Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[C:5]([CH3:8])[CH2:6][CH3:7])[CH2:3][CH3:4].[CH3:9][SiH:10]([CH3:12])[Cl:11].[Al+3].[Cl-].[Cl-].[Cl-]>>[CH2:3]([C:2]([Si:10]([CH3:12])([CH3:9])[Cl:11])([CH3:1])[CH:5]([CH2:6][CH3:7])[CH3:8])[CH3:4]
Reactant: CCC(C)=C(C)CC
Reactant: C[SiH](C)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(C)C(C)(CC)[Si](C)(C)Cl

Procedure:
According to Example 2, 200 mg of 3,4-dimethylhex-3-ene, 0.2 ml (1.8 mmol) of dimethylchlorosilane and 50 mg (0.37 mmol) of AlCl3 are reacted and the product is worked up. This gives 180 mg (50% of theory) of colourless liquid of boiling point=95°-97° C./0.26 mbar.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CN1CCCC1=O.CCN(CC)CC>[Cu]I.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>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.6 mmol), CuI (141 mg, 0.74 mmol), Pd(PPh3)4, (367 mg, 0.32 mmol) and 2-Methyl-3-butyn-2-ol (1.5 mL, 15.8 mmol) was added 1-methyl-2-pyrrolidone (20 mL) followed by Et3N (6 mL, 22 mmol). After stirring for 4 h 30 min at room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel (EtOAc/Hexanes, 2:98, then 5:95) to provide 4-(5-chloro-3-nitro-pyridin-2-yl)-2-methyl-but-3-yn-2-ol. MS m/z: 241.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:27][C:26]([F:29])([F:28])[C@:25]([C:23]1[N:22]=[N:21][N:20]([CH2:19][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[CH:11][C:2]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=1)([OH:32])[CH2:30][CH3:31]
Reactant: OB(O)c1ccccc1
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(-c4ccccc4)nc3c2)nn1)C(F)(F)F

Procedure:
To a solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (100 mg, 0.22 mmol) in DME (5 mL) was added Pd(PPh3)4 (12 mg, 0.01 mmol), phenylboronic acid (34 mg, 0.29 mmol) and sodium carbonate (2M, 0.2 mL, 0.44 mmol). The mixture was refluxed for 14 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 1:9) gave the title compound. MS (+ESI): 507. (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](Cl)=[O:5].N1C=CC=CC=1.[OH:13][C:14]1[CH2:19][CH:18]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[CH2:17][C:16](=[O:29])[CH:15]=1.ClCCl>O>[C:4]([C:15]1[C:14](=[O:13])[CH2:19][CH:18]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[CH2:17][C:16]=1[OH:29])(=[O:5])[CH2:3][CH2:2][CH3:1]
Reactant: CCCC(=O)Cl
Reactant: Cc1cc(C)c(C2CC(=O)C=C(O)C2)c(C)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
n-Butyryl chloride (2.3 g; 21.7 mmole) and then pyridine (1.7 g; 21.7 mmole) were added to a stirred mixture of 3-hydroxy-5-mesitylcyclohex-2-en-1-one (5.0 g; 21.7 mmole) and dichloromethane (50 ml) under a nitrogen atmosphere. The mixture was stirred at room temperature for a period of two hours and then poured into slightly acidic water. The organic phase was separated and the aqueous phase was thoroughly extracted with dichloromethane. The combined organic phase and extracts were washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The residue was dissolved in 1,2-dichloroethane (50 ml), stannic chloride (5.7 g; 22 mmole) was added and the mixture was heated under reflux for a period of 8 hours. The mixture was cooled and poured into water and the aqueous mixture was extracted several times with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The residue was purified by chromatography over silica gel (eluant dichloromethane) to give 2-butyryl-3-hydroxy-5-mesitylcyclohex-2-en-1-one (2.4 g). Proton nuclear magnetic resonance spectrum (CDCl3 : δ in ppm): 1.01 (3H, t); 1.30-1.60 (2H, m); 2.23 (3H, s); 2.37 (6H, s); 2.40-3.45 (7H, m); 6.83 (2H, s); 18.24 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:11])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:11])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)(CCc1cccs1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(CCc1cccs1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
2-Methyl-2-(2-thienyl)ethylmalonic acid diethylester (52.7 g, 0.19 mol) obtained in Example 1(a) was dissolved in a mixture of ethanol (240 ml) and water (80 ml), potassium hydroxide (11.4 g, 0.20 mol) was added thereto in an ice bath, and the solution was stirred for 2 hours. And then potassium hydroxide (5.7 g, 0.1 mol) was added thereto three times, one portion every 1 hour, and the reaction solution was stirred for 6 hours in total. Water (300 ml) and ice-cold 10% hydrochloric acid (500 ml) were added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=2:1-0:1) to afford the title compound (28.6 g, 60% yield) as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34]>>[F:34][C:28]1[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1cccc(OCCCBr)c1F
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(F)c3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.776 g of 1-(3-bromopropoxy)-2,3-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.11 (1:2 EtOAc-heptane); Rt=5.13.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[CH:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1>>[N:33]12[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34]1)[CH:31]([N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]1=[O:22])[CH2:32]2
Reactant: OC1CN2CCC1CC2
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CN2CCC1CC2

Procedure:
(5Z)-3-(1-Azabicyclo[2.2.2]oct-3-yl)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 3-hydroxy-1-azabicyclo[2.2.2]octane following General Procedure J.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH:23]=[C:22]([S:24](Cl)(=[O:26])=[O:25])[N:21]=[CH:20]1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH:15][S:24]([C:22]2[N:21]=[CH:20][N:19]([CH3:18])[CH:23]=2)(=[O:26])=[O:25])[C:9]=1[F:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(N)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(NC(=O)OC(C)(C)C)c2F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
The tert-butyl-3-amino-2,6-difluorophenylcarbamate (50 mg, 0.20 mmol) prepared at Step 3 was added and dissolved into dichloromethane solvent. 1-methyl-1H-imidazole-4-sulfonyl chloride (44 uL, 0.25 mmol) and pyridine (50 uL, 0.61 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 74 mg of the target compound, tert-butyl-2,6-difluoro-3-(1-methyl-1H-imidazole-4-sulfonamido)phenylcarbamate (percentage yield: 95%), was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O.[F:30][S:31]([F:50])([F:49])([F:48])([F:47])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([CH2:41][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[CH:40]=1)[C:35](O)=[O:36]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:35](=[O:36])[C:34]2[CH:38]=[C:39]([CH2:41][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:40]=[C:32]([S:31]([F:50])([F:49])([F:48])([F:30])[F:47])[CH:33]=2)=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1
Reactant: O=C(O)c1cc(CN2CCCC2)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(CN3CCCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
45 mg (0.16 mmol) of the compound of Example 6A and 70 mg (0.16 mmol) of the compound of Example 38A were reacted analogously to the procedure of Example 16, except that here the reaction was, after the reaction had ended, directly separated into its components by preparative HPLC (Method 15). The product-containing fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 48 mg (51% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][N:16]=[C:17]3[CH2:22][CH2:21][N:20]([C:23]4[C:28]([F:29])=[CH:27][C:26]([CH2:30][C:31]([OH:33])=O)=[C:25]([F:34])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1.C1C=CC2N(O)N=NC=2C=1.CO>ClCCCl>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([O:15][N:16]=[C:17]3[CH2:22][CH2:21][N:20]([C:23]4[C:28]([F:29])=[CH:27][C:26]([CH2:30][C:31]([NH:35][CH:36]5[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]5)=[O:33])=[C:25]([F:34])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC(ON=C3CCN(c4cc(F)c(CC(=O)O)cc4F)CC3)CC2)nc1
Reactant: CN1CCC(N)CC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCCl
Product: CCc1cnc(N2CCC(ON=C3CCN(c4cc(F)c(CC(=O)NC5CCN(C)CC5)cc4F)CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound 77e (9 mg, 0.019 mmol) was dissolved in DCE (0.5 mL) and 4-amino-1-methylpiperidine (0.01 mL) was added followed by HOBt (4 mg, 0.03 mmol) and EDC (12 mg, 0.06 mmol) and stirred at r.t. for 16 h. MeOH was added and the mixture purified by HPLC to give 2-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-piperidin-1-yl}-2,5-difluoro-phenyl)-N-(1-methyl-piperidin-4-yl)-acetamide 77-1. LC-MS 570.2 (MFE).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[N:3]=[C:4]3[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[CH:7]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reaction time: 1 h

Procedure:
A mixture of 1 g of (8S)-2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one and of 15 mL of morpholine is heated to 80° C. After one hour and a half of heating and after monitoring with LC/MS, the reaction is completed. After cooling, the reaction mixture is concentrated under reduced pressure. On the obtained residue, 10 mL of cold water and 100 mL of ethyl acetate are added. The resulting organic phase is separated and then dried on magnesium sulfate, filtered and concentrated under reduced pressure in order to obtain 1.2 g of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one including the following characteristics:
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:14][CH:13]=1)[C:9]#[C:10][CH3:11])C.Cl>C(O)C.O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:8]([C:9]#[C:10][CH3:11])[CH2:7][C:6]([OH:36])=[O:5])=[CH:17][CH:16]=1
Reactant: CC#CC(CC(=O)OCC)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC#CC(CC(=O)O)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
2N KOH(aq) was added to a solution of 18.3 (304 mg, 0.65 mmol) in ethanol (5 mL). The reaction was stirred at room temperature overnight and then taken up in copious water. The aqueous solution was adjusted to pH=2.0 with 1N HCl(aq) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (40% ethyl acetate in Hexanes+0.1% AcOH) to yield 150 mg (52%) of compound 18 as a glass. LC/MSD m/e: 444.0 (M+H); 1H NMR (400 MHz) (acetone) ∂ 8.21 (2H, m), 7.89 (2H, d, J=8.0 Hz), 7.38 (2H, m), 7.03 (2H, m), 5.06 (2H, s), 4.06 (1H, m), 2.70 (2H, m), 2.52 (3H, s), 1.81 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[CH2:27].C(N(CC)CC)C>CN(C=O)C.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>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:26]=[CH:27][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccccn1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(C=Cc2ccccn2)cc1-3
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), 2-vinylpyridine (54 mg, 0.6 mL, 0.51 mmol) and triethylamine (0.5 mL) in DMF (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (30 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 48 h. The mixture was cooled to ambient temperature, filtered through a pad of Celite®, then the solvent was concentrated at reduced pressure. The product was triturated with MeOH to give 90 mg (84%) of Compound I-31 as a yellow solid, purification by column chromatography (silica gel, EtOAc:MeOH, 9:1), mp>320° C. 1H NMR (DMSO-d6, 300 MHz): δ 4.2 (s, 2H), 5.0 (s, 2H), 7.2-7.42 (m, 4H), 7.58-7.7 (m, 4H), 7.8-7.95 (m, 2H), 8.3 (s, 1H), 8.6 (d, 1H, J=6 Hz), 8.63 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.1 (s, 1H). MS(FAB): m/e 414 (m+1)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]=[CH:7][O:6]1.[H][H].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCCCC.O1CCCC1.O>[O:6]1[CH:7]=[CH:8][CH2:9][CH2:10][CH:5]1[CH2:4][O:3][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: OCC1CCC=CO1
Reactant: CCOC(=O)CBr
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)COCC1CCC=CO1
Yield: 62.5 %

Procedure:
In a dried round bottomed flask under argon atmosphere, 60% sodium hydride (240 mg, 6.0 mmol) was rinsed three times with anhydrous n-pentane. A solution of 2-hydroxymethyl-3,4-dihydro-2H-pyran (570.8 mg, 5 mmol) in tetrahydrofuran (10 ml) was cooled at 0° C. and then added to the NaH. The reaction mixture was stirred at 0° C. until hydrogen evolution ended. A solution of ethyl bromoacetate (1253 mg, 7.5 mmol) in tetrahydrofuran (6 ml) was added to the reaction mixture and the stirring was continued at room temperature until disappearance of the starting alcohol (TLC analysis). After cooling, H2O was added, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (AcOEt:hexane=1:12) on silica gel (230-400 mesh), affording 626 mg (yield 57%) of ethyl (3,4-dihydro-2H-pyran-2-ylmethoxy)acetate as a colorless oil; 1H NMR (401 MHz, DMSO-d6) δ ppm 1.18-1.23 (m, 3H) 3.55-3.59 (m, 2H) 3.93 (m, J=10.08, 5.11, 5.11, 2.38 Hz, 1H) 4.13 (q, J=7.07 Hz, 2H) 4.14 (s, 2H) 4.67 (dddd, J=6.14, 4.83, 2.56, 1.34 Hz, 1H) 6.36 (dt, J=6.13, 1.75 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].C([O:8][C:9](=O)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]([F:24])[CH:13]=1)[CH3:11])C.C(O)(C)C>O1CCCC1>[F:24][C:14]1[CH:13]=[C:12]([CH:10]([CH3:11])[C:9](=[O:8])[CH2:4][C:3]#[N:5])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC#N
Reactant: CCOC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C(=O)CC#N)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 55 %

Procedure:
After 60% sodium hydride (6.5 g, 0.163 mmol) was suspended in tetrahydrofuran under nitrogen atmosphere, the mixture was refluxed for 0.5 h, then added dropwise acetonitrile (7.6 g, 0.185 mol) and ethyl-2-(2-fluoro-4-biphenylyl)-propionate described above in tetrahydrofuran (100 ml). After refluxed for 2 h, the mixture was cooled at room temperature and added isopropylalcohol. After stirring for a while, the mixture was evaporated under reduced pressure to a residue, which was made acid with 2N hydrochloric acid and extracted with chloroform. The extracts were washed with water, dried over, and evaporated under reduced pressure to a residue, which was chromatographed and recrystallized with ethanol to afford 4-(2-fluoro-4-biphenylyl)-3-oxo-pentanenitril (18.0 g, 55% yield) as pale yellow crystalline material: mp 84°-85° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11](N)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1.Cl.N([O-])=[O:23].[Na+].S(=O)(=O)(O)O>O>[OH:23][C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[CH:16]=[CH:17][C:5]([CH:4]([CH3:19])[C:3]([OH:2])=[O:20])=[CH:6][C:7]=3[CH2:15]2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)Cc1cc(N)ccc1-2
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cc(O)ccc1-2

Procedure:
The ester is dissolved in water (300 ml) containing concentrated HCl (11ml) with the aid of heat. The solution is cooled to 3°, stirred and treated dropwise with a solution of sodium nitrite (2.84 g) in water (15 ml) over a 30 minute period. The resulting diazonium solution is then added dropwise over a 1 hour period to boiling water (800 ml) containing concentrated sulfuric acid (13 ml), and then stirred for 30 minutes and cooled. The precipitate is collected by filtration and heated in 10% aqueous potassium hydroxide containing charcoal for 1 hour, cooled and acidified with 4N HCl. The solid is collected by filtration to give 8.0 g, mp 205°-207° of the tilted product. The analytical sample is prepared by sublimation, mp 218°-219°.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[Cl:12][C:13]1[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)[CH:21]=2)=[O:18])=[CH:15][C:14]=1I>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[C:22]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)[CH:21]=2)=[O:18])=[CH:36][C:37]=1[C:2]#[C:1][C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#Cc1cnc2cccnn12
Product: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(C#Cc4cnc5cccnn45)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The title compound was obtained as a light yellow solid. Mp: 153-154° C.; 1H NMR (300 MHz, CDCl3) δ: 9.35 (1 H, s), 8.48-8.49 (1 H, d, J=3.6 Hz), 8.25 (1 H, s), 8.15 (2 H, brs), 7.89-7.92 (4 H, m), 7.57-7.60 (1 H, d, J=8.4 Hz), 7.37 (1 H, s), 7.12-7.16 (1 H, dd, J=4.2 and 9.3 Hz), 2.27 (3 H, s). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C26H18ClF3N6O: 261.0586. found: 261.0584.