49 (s, 2H), 3.16-2.98 (m, 4H), 2.71 (t, J=11.8 Hz, 1H), 2.29 (d, J=13.2 Hz, 1H), 1.75 (t, J=11.0 Hz, 1H), 1.58-1.50 (m, 2H), 1.46-1.23 (m, 11H). LCMS Method C: rt 6.59 min; m/z 584.3 [M+H]+.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][C:45]1[S:46][C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)=[CH:48][N:49]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][CH2:44][C:45]1[S:46][C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:53]=[N:52]2)=[CH:48][N:49]=1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: COCc1ncc(Cn2ncc(N)n2)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCc1ncc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (70.0 mg, 0.32 mmol) in CH2Cl2 (1.5 mL) was treated at rt with DMAP (9.8 mg, 0.08 mmol), HOBt (52 mg, 0.39 mmol), EDC (154 mg, 0.81 mmol) and DIPEA (0.22 mL, 1.3 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 2-((2-(methoxymethyl)thiazol-5-yl)methyl)-2H-1,2,3-triazol-4-amine (73 mg, 0.32 mmol) in CH2Cl2 (1.5 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (5.0 mL), the layers were separated and the org. phase was washed with water (5.0 mL) dried over Na2SO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil: TLC: rf (4:6 hept-EA)=0.29. LC-MS-conditions 07: tR=0.94 min, [M+H]+=425.09.
Reaction SMILES: C([N:8]([CH2:16][CH:17]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:8][CH2:16][CH:17]1[CH2:26][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:18]1
Reactant: C1=C(c2ccccc2)c2ccccc2OC1CN(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: NCC1CC(c2ccccc2)c2ccccc2O1

Procedure:
2-(N,N-dibenzylaminomethyl)-4-phenyl-3-chromene (2.2 g) was hydrogenated at 651b in -2 in glacial acetic acid in the presence of 5% palladium on carbon (15 mg) until no more hydrogen was taken up. After filtration and removal of solvent in vacuo the residue was treated with ethereal HBr and the resulting solid recrystallised from ethanol/ether to give the title compound as the hydrobromide salt (0.9 g), mp 243°-245° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[Br:8][C:9]1[C:17]2[N:16]([CH3:18])[C:15]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[N:26]=[CH:27][NH:28][C:29]=4[CH3:30])[C:22](=[O:23])[C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:9]1[C:17]2[N:16]([CH3:18])[C:15]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[N:26]=[CH:27][N:28]([S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:29]=4[CH3:30])[C:22](=[O:23])[C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(Br)c3n2C)C1=O
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CN2CCc3c(c4cccc(Br)c4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Reaction time: 60 h

Procedure:
Dimethylsulphamoyl chloride (0.31 ml) was added dropwise to a stirred suspension of 6-bromo-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl) methyl]-1H-pyrido[4,3-b]indol-1-one (1.1 g) and triethylamine (0.48 ml) in dry dichloromethane (100 ml). The mixture was heated at reflux for 18 h, then a further quantity of triethylamine (0.48 ml) and dimethylsulphamoyl chloride (0.31 ml) was added. The solution was heated at reflux for 8 h then left at 21° for ca. 60 h. The solution was concentrated in vacuo and purified by FCC eluting with System A (100:8:1) to give a solid, which was triturated with hexane (50 ml) to give the title compound (500 mg), m.p. 182°-185°.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9]([C:12]([OH:14])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[N:10]=[N:11][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: O=C(O)c1ccc(-n2cccn2)nn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccc(-n2cccn2)nn1
Yield: 26 %

Procedure:
6-(1H-pyrazol-1-yl)pyridazine-3-carboxylic acid (100 mg, 0.53 mmol) was coupled with (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile as described in Example 34(d). Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-100% EtOAc in heptane; 2nd column: silica, eluent: 0-15% MeOH in DCM) to obtain 54 mg (26%) of the title compound. 1H-NMR (400 MHz; DMSO): δ 1.23 (d, 3H), 4.35-4.50 (m, 2H), 4.51-4.64 (m, 1H), 6.75 (dd, 1H), 6.94 (d, 1H), 7.87 (d, 1H), 7.92-7.98 (m, 2H), 8.03 (dd, 2H), 8.30 (m, 2H), 8.87 (d, 1H), 9.38 (d, 1H).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[F:14][C:15]([F:35])([F:34])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([O:29][Si](C)(C)C)C#CC(OC)=O)=[CH:18][CH:17]=1.CC(O)C>CC(C)=O>[F:14][C:15]([F:34])([F:35])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:29])=[CH:18][CH:17]=1
Reactant: COC(=O)C#CC(O[Si](C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Under cooling in an ice-bath, a 8N Jones' reagent (50 ml) was added dropwise to a solution of the crude product of silyl ether 8a obtained above in 170 ml of acetone over 15 minutes. After completion of the addition, the mixture was stirred for 35 minutes and then 11.4 ml (150 mmoles) of 2-propanol was added. The mixture was allowed to warm to room temperature while being stirring for 1 hour. The reaction mixture was filtered and the residual chromium sulfate was washed with acetone. The washing was combined with the reaction mixture, and the mixture was concentrated in vacuo. The residue was dissolved in 40 ml of ethyl acetate, 150 ml of water and 120 ml of n-hexane were added to the solution, and then the solution was extracted. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. n-Hexane (80 ml) was added to the residue, the insoluble materials were filtered off, the filtrate was concentrated in vacuo and the residue was dried in vacuo at 40° C. for 30 minutes with stirring to give 21.6 g (84.6% from compound 7a) of the crude product of the desired compound III-a as an oil. When this was stored in a refrigerator overnight, it gave crystals with low melting point. However, this was used in the next reaction without further purification. Melting point: 28°-29° C. (methanol).
Reaction SMILES: [C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]#1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+].[F-].[Cs+]>CC#N>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:22])[C:16]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=1
Reactant: c1ccccc#1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
To the stirred solution of benzyne precursor 1 (100 mg, 0.33 mmol) and malonamide ester 2 (40 mg, 0.16 mmol) in anhydrous MeCN (2 mL) was added NaHCO3 (28 mg, 0.33 mmol), CsF (200 mg, 1.34 mmol). Reaction mixture was allowed to stir at room temperature 30° C. for 48 hrs. The reaction mixture was concentrated in vacuo and directly loaded on silica gel and purified by using gradient solvent combination of ethyl acetate/Pet ether to yield a low melting solid compound 4 (43 mg, 65%).