Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[C:3]([C:10](=O)[C@@H:11]([C@@H:13]1[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[NH:14]1)[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH2:39]([O:42][C:43]([N:45]1[CH2:49][C@@H:48]([SH:50])[CH2:47][C@H:46]1[CH2:51][O:52][CH2:53][CH2:54][F:55])=[O:44])[CH:40]=[CH2:41].O>C(OCC)(=O)C.C(#N)C.C(N(C(C)C)CC)(C)C.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[CH2:39]([O:42][C:43]([N:45]1[CH2:49][C@@H:48]([S:50][C:10]2[C@H:11]([CH3:12])[C@H:13]3[N:14]([C:15](=[O:20])[C@@H:16]3[C@H:17]([OH:19])[CH3:18])[C:3]=2[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH2:47][C@H:46]1[CH2:51][O:52][CH2:53][CH2:54][F:55])=[O:44])[CH:40]=[CH2:41]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1COCCF
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
To a solution of allyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (3.80 g) in ethyl acetate (20 ml) was added rhodium(II) octanoate (20 mg) under reflux in a stream of nitrogen. After 20 minutes, rhodium(II) octanoate (20 mg) was added to the mixture at the same condition. The mixture was refluxed for 40 minutes and concentrated under reduced pressure to give a syrup. The syrup was dissolved in acetonitrile (20 ml) and cooled at 0°-5° C. under atmosphere of nitrogen. To the solution was added diphenyl chlorophosphate (2.94 ml) and N,N-diisopropyl-N-ethylamine (2.69 ml) successively and the mixture was stirred at the same condition for 18 hours. To this mixture were added a solution of (2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-mercaptopyrrolidine (3.65 g) in acetonitrile (4 ml) and N,N-diisopropyl-N-ethylamine (2.69 ml) successively at 0°~5° C. The mixture was stirred at 0°-5° C. for one hour and at ambient temperature for 3 hours, and then poured into a mixture of ethyl acetate (100 ml) and water (60 ml). The organic layer was washed with water (60 ml) and brine (60 ml) in turn, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (60 g) and eluted with a mixture of hexane and ethyl acetate (4:1 V/V) to give allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.58 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][CH2:5][CH2:4]/[C:3]/1=[N:7]\[C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].[BH4-].[Na+].Cl>C(O)C>[CH3:16][C:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C@@H:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: C[C@@H](/N=C1\CCCC1(C)C)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](N[C@@H]1CCCC1(C)C)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
(R,E)-N-(2,2-dimethylcyclopentylidene)-1-phenylethanamine (4.61 g, 21.4 mmol) in ethanol (50 mL) was cooled to −78° C. and sodium borohydride (0.41 g, 10.7 mmol) was added and the resulting mixture was allowed to stir at −78° C. for 2 h. At this time, the mixture was slowly treated with 6 N aq HCl (15 mL) followed by warming to rt with vigorous stirring. The organics were removed under vacuum and the remaining aqueous portion was cooled and made basic by addition of 10% aq sodium carbonate and the mixture was then extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine, dried over anhyd. sodium sulfate and the organic was decanted and concentrated on rotovap to yield a yellow liquid as the crude product. This material was purified by flash chromatography on silica gel using ethyl acetate/hexanes mixture as the eluent to afford 3.50 g (75%) of the title compound as a clear oil. HPLC (condition B): retention time=1.90 min. LCMS (condition E): m/z 218+ve. 1H NMR (400 MHz, MeOD) δ 7.29-7.41 (4 H, m), 7.20-7.29 (1 H, m), 3.90 (1 H, q, J=6.60 Hz), 2.59 (1 H, dd, J=9.46, 7.92 Hz), 1.66-1.81 (1 H, m), 1.51-1.67 (1 H, m), 1.38-1.50 (3 H, m), 1.37 (3 H, d, J=6.60 Hz), 1.24-1.36 (1 H, m), 1.05 (3 H, s), 0.92 (3 H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17]C(=O)C(F)(F)F)[CH:16]=2)(=[O:10])=[O:9])[CH:7]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([CH:16]=2)[NH2:17])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(S(=O)(=O)c2cc(Br)ccc2OC)cc1NC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)c2cc(Br)ccc2OC)cc1N
Temperature: 5 °C

Procedure:
In a 500 mL 3-neck round bottom flask equipped with reflux condenser, addition funnel, thermometer socket and magnetic bar inside was added N-[5-(5-Bromo-2-methoxybenzenesulfonyl)-2-methoxyphenyl]-2,2,2-trifluoroacetamide (18.0 grams, 38.54 mmol) in methanol (200 mL). The contents of the flask were cooled to 5° C. and 6N sodium hydroxide (3.1 grams dissolved in 12.4 mL) solution (3.1 grams, 77 mmol) was added slowly over a period of 30 minutes at 5° C. The reaction mass was bought to room temperature and refluxed the reaction mass for 3 hours at 70° C. Reaction mass was cooled to room temperature and methanol was evaporated under vacuum and the obtained residue was treated with water (50 mL) and the mass was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine solution and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain technical product and it was further purified by recrystallisation from methanol/n-hexane to obtain the title product. Yield: 2.85 grams
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:17][CH2:16][O:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C.O.[OH-].[Na+]>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:1][C:2]2[CH:3]=[C:4]([C@:8]34[CH2:17][CH2:16][O:15][CH2:14][CH:13]3[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[N:9]4)[CH:5]=[CH:6][CH:7]=2)=[O:34])=[N:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N)c3)CCOCC2CS1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(NC(=O)c4ccc(Cl)cn4)c3)CCOCC2CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a mixture of tert-butyl (8aS)-8a-(3-aminophenyl)-4,4a,5,7,8,8a-hexahydropyrano[4,3-d][1,3]thiazin-2-ylcarbamate (0.15 g, 0.413 mmol), 5-chloropyridine-2-carboxylic acid (0.078 g, 0.495 mmol) and 1-hydroxybenzotriazole (0.073 g, 0.536 mmol) in CH2Cl2 (2.75 mL) and DMF (0.3 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.103 g, 0.536 mmol). The reaction is stirred overnight at room temperature. The reaction mixture is diluted with water, 5 N NaOH (0.5 mL) and extracted three times with CH2Cl2. The combined organic layer is dried over Na2SO4 and the crude product is purified by silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (0.176 g, 85%). ES/MS m/e: (35Cl/37Cl) 503, 505 (M+1).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH3:12].[O-]S([O-])=O.[Na+].[Na+].[OH-].[Na+]>[Fe].O>[Br:1][C:8]1[C:7]([CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([CH3:3])[CH:9]=1
Reactant: COc1cc(C)ccc1C
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C)c(Br)cc1C
Reaction time: 4 h

Procedure:
Bromine (291.5 g, 1835 mmol) was added dropwise with stirring to an initially introduced mixture of 2,5-dimethylanisole (250 g, 1835 mmol) and Fe powder (3.25 g). The commencement of the reaction was evident from gas evolution. The remainder of the bromine was subsequently added dropwise over the course of 30-40 minutes at room temperature with water-bath cooling. The reaction mixture was stirred for about a further 4 hours. The Fe powder was subsequently separated off, a little chloroform was added to the solution, and the solution was washed by shaking with water, resulting in the solution becoming paler. After the solution had been shaken with 50 ml of saturated aqueous Na2SO3 solution, it had become completely colorless. The solution was shaken again with dilute aqueous NaOH and twice with H2O and dried, and the solvent was stripped off. The crude product was subjected to fractional distillation under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Reactant: CNc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccccc3Cl)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2-chloroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 168bp. 1H (500 MHz, CDCl3) δ 7.53 (d, J=7.7 Hz, 1 H), 7.35-7.41 (m, 3 H), 6.97 (s, 1 H), 6.94 (d, J=8.2 Hz, 1 H), 6.76 (d, J=8.2 Hz, 1 H), 6.56 (s, 1 H), 5.00 (s, 2 H), 3.39 (s, 3 H), 2.26 (s, 3 H). LCMS (ESI) m/z: 370.1
Reaction SMILES: [OH:1][CH2:2][C@H:3]([OH:14])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].N1C=CC=CC=1.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[C:21]1([C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:1][CH2:2][C@H:3]([OH:14])[CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1SC[C@@H](O)CO
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccccc1SC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.4 %

Procedure:
19.3 g (0.09 mol) of 1-(3-hydroxy-2-(S)-hydroxy-propylthio)-2-methoxybenzene (XI-1), 150 ml of acetonitrile, 11 ml (0.136 mol) of pyridine and 27.5 g (0.098 mol) of triphenylmethyl chloride are introduced into a round-bottomed flask under an inert atmosphere. The solution is stirred at ambient temperature for 5 hours. The mixture is concentrated under reduced pressure and the residual pyridine is entrained by azeotropic distillation with toluene. The residue is taken up in water and then extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and evaporated, and the residue is purified by flash chromatography on silica gel (eluent: cyclohexane/dichloromethane=30:70). 34.8 g (0.076 mol) of the title compound (XII-1) are recovered in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.Cl.[CH:25]12[CH2:30][CH:29]1[CH2:28][NH:27][CH2:26]2.C(N(CC)CC)C.O>C1COCC1>[CH:25]12[CH2:30][CH:29]1[CH2:28][N:27]([C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1)[CH2:26]2
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)O)cc1Cl
Reactant: C1NCC2CC12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Temperature: 25 °C

Procedure:
In THF (15 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-carboxylic acid (196 mg, 0.55 mmol) and 3-azabicyclo[3.1.0]hexan hydrochloride salt (79 mg, 0.66 mmol). The solution was cooled in an ice bath and triethylamine (167 mg, 1.65 mmol) was then added dropwisely. The reaction was warmed to ambient temperature for 5 h. Then water was added and the reaction mixture was extracted with DCM. The organic phase was dried and concentrated to give a solid. The product was used in the subsequent procedure without further purification.
Reaction SMILES: N1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.C(N1CCC(N)CC1)[C:34]1[CH:39]=[CH:38]C=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:9]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]1)[C:8]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(Cc4ccccc4)CC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Isobutoxy-1H-indole-2-carboxylic acid 80 (4.7 g, 20.1 mmol, preparation see Example 8) and 1-benzyl-piperidin-4-ylamine (4.2 ml, 20.1 mmol) are dissolved in 70 ml of DMF and after addition of TBTU (7.3 g, 22.1 mmol) and ethyldiisopropylamine (13.8 ml, 80.4 mmol) the mixture is stirred at room temperature for 2 h. Then the solvent is evaporated at high vacuum. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layers are dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].O>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1

Procedure:
4-Hydroxyphenylacetic acid (50 g, 0.32 m) in 300 ml of glacial acetic acid was cooled to 10° at which temperature 100 ml of nitric acid was slowly added. The mixture was allowed to reach room temperature, then was poured into 1 l of water. The separated solid was washed with water and recrystallized from ethanol to give 35 g of 4-hydroxy-3-nitrophenylacetic acid, m.p. 144°-146°.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH2:22][N:23]([CH3:35])[CH2:24][CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[N:13][N:14](C3CCCCO3)[CH:15]=2)=[CH:7][CH:6]=1.O.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].CC#N>Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[F:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH2:22][N:23]([CH3:35])[CH2:24][CH2:25][NH:26][CH3:27])=[N:13][NH:14][CH:15]=2)=[CH:9][CH:10]=1
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1nn(C2CCCCO2)cc1-c1ccc(Oc2ccccc2F)cc1
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNCCN(C)Cc1n[nH]cc1-c1ccc(Oc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
A solution of tert-butyl 2-(((4-(4-(2-fluorophenoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)(methyl)amino)ethyl(methyl)carbamate (160 mg, 0.30 mmol, 1.00 equiv) in 4N hydrochloric acid (10 mL) was stirred at 60° C. for 2 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, XBridge Shield RP 18, 5 μm, 19×150 mm; mobile phase, water with 50 mmol CF3COOH and CH3CN (10.0% CH3CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm to give 53.2 mg (31%) of N1-((4-(4-(2-fluorophenoxy)phenyl)-1H-pyrazol-3-yl)methyl)-N1,N2-dimethylethane-1,2-diamine trifluoroacetate as a yellow oil. 1H NMR (300 MHz, D2O): δ 7.89 (s, 1H), 7.40-7.03 (m, 8H), 4.56 (s, 1H), 3.40-3.23 (m, 4H), 2.73 (s, 3H), 2.64 (s, 3H) ppm. LCMS (method H, ESI): RT=1.34 min, m/z=355.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CC[C:21]([O-:23])=[O:22].[OH-].[K+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:21]([OH:23])=[O:22])[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cccc(Cn2ccc3cc(F)cnc32)c1
Reactant: CCC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(F)cnc2n1Cc1cccc(F)c1
Yield: 90.2 %

Procedure:
A mixture of 6.9 g (20.58 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate (WO07/010,138) and 1.89 g (33.7 mmol) of potassium hydroxide in a mixture of 80 mL of ethanol and 10 mL of water is heated under reflux for 1.5 h. After this time, the reaction mixture is concentrated at reduced pressure, and is then taken up in 200 mL of water. The solution is acidified with additions of concentrated hydrochloric acid, and then extracted three times with 50 mL of dichloromethane. The organic phases are combined, dried over sodium sulfate and then concentrated at reduced pressure. The resultant product is triturated in 5 mL of dichloromethane. A precipitate is collected by filtration and is dried at reduced pressure. In this way we isolate 5.35 g of the expected product, which is used as it is in the rest of the synthesis.
Reaction SMILES: C([O:6][CH2:7][C:8](=[C:14]([CH3:16])[CH3:15])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=O)CCC.C(C(CC=C(C)C)CO)(C)=C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[C:14]([CH:8]([CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH:7]=[O:6])([CH3:16])=[CH2:15]
Reactant: CCCC(=O)OCC(CC=C(C)C)=C(C)C
Agent: C=C(C)C(CO)CC=C(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: C=C(C)C(C=O)CC=C(C)C

Procedure:
Tabata has reported the synthesis of 2-isopropylidene-5-methyl-4-hexenyl butyrate in which 2-isopropenyl-5-methyl-4-hexenol as a starting material is subjected to an oxidation reaction with Dess-Martin reagent to form 2-isopropenyl-5-methyl-4-hexenal (lavandulal), the resulting aldehyde is isomerized under an acidic condition through migration of the double bond to form 2-isopropylidene-5-methyl-4-hexenal (another name: fujikonal), and the isomerized aldehyde is reduced and then esterified to form 2-isopropylidene-5-methyl-4-hexenyl butyrate (Appl. Entomol. Zool., 48, 229-232 (2013)).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19](O)=[O:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.Cl.[NH:55]1[C:59]2([CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:58][NH:57]/[C:56]/1=[N:65]\[C:66]([C:68]1[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=1)=[O:67]>CN(C=O)C.O.[OH-].[Na+].CCOC(C)=O.C(#N)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([N:62]3[CH2:63][CH2:64][C:59]4([NH:55]/[C:56](=[N:65]/[C:66]([C:68]5[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=5)=[O:67])/[NH:57][CH2:58]4)[CH2:60][CH2:61]3)=[O:20])=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: O
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cn(S(=O)(=O)c5ccccc5)c5ccccc45)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(phenylsulfonyl)-1H-indole-3-carboxylic acid (1.0 g, 3.32 mmol) in DMF (15 ml) is added HATU (1.388 g, 3.65 mmol) and N-methyl morpholine (1.095 ml, 9.96 mmol) and the solution is stirred at room temperature for 5 minutes. 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (1.452 g, 3.65 mmol) is added and the reaction stirred at room temperature for 45 minutes. The reaction mixture is diluted with water (100 ml) and the precipitate that forms is isolated by filtration. The crude product is suspended in 2N NaOH and extracted into EtOAc. The organic portion is dried over MgSO4 and concentrated in vacuo to yield a brown solid. The solid is suspended in a 1:1 mixture of water (+0.1% TFA) and acetonitrile. A fine brown solid is removed by filtration and the yellow filtrate is concentrated in vacuo until 10 ml of solvent remains and a pale yellow solid has precipitated. This solid is washed with 2N NaOH (60 ml) and then suspended in 2N NaOH (100 ml) and extracted into EtOAc (2×100 ml). The organic phases are combined, dried over MgSO4 and concentrated in vacuo to yield a pale cream solid. The cream solid is suspended in a 1:4 mixture of EtOAc:iso-hexane (100 ml) and the solid filtered off to give the free base of the title compound, which is suspended in 5 N HCl (20 ml) and stirred for 2 hours. MeOH (20 ml) is added to dissolve all solid and the solvent is concentrated in vacuo until a yellow solid precipitates. This solid is filtered off, rinsed with water and dried at 40° C. for 18 hours to give the title compound; [M+H]+ 607.42; 1H NMR (DMSO-d6): 1.86-1.92 (4H, m), 3.42-3.63 (4H, m), 3.68 (2H, s), 7.34 (1H, dd, J+7.5 Hz, J=7.5 Hz), 7.43 (1H, dd, J=7.5 Hz, J=7.5 Hz), 7.36-7.55 (2H, br), 7.62 (1H, dd, J=7.5 Hz), 7.63 (2H, m), 7.73 (1H, m), 7.99 (1H, d, J=7.5 Hz), 8.06 (2H, obs), 8.07 (1H, s), 7.50-8.16 (2H, br), 9.18 (1H, s), 9.77 (1H, s), 11.09 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#N.C(O)=[O:16]>O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:16]
Reactant: COc1cc(C#N)cc(C(F)(F)F)c1
Reactant: O=CO
Agent: O=[Pt]=O
Product: COc1cc(C=O)cc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
A mixture of 3-methoxy-5-(trifluoromethyl)benzonitrile (88 mg, 0.43 mmol) and PtO2 (9.8 mg, 0.043 mmol) in 88% formic acid (651 μL) was heated to 60° C. The reaction was stirred at this temperature for thirty minutes. The reaction was then cooled to room temperature, diluted with hexanes (5 mL), loaded on a silica gel column, and purified with 1% to 15% EtOAc/hexanes to afford 3-methoxy-5-(trifluoromethyl)benzaldehyde. Rf=0.56 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 10.01 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.39 (s, 1H), 3.92 (s, 3H).
Reaction SMILES: C([C:3]1[C:4](=[O:14])[NH:5][C:6]([CH3:13])=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2)#N.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:13][C:6]1[NH:5][C:4](=[O:14])[CH:3]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: Cc1[nH]c(=O)c(C#N)c2c1CCCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]c(=O)cc2c1CCCC2
Temperature: 0 °C
Yield: 78.5 %

Procedure:
4-Cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxoisoquinoline (1.88 g) was dissolved in 20 ml of 85% sulfuric acid, and the resultant solution was heated at 180°-190° C. for 10 hours. After cooling, the reaction mixture was poured into ice water and an aqueous sodium hydroxide solution was added to adjust the pH to about 5. Deposited crystals were filtered out and recrystallized from methanol. Thus, there was obtained 1.28 g of 2,3,5,6,7,8-hexahydro-1-methyl-3-oxoisoquinoline.