Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCC3CCC(C(=O)O)CC3)c3ccccc3nc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc2c(NCC3CCC(CO)CC3)c3ccccc3nc21

Procedure:
A mixture of 1-ethyl-N-[(4-carboxycyclohexyl)methyl]-1H-pyrazolo[3,4-b]quinolin-4-amine (5.0 g), THF (100 ml) and lithium aluminum hydride (3.0 g) was refluxed overnight. Additional lithium aluminum hydride (1.0 g) was added and the mixture was heated at reflux for another hour. The reaction mixture was cooled, water (4 ml), then 10% NaOH (4 ml) and finally water (12 ml) were added and the mixture was heated to reflux and then filtered. The collected solids were heated at reflux in THF for 10 minutes, then filtered again. The filtrates were combined, dried over MgSO4 and then evaporated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and then was crystallized from hexanes/ethyl acetate. The product was dissolved in methanol, treated with methanesulfonic acid and then the methanol was evaporated. The residue was crystallized from 2-propanol and then recrystallized from 2-propanol to afford 1-ethyl-N-[(4-hydroxy methylcyclohexyl)methyl]-1H-pyrazolo[3,4-b]quinolin-4-amine.CH3SO3H, as a white solid, m.p. 188°-190° C.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]>C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)C(=Cc1ccccc1)NC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Yield: 82.4 %

Procedure:
A second recycling of the catalyst is performed under the conditions described above, but introducing methyl α-acetamidocinnamate (1.6 g) and ethyl acetate (10 cc). Pure N-acetylphenylalanine methyl ester (1.33 g) is thus obtained with a conversion of 100%, its rotatory power being:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:3][CH:2]=1.[Br:27]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:20]3[C:15]([C:14]([Br:27])=[C:13]4[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: c1ccc(-c2ccc(-c3c4ccccc4cc4ccccc34)cc2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccc(-c3ccccc3)cc2)c2ccccc12

Procedure:
5.3 g (16 mmol) of 9-(biphenyl-4-yl)anthracene and 90 mL of carbon tetrachloride were put into a 200-mL three-neck flask and were stirred. A solution in which 2.8 g (18 mmol) of bromine was dissolved in 10 mL of carbon tetrachloride was dropped into the above solution through a dropping funnel. After that, the solution was stirred at the room temperature for 1 hour, and a sodium thiosulfate aqueous solution was added to the reaction solution to complete the reaction. A water layer of the reaction mixture was extracted by chloroform, and the extracted solution and an organic layer were together washed with a saturated sodium hydrogen carbonate solution and saturated saline in this order. The organic layer was dried with magnesium sulfate, and the mixture was filtrated naturally to remove the magnesium sulfate. Then, the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with ethanol, whereby 5.4 g of a yellow powdery solid, which was a target matter, was obtained with the yield of 82%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:34]2[C@@H:33]3[C@H:24]([C@H:25]4[C@@:29]([CH2:31][C@H:32]3[OH:37])([CH3:30])[C@@H:28]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:34]2[C@@H:33]3[C@H:24]([C@H:25]4[C@@:29]([CH2:31][C:32]3=[O:37])([CH3:30])[C@@H:28]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@]12C[C@@H](O)[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@]12CC(=O)[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
Dichloromethane (92.25 ml) was added to oxalyl dichloride (3.54 ml, 40.59 mmol) under nitrogen atmosphere and the resulting mixture was cooled to −78° C. To this mixture, a solution of dimethyl sulfoxide (5.76 ml, 81.18 mmol) diluted in dichloromethane (18.45 ml) was added dropwise. After the mixture was stirred for 2 minutes at −78° C., a solution of 3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11α-ol (17.29 g, 36.90 mmol) in dichloromethane (36.90 ml) was added dropwise, followed by stirring for 15 minutes at −78° C. Triethylamine (25.7 ml, 184.5 mmol) was added dropwise to the reaction mixture, which was then stirred for 5 minutes at −78° C. and warmed to room temperature. The reaction mixture was cooled again on ice, quenched by addition of ice and water, and then extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure using an evaporator to give crude 3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11-one (crude 18.76 g, quant from crude 1H-NMR).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:17].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=2)[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]1=[O:17]
Reactant: BrCc1ccccc1
Reactant: COC(=O)CC1Cc2ccc(OC)cc2NC1=O
Product: COC(=O)CC1Cc2ccc(OC)cc2N(Cc2ccccc2)C1=O
Yield: 88 %

Procedure:
The title compound (4.3 g, 88% yield) was prepared using the conditions of Example 124 using (7-methoxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester in place of (7-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)acetic acid methyl ester and benzyl bromide in place of ethyl iodide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([Cl:11])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:65]([NH2:69])([CH2:67][CH3:68])[CH3:66]>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([Cl:11])[N:7]=[C:8]([NH:69][C@H:65]([CH2:67][CH3:68])[CH3:66])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(Cl)n1
Temperature: 25 °C
Yield: 73 %

Procedure:
Dissolve 2,6-dichloro-isonicotinic methyl ester (2.0 g, 10 mmol), palladium (II) acetate (224.0 mg, 1.0 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (632 mg, 1.0 mmol) and cesium carbonate (3.96 g, 12 mmol) in toluene (20 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen gas. Add (S)-(+)-sec-butylamine (1.2 mL, 12 mmol) to the solution and heat the sealed mixture overnight at 100° C. Cool to room temperature and dilute with diethyl ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the title compound (73%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26]C)=[O:25])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([OH:26])=[O:25])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2cccc(C(=O)OC)c2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2cccc(C(=O)O)c2)nc1Cl
Yield: 71.3 %

Procedure:
The same operation as in Example (91d) was performed using methyl 3-[(7-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (100c) (0.16 g, 0.35 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (8 mL), to obtain 0.11 g of the title compound as a light pink solid (71%).
Reaction SMILES: [C:1]1([CH3:44])[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:43])[CH2:21][CH2:22][S:23]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:1]1([CH3:44])[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:43])[CH2:21][CH2:22][SH:23])=[CH:5][CH:6]=1
Reactant: Cc1ccc(OCCCCCCCCCCCNC(=O)CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(OCCCCCCCCCCCNC(=O)CCS)cc1

Procedure:
The compound 25 (0.181 g) was dissolved in 1 ml of methylene chloride, and 0.5 ml of trifluoroacetic acid was added to that while being stirred, to obtain a brown-colored solution. After a white-colored precipitate was generated by adding 0.16 ml of triethylsilane, the supernatant solution was distilled away under reduced pressure. The solid obtained was dissolved by the new addition of 20 ml of methylene chloride, and was washed twice with 30 ml of aqueous saturated sodium hydrogen carbonate solution and twice with 30 ml of saturated brine. After the collected organic phase was dehydrated with magnesium sulfate, the desiccant agent was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. The reaction mixture was purified by chromatography, and 0.1 g of the compound f, which was a white solid, was obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2n[nH]c(-c3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2n[nH]c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of methyl 4-(5-phenyl-1H-1,2,4-triazol-3-yl)benzoate (0.500 g), 1 M aqueous sodium hydroxide solution (5.4 ml), tetrahydrofuran (6 ml) and methanol (3 ml) was stirred at room temperature for 2 hrs. and heated under reflux for 2 hrs. After cooling, 1 M hydrochloric acid was added to acidify the reaction mixture. The crystals were collected by filtration to give 4-(5-phenyl-1H-1,2,4-triazol-3-yl)benzoic acid (0.380 g, yield 79%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: >300° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:27]CCl>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([Cl:27])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)O)cc2)cc1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Yield: 74.4 %

Procedure:
To a stirred suspension of 4-(5-p-methylphenyl-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonic acid (43 g, 0.112 mol) in dichloromethane (250 ml) phosphorous pentachloride (34.20 g, 0.168 mol) was added portion-wise at room temperature, followed by addition of N,N-dimethylformamide (10 ml). The so obtained suspension was refluxed for 8 h, then concentrated in vacuo. The residue was partitioned between ethyl acetate (150 ml) and water (150 ml) and separated. The aqueous phase was extracted with ethyl acetate (1×50 ml), the combined organic layers were dried over MgSO4, filtered and concentrated. The obtained oil was crystallized from cyclohexane (120 ml) to yield 33.40 g (74%) of the title compound as white crystals. Mp: 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([O:17][C:18]([C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[C:21]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:19])[CH3:16]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[N:22]([CH3:25])[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH:24]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)ccn1C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)cc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A solution of 28 ml. (0.22 mole) of p-chlorobenzoyl chloride and 29.4 g. (0.22 mole) of aluminum chloride in 160 ml. of 1,2-dichloroethane (DCE) is added to a refluxing solution of 52.7 g. (0.22 mole) of ethyl 3-ethoxycarbonyl-1-methylpyrrole-2-acetate in 160 ml. of DCE. The mixture is heated under reflux for 41/2 hours, after which it is poured into ice-hydrochloric acid. The mixture is extracted with CHCl3 and the extract is washed successively with dimethyl-amino-n-propylamine solution, dilute hydrochloric acid, and brine, and is dried over magnesium sulfate. Evaporation of the solvent in vacuo and chromotographing the resulting residue on silica gel with a benzene to ether gradient yields the desired product in the first compound-bearing fractions. The solvent is evaporated from these combined fractions, and the resulting residue is recrystallized successively from methylcyclohexane and isopropanol to yield ethyl 5-(p-chlorobenzoyl)-3-ethoxy -carbonyl-1-methylpyrrole-2-acetate as a white solid; m.p. 91°-93° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10]=O>O.[Pd]>[CH3:10][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: C=O
Reactant: NC(=O)C1CCNCC1
Agent: [Pd]
Solvent: O
Product: CN1CCC(C(N)=O)CC1
Reaction time: 43 h
Yield: 64.5 %

Procedure:
Isonipecotamide (10 g, 78.0 mmoles) was dissolved in distilled water (100 mL) and 37% aqueous formaldehyde (7.6 mL, equivalent to 2.81 g HCHO, 93.6 mmoles) was added. Wet 10% Pd—C (8 spoon spatulas) was added under argon and the mixture was hydrogenated at 25° C. and 50 psi for 43 h. The catalyst was filtered off through Celite and the latter was washed with water and methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on a silica gel column (60×5 cm) using 8%-10%-20% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 1-methylisonipecotamide (7.15 g, 64%): FABMS: m/z 143.1 (MH+); HRFABMS: m/z 143.1184 (MH+). Calcd. for C7H15N2O: m/z 143.1184; δH (d6-DMSO) 1.50/1.57 (4H, m, CH2), 1.76/1.94 (4H, m, CH2), 2.10 (3H, s, —NCH3), 2.72 (1H, m, CH) and 6.68/7.18 ppm (2H, m, CONH2); δC (d6-DMSO)CH3: 41.2; CH2: 28.5, 28.5, 54.9, 54.9; CH: 46.2; C: 176.7.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][C:32]=1[F:39].[K]>CN(C=O)C>[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:11][CH2:10][C:9]2[S:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)=[N:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:33][C:32]=1[F:39]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: COC(=O)c1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COCc1ccc(C(=O)OC)c(F)c1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of [4-butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol (1.02 g, 3.24 mmol) in anhydrous DMF (150 mL) add cesium carbonate (2.7 g, 8.10 mmol) and 4-bromomethyl-2-fluoro-benzoic acid methyl ester (0.8 g, 3.24 mmol). Stir the resulting mixture overnight then pour into a 1M aqueous solution of potassium hydrogenophosphate and extracted three times with diisopropyl ether. Wash the combined extracts with water, dry over MgSO4, filter and concentrate under vacuum. Purify the residue by flash chromatography on silica gel (eluting with a gradient of heptane/ethyl acetate) to give the title compound (0.3 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[F:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][C@H:21]([NH:24][CH2:4][C:3]3[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=3[Br:1])[CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1Br
Reactant: N[C@H]1CCN(c2ccc(F)nc2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: Fc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Br)C2)cn1
Reaction time: 18 h

Procedure:
Add 2-bromo-4-chlorobenzaldehyde (159 mg, 0.73 mmol) to a solution of (S)-1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride (144 mg, 0.66 mmol) and triethylamine (292 μL, 2.1 mmol) in methanol (5 mL). Stir the resulting mixture for 18 h. Add sodium borohydride (80 mg, 2.1 mmol). Stir for 1 h. Dilute the reaction mixture with methanol (10 mL) and pour onto a column of Dowex® 50Wx2 (H+ form). Rinse the column with methanol then elute the product with 5% triethylamine in methanol. Concentrate and dissolve the residue in methanol. Dilute with acetonitrile and concentrate to give the title compound as a oil. Dissolve the oil in methanol and add excess 1 N HCl in methanol. Concentrate to dryness and crystallize from methanol/acetonitrile to give the title compound as its hydrochloride salt, an off white solid (84 mg, 30%). Elemental analysis calculated for C16H17BrCl2FN3: C, 45.63; H, 4.07; N, 9.98. Found: C, 45.39; H, 4.02; N, 9.85. MS (ES): m/z=386 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[F:11][CH:12]([F:27])[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1S(C)(=O)=O.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[N:14]([CH2:13][CH:12]([F:11])[F:27])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1nc2cccnc2n1CC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Cn1c(Oc2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirred solution of 4-bromophenol (238 mg) in DMF (4 mL) was added NaH (60% in oil, 55.1 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-(2,2-difluoroethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (360 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (387 mg).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][NH:36][C:35](=[O:39])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>[Cu](I)I>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:35](=[O:39])[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: COc1ccc(I)cc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2=O)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Charge in a pressure tube copper iodide (42 mg, 0.22 mmol), potassium phosphate (1.6 g, 7.5 mmol), trans-1,2-diaminocyclohexane (0.053 ml, 0.44 mmol), p-methoxyphenyl iodide (868 mg, 3.7 mmol) and 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (1.05 g, 4.7 mmol). Purge with nitrogen and add 6 ml of dry toluene. Cap the tube and stir at 100° C. overnight. Filter through celite eluting with EtOAc and concentrate. Purify in a silica gel cartridge (20 g) eluting with EtOAc/hexane 1:1 followed by 100% EtOAc to give the title compound as a white solid (1.03 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[NH2:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:16]2[N:15]=[C:14]([N:26]2[CH2:31][CH2:30][N:29]3[CH2:32][CH:33]([CH2:36][O:37]S(C)(=O)=O)[CH2:34][CH2:35][CH:28]3[CH2:27]2)[N:13]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[O:37][CH2:36][CH:33]1[CH2:32][N:29]2[CH2:30][CH2:31][N:26]([C:14]3[N:13]=[C:12]([NH2:11])[N:17]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:16]4[N:15]=3)[CH2:27][CH:28]2[CH2:35][CH2:34]1
Reactant: Oc1cccc(F)c1
Reactant: CS(=O)(=O)OCC1CCC2CN(c3nc(N)n4nc(-c5ccco5)nc4n3)CCN2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN3CC(COc4ccccc4F)CCC3C2)nc2nc(-c3ccco3)nn12
Temperature: 100 °C

Procedure:
A solution containing 3-fluorophenol (1.5 eq.) in DMF was treated with sodium hydride (60% oil dispersion, 4 eq.) for 2 hours at around 50° C. A solution containing containing methanesulfonic acid 2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl ester (1 eq., see subpart (a) above) in DMF was added. The resulting mixture was then heated at around 100° C. for 24 hours. The solvent was removed, and the residue was dissolved in DMSO, filtered and purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to afford the desired product as a white powder: 1H NMR (400 Hz, DMSO-d6) δ 7.96 (d, J=2.0 Hz, 1H), 7.39 (m, 1H), 7.15 (d, J=3.0 Hz, 1H), 6.92-6.83 (m, 3H), 6.75 (dd, J=3.0, 2.0 Hz, 1H), 4.84 (m, 2H), 4.08 (dd, J=10.0, 5.0 Hz, 1H), 3.74 (dd, J=10.0, 7.0 Hz, 1H), 3.65 (m, 2H), 3.33 (m, 3H), 3.10 (m, 1H), 2.97 (m, 1H), 2.39 (m, 1H), 1.99 (m, 2H), 1.67 (m, 1H), 1.48 (m, 1H). MS m/z: 465 [M+H]+.
Reaction SMILES: [H][H].[BrH:3].[CH3:4][NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[C:12]=2[OH:16])[C:7]1=[O:18]>O.[Pt](=O)=O>[BrH:3].[CH3:4][NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[C:12]=2[OH:16])[CH:7]1[OH:18]
Reactant: [H][H]
Reactant: CNC1CCc2c(ccc(O)c2O)C1=O
Agent: O=[Pt]=O
Agent: Br
Solvent: O
Product: CNC1CCc2c(ccc(O)c2O)C1O

Procedure:
In 5 volume parts of water is dissolved 0.200 part of 3,4-dihydro-2-methylamino-5,6-dihydroxy-1(2H)-naphthalenone hydrobromide and, using 0.050 part of platinum dioxide, the catalytic reduction is carried out in a current of hydrogen gas until a substantially stoichiometric amount of hydrogen gas is absorbed. The catalyst in the reaction mixture is filtered off and to the filtrate is added a mixture of ethyl ether, methanol and water. The procedure gives white prisms of 2-methylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide. Melting point: 165° to 169° C.(decomp.)