Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.O=S(Cl)Cl.N1C=CC=CC=1.Cl>C1COCC1>[C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: COc1cccc(C2(O)CCCCC2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc(C2=CCCCC2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 1L 3-neck RBF under argon was charged with crude 1-(m-methoxyphenyl)cyclohexanol (59.2 g, 287 mmol). To the flask was added 592 mL of dry THF. The reaction was cooled to 0° C., and to it was slowly added SOCl2 (58.6 mL, 803.6 mmol). After stirring for 10 minutes, pyridine (104 mL, 1.29 mol) was added slowly. The reaction mixture stirred slowly at 22° C. for 2 hours, and then it was cooled back to 0° C. 1N HCl (500 mL) was slowly added to the reaction. The layers were separated. The THF layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was chromatographed using 100% hexane as eluent to provide 39.5 g (82%, 2 steps) of product. 1H NMR (CDCl3) δ1.72 (m, 2H), 1.83 (m, 2H), 2.24 (m, 2H), 2.45 (m, 2H), 3.86 (s, 3H), 6.18 (m, 1H), 6.83 (dd, J=8.1, 1.7 Hz, 1H), 6.98 (m, 1H), 7.03 (d, J=6.1 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
To a mixture of 2-chloro-4-fluorobenzaldehyde (20.0 g, 0.13 mol, Aldrich) and malonic acid (26.2 g, 0.25 mol, Aldrich) in pyridine (100 ml) at 50° C. was added dropwise piperidine (10 ml). After 18 h at 70° C., the mixture was poured into an ice cold solution of concentrated HCl (120 ml) and water (1.5 L). The resulting solid was filtered and washed repeatedly with water to give 24.4 g (96%) of 2-chloro-4-fluoro-cinnamic acid as a white solid: Recrystallization of 1.5 g from acetone:water mixtures gave 1.1 g of 2-chloro-4-fluorocinnamic acid as a white solid: mp 243°-245° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14](S(C2C=CC=CC=2)(=O)=O)[C:13]2[C:8](=[N:9][C:10]([N:24](C(OC(C)(C)C)=O)[NH:25][C:26](OC(C)(C)C)=O)=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].[CH3:42]C(O)=O>>[CH3:42][C:26]1[N:9]2[C:8]3[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[NH:14][C:13]=3[CH:12]=[CH:11][C:10]2=[N:24][N:25]=1
Reactant: CCOC(=O)c1cc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nnc2ccc3[nH]c(C(=O)O)cc3n12
Temperature: 180 °C
Yield: 50 %

Procedure:
A solution of di-tert-butyl 1-[2-(ethoxycarbonyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (2.11 g, 3.76 mmol, from Step 2) in AcOH (32 mL) was split into four portions and each was heated in the microwave to a temperature of 180° C. for 3 minutes. The reaction contents were pooled and the AcOH was removed in vacuo. The residue was azeotroped with toluene twice. The residue was reconstituted in EtOH (10 mL) and was treated with 1.0 M NaOH (10 mL, 10 mmol) overnight. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product (0.42 g, 50%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]=[CH:10][N:9]([C:12]3[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH:17]=3)[C:6]2=[N:7][CH:8]=1)#[CH:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C.[Cu](I)I>[NH:30]1[CH:2]=[C:1]([C:3]2[CH:4]=[C:5]3[N:11]=[CH:10][N:9]([C:12]4[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=5[F:25])[CH:17]=4)[C:6]3=[N:7][CH:8]=2)[N:32]=[N:31]1
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1cnc2c(c1)ncn2-c1cc(NC(C)=O)cc(-c2ccc(F)cc2F)c1
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4c[nH]nn4)cnc32)c1
Yield: 90 %

Procedure:
A mixture N-(5-(6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (300 mg, 0.77 mmol), sodium azide (75 mg, 1.15 mmol, 1.5 eq.), copper iodide (14 mg, 0.07 mmol, 0.1 eq.) in DMF was stirred for 16 h at RT. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product which was purified by preparative HPLC to give the product in 90% yield (300 mg).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A solution of (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.54 g, 1.00 mmol) in dichloromethane (10 mL) and methanol (10 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (0.04 g, 0.21 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane gradient) afforded (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.38 g, 78%) as a light, yellow solid: HR-ES-MS m/z calculated for C23H27N4O5F3 [M+H]+ 497.2007, observed 497.2007; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 1.36-1.54 (m, 1H), 1.54-1.64 (m, 1H), 1.70-1.84 (m, 1H), 3.22-3.32 (m, 2H), 3.72-3.81 (m, 1H), 3.87 (dd, J=13.6, 7.7 Hz, 1H), 4.09 (dd, J=13.6, 4.0 Hz, 1H), 4.21 (d, J=18.3 Hz, 1H), 4.60 (d, J=18.3 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 4.86-4.96 (m, 3H), 6.42 (d, J=2.1 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.65-7.74 (m, 3H), 7.75 (s, 1H), 10.76 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C[N:28]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][N:28]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1[N+](=O)[O-])C(=O)O
Product: CC(C)(C)OC(=O)NC(CNc1ncccc1N)C(=O)O

Procedure:
was prepared by a similar method to (2S) 2-tert-Butoxycarbonylamino-3-(2-aminophenylamino)-propionic acid in Step B of the synthesis of 600a/103 to give 3.68 g (quant.) as a dark solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[CH2:42](I)[CH2:43][CH3:44]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([CH2:42][CH2:43][CH3:44])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Reactant: CCCI
Product: CCCc1cc2ccn3c(=O)c(-c4ccc(OCc5ccccc5)cc4)cc(C(=O)N(CCOC)c4ccccc4)c3c2s1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with propyl iodide.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:33])[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:11][C:5]=2[S:4]1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:33][C:3]1([CH3:2])[S:7][C:6]2[CH:8]=[CH:9][C:10](/[C:12](/[CH3:13])=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:11][C:5]=2[S:4]1
Reactant: CC(c1ccc2c(c1)SC(C)(C)S2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Br-]
Product: C/C(=C\c1ccccc1)c1ccc2c(c1)SC(C)(C)S2

Procedure:
In analogy to Example 45, by reacting [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide with benzaldehyde, there was obtained 2,2-dimethyl-5-[(E)-α-methylstyryl]-1,3-benzodithiol, melting point 57°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10](C(OCC)=O)([CH2:24][C:25]([OH:27])=[O:26])[N:9]=2)=[CH:4][CH:3]=1.C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C=CN=C4C=CC=CC=34)N(CC2)C1.C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25]([OH:27])=[O:26])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(CC(=O)O)N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Reaction time: 8 h

Procedure:
(±)-4-(4-Chlorophenyl)-6-ethoxycarbonyl-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (82 g) and cinchonidine (50 g) are thoroughly dissolved in methanol (1 l), and the solvent is distilled away to give an amorphous product. Ethyl acetate (980 ml) is added and the amorphous product is dissolved in a similar way. The mixture is left standing overnight at room temperature, and a salt precipitated is removed by filtering by suction. The solvent is distilled away from the filtrate (S-isomer 76% ee) under reduced pressure, and chloroform (500 ml) is added to the residue. The mixture is washed twice with 10% hydrochloric acid, and the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (3720 ml) is added to the residue (62 g), and the residue is completely dissolved. The resulting mixture is left standing overnight at room temperature, and a precipitated racemate is removed by filtering by suction. The solvent is distilled away under reduced pressure from the filtrate, and ethanol (500 ml) is added to the residue (43 g) (94% ee). A 2N aqueous solution (182 ml) of sodium hydroxide is added at room temperature with stirring, and the mixture is stirred at 50° C. overnight. After the completion of the reaction, ethanol is distilled away, and the resulting mixture is adjusted to pH 4 with acetic acid. The mixture is stirred at 60° C. for 30 minutes. The reaction mixture is extracted with chloroform, and the organic layer is washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent is distilled away, ethanol (1920 ml) is added to the residue (32 g) (92% ee) and the mixture is stirred. The insoluble racemate is removed by filtering by suction, and the solvent is distilled away under reduced pressure from the filtrate. The residue is crystallized from chloroform to give an S-isomer [(S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid](20 g) as white powdery crystals (>99% ee). An R-isomer [(R)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid], melting point 166-177° C., is obtained by similarly treating the crystals precipitated as a cinchonidine salt.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:15]([N:18]([CH2:23][CH:24]=[CH2:25])[S:19]([NH2:22])(=[O:21])=[O:20])[CH2:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:22][S:19]([N:18]([CH2:23][CH2:24][CH3:25])[CH2:15][CH:16]=[CH2:17])(=[O:21])=[O:20])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: C=CCN(CCC)S(N)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(CCC)S(=O)(=O)NC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At from −5° C. to 0° C., 11.62 g (0.0474 mol) of 2-chloro-4-fluoro-5-nitrobenzoyl chloride in 50 ml methylene chloride were added with stirring, over 30 minutes, to a mixture of 8.50 g (0.048 mol) of N′-propyl-N′-allylsulfamide, 10.38 g (0.103 mol) of triethylamine and 0.09 g (0.736 mmol) of 4-N,N-dimethylaminopyridine in 90 ml of methylene chloride. The funnel was rinsed with 10 ml of the solvent. The mixture was initially stirred at 0° C. for 1 hour and then at 22° C. for 2 hours. 50 ml of 1N hydrochloric acid were then added, the mixture was stirred and the phases were separated. The organic phase was washed two more times with 1N hydrochloric acid and the aqueous phase was extracted with methylene chloride. Drying of the organic phase over magnesium sulfate was followed by filtration and concentration of the solution. The residue was triturated with diethyl ether/pentane, filtered off with suction and dried, giving 18.41 g (91.9% of theory) of the title compound of melting point (m.p.) of 110-112° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[CH2:20]([NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[C:28]([F:41])[CH:27]=1)=[O:24])[CH3:21]>>[C:11]([N:9]1[CH2:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH:25][C:23]([NH:22][CH2:20][CH3:21])=[O:24])=[CH:27][C:28]=3[F:41])=[N:7][C:6]=2[CH2:8]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(C)=O)C3)c(F)c1
Yield: 8 %

Procedure:
Method as described for example 147 using 1-(2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)ethanone (intermediate 23) and 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) (intermediate 28) as starting materials. The crude reaction mixture was purified by SCX-2 cartridge (loaded in MeOH eluted with 2M methanolic ammonia). Ammonia eluent was concentrated in vacuo. Residue was then purified by prep. HPLC at high pH to afford an off white solid (17.4 mg, 0.04 mmol, 8%).
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[CH:6]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:8]2.[C:20]([O-])(=[O:22])[CH3:21].[K+]>CN(C=O)C.O>[C:20]([C:6]1[C:5](=[O:19])[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][CH:3]=2)[O:8][C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH3:21]
Reactant: O=c1cc(-c2ccccc2)oc2cccc(CBr)c12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(-c2ccccc2)oc2ccccc2c1=O
Temperature: 100 °C
Yield: 107.2 %

Procedure:
The diketone compound (2.3 g, 6.92 mmol) was taken into a mixture of HCl (1 mL) and acetic acid (15 mL) and heated at 100° C. for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated to give 1.75 g of the intermediate in 80.6% yield. In a 100 mL dry round-bottomed flask fitted with condenser and magnetic stirrer were placed this intermediate (925 mg, 2.94 mmol) in CH2Cl2 (30 mL). BBr3 (2.21 g, 8.83 mmol, 1M solution in CH2Cl2) was added slowly at 0° C. The reaction mixture was stirred for 16 h at rt under nitrogen. The reaction mixture was quenched by carefully adding methanol. The solvent was removed under reduced pressure and the resulting solid was washed with water and dried to give 1.0 g of crude 3′-fluoro-4′-methoxy-5-bromo methyl flavone in 97% yield. To a solution of 5-bromomethyl flavone (1.0 g, 2.86 mmol) in DMF (20 mL), potassium acetate (845 mg, 8.60 mmol) was added. The mixture was heated at 100° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give crude acetyl flavone (810 mg, 86%). To a solution of the acetyl flavone (810 mg, 2.47 mmol) in methanol (15 mL), K2CO3 (1.02 g, 7.41 mmol) was added and the reaction mixture was stirred for 2 h at rt. The solvent was removed and the product was taken in to water and neutralized by dilute HCl. The solid was separated by filtration, washed with water and dried to give 2-(3-fluoro-4-hydroxyphenyl)-6-(hydroxymethyl)-4H-chromen-4-one in 38% yield. MS (ES) m/z: 286.96 (M); Mp. 256-258° C.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].CC1C=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1.CI>C1COCC1>[CH2:10]([C:9]1[CH:8]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)[CH3:11]
Reactant: [Li]CCCC
Reactant: Cc1cc(Cl)ccn1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cc(Cl)ccn1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a stirred solution of diisopropylamine (0.86 ml, 6.1 mmol) in THF (15 ml) at −20° C. was added dropwise a solution of n-butyllithium in hexanes (1.2M, 5.07 ml, 6.1 mmol). The reaction mixture was stirred at −20° C. for 20 minutes and was then cooled to −70° C. A solution of 2-methyl-4-chloropyridine (0.74 g, 5.8 mmol) in THF (10 ml) was added dropwise over 20 minutes and the reaction mixture was stirred for 1 hour at −70° C. Methyl iodide (0.38 ml, 6.1 mmol) was then added dropwise and the reaction was allowed to warm to room temperature with stirring. The solvent was evaporated at reduced pressure and the resulting residue purified by FCC. 1H NMR indicated a ˜2.2:1 mixture of 2-ethyl and 2-(1-methylethyl) compounds. Re-purification by silica FCC [pentane/ether eluting with gradient 9:1 to 1:1] gave the title compound (209 mg, 24%) as colourless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)=[N:5][N:4]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>O1CCCC1>[ClH:1].[CH:20]1([CH2:19][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:8]([C:6]3[O:7][C:3]([CH2:2][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[N:4][N:5]=3)=[CH:9]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1cccc2c(-c3nnc(CCl)o3)cn(CC3CCCCC3)c12
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)Cc1nnc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)o1
Product: Cl
Yield: 84.6 %

Procedure:
To a solution of 3-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (92 mg, 0.26 mmol) in tetrahydrofuran (1 ml) was added diethylamine (0.134 ml, 1.28 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 15 minutes. The resulting mixture was purified by flash column chromatography to afford the title compound (87 mg, 0.22 mmol) as the free base. The free base was dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol) was added. The excess reagent and solvent were removed by evaporation to the leave the title compound (1:1 hydrochloride salt) as a white solid. 1H NMR (400 MHz, CD3OD): 0.97-1.12 (2H, m), 1.15-1.26 (3H, m), 1.46 (6H, t, J 7), 1.53-1.63 (2H, m), 1.63-1.78 (3H, m), 1.8-1.95 (1H, m), 3.44 (4H, q, J 7), 3.98 (3H, s), 4.33 (2H, d, J 7), 4.84 (2H, s), 6.85 (1H, d, J 7), 7.19 (1H, t, J 7.9), 7.73 (1H, d, J 8), 7.94 (1H, s); EsIMS: m/z 397.1 [M+H]+, 324.4, 270.5.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]1[C:10](=[O:11])[O:9][CH2:8][C:6]1=O.C1(C)C=CC=CC=1.O>C(O)(=O)C>[CH:1]1([NH:4][C:6]2[CH2:8][O:9][C:10](=[O:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C1COC(=O)C1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(NC2CC2)CO1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
At 0° C., 10.5 ml of cyclopropylamine (149.9 mmol) are added dropwise to 10.0 g of tetronic acid (99.9 mmol) in 57 ml of acetic acid, and the mixture is stirred at 120° C. for 2 h. After addition of 200 ml of toluene, the mixture is heated under reflux on a water separator for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between 2.5 N of aqueous sodium hydroxide solution and dichloromethane. The aqueous phase is extracted a few more times with dichloromethane and the combined organic phases are dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethanol gives 5.2 g (37% of theory) of 4-(cyclopropylamino)furan-2(5H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.[F:8][C:9]([F:26])([F:25])[C:10](=O)[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=O>C(O)(=O)C.O>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[C:10]([C:9]([F:8])([F:26])[F:25])=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=3)=[N:1][C:2]=12
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1n[nH]cc1Br
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(Br)c3n2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A stirred mixture of commercially available 3-amino-4-bromo-pyrazole (14.00 g, 86.4 mmol) and 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (Example C.1 step 1) (24.56 g, 86.4 mmol) in acetic acid (170 mL) was heated under reflux conditions for 2.5 h. The reaction mixture was cooled to room temperature, diluted with water (340 mL), the precipitate was filtered off, washed with water and dried in air at 60° C. to give the 3-bromo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (31.77 g, 90%) as a yellow solid. MS (EI) 410.0 [(M)+], 412.0 [(M+2)+]; mp 136° C.