Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH:10]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[C:19]1([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:12])[CH:10]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:8][OH:7])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C(CCOC1CCCCO1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The evaporation residue obtained in step (b) is dissolved in a mixture containing 400 ml of absolute ethanol, 10 g of concentrated sulfuric acid and 75 ml of water. The mixture is stirred for 2 h at room temperature. The solution is neutralized with 2 M sodium hydroxide solution, after which the ethanol is evaporated. Water is added to the residue. Then the product is extracted in ethyl acetate. The ethyl acetate solution is dried over sodium sulfate, and the solvent is evaporated. The product is recrystallized from toluene. The yield is 16.5 g (52% from desoxybenzoin) and m.p. 185°-7° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[CH:28]=[CH:27][C:19]2[S:20][C:21]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:22][C:18]=2[CH:17]=1.O>CO>[N:1]1([CH2:15][C:16]2[CH:28]=[CH:27][C:19]3[S:20][C:21]([S:23](=[O:25])(=[O:26])[NH2:24])=[CH:22][C:18]=3[CH:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: NS(=O)(=O)c1cc2cc(CN3CCOCC3)ccc2s1
Yield: 9.6 %

Procedure:
To a stirred solution of morpholine (0.91 g, 10.5 mmol) and triethylamine (1.01 g, 10 mmol) in 20 ml of methanol was added 5-bromomethyl-2-sulfamoylbenzo[b]thiophene (3.06 9, 10 mmol) portionwise over 5 minutes at ambient temperature. Stirring was continued for 11/4 hours. The resulting suspension was cooled and filtered after an additional 1 hour to give 2.76 g. of yellow solid. Concentration of the filtrate in vacuo followed by trituration of the residue with water and filtering gave an additional 0.3 g of yellow solid. (Total crude yield was 98%). Recrystallization from nitromethane gave material with m.p. 221.5°-224° C.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3NC4C([C:15]=3[CH:16]([C:18]([OH:20])=O)[S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=CC=CC=4.[C:21]([O:25][C:26]([CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:27])([CH3:24])([CH3:23])[CH3:22].O.O[N:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:21]([O:25][C:26]([CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][N:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:18]([CH:16]1[C:15]2[C:46]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:43][C:7]=2[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:17]1)=[O:20])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCCCCCNCCNCCCC(=O)OC(C)(C)C
Reactant: O=C(O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCN(CCNCCCC(=O)OC(C)(C)C)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 844 mg of 6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxylic acid and 1.66 g of N-2-(N-t-butoxycarbonylpropylamino)ethyl-hexylamine in 44 ml of dichloromethane were added 552 mg of 1-hydroxybenzotriazole monohydrate and 863 mg of N-ethyl-N′-dimethylaminopropylcarbodiimide hydrochloride, followed by stirring at room temperature overnight. The reaction solution, after concentration under reduced pressure, was dissolved in ethyl acetate, washed with water 5% aqueous potassium bisulfate solution, a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica gel; Chromatorex NHDM1020 produced by Fuji-Davison Chemical Co., developing solvent; hexane-ethyl acetate=2:1-3:2) to give 1.35 g of N-2-(N-t-butoxycarbonylpropylamino)ethyl-N-hexyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxamide as an amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([Br:31])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][S:33]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][C:22]=1[Br:31])(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCOS(C)(=O)=O)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
To a solution of the product of Example 1A (300 mg, 0.598 mmol) dissolved in anhydrous CH2Cl2 (6.0 mL) was added MsCl (55.8 μL, 0.718 mmol), DMAP (87.7 mg, 0.718 mmol) and Et3N (0.125 mL, 0.897 mmol). The reaction mixture was stirred at room temperature for 45 min then concentrated to yield an oil. The crude material was directly purified using silica gel chromatography (4:1 hexanes:EtOAc) to yield a colorless oil (245.6 mg, 71% yield). 1H NMR (CDCl3, 300 MHz): δ 9.35 (brs, 2H), 7.56 (d, J=3.0 Hz, 1H), 7.26 (m, 1H). 6.84 (d, J=9.0 Hz, 1H), 5.09 (brs, 2H), 4.53 (t, J=6.0 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H), 3.01 (s, 3H), 2.29 (m, 2H), 1.52 (s, 9H), 1.43 (s, 9H); 13C(CDCl3, 150 MHz): δ 160.7, 154.9, 154.1, 133.3, 133.1, 128.0, 132.2, 113.2, 110.7, 128.3, 84.7, 80.5, 66.9, 64.6, 46.7, 29.9, 28.5, 28.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:3]=1.[F-:18].[Cs+]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:3]=[C:2]2[F:18]
Reactant: COCCOc1cc2c(Cl)cccc2c(Cl)n1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCOc1cc2c(Cl)cccc2c(F)n1
Temperature: 140 °C

Procedure:
To a solution of 1,5-dichloro-3-(2-methoxyethoxy)isoquinoline (578 mg, 2.124 mmol) in DMSO (5 mL) was added CsF (323 mg, 2.124 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with ethyl acteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. Crude product purified via biotage (90 g column, 5-50% EtAOc:Hex) to give the product 5-chloro-1-fluoro-3-(2-methoxyethoxy)isoquinoline (250 mg, 46% yield) as a light yellow solid. MS: MS m/z 256.15(M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:4]2([CH:8]=[CH:7][CH:6]=[CH:5]2)[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[H][H]>C(O)C>[CH3:1][C:2]1([CH3:14])[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1C(C)(C)C12C=CC=C2
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)C1C(C)(C)C12CCCC2

Procedure:
A solution of 1.54 g. of ethyl 2,2-dimethylspiro[2.4]hepta-4,6-diene-1 carboxylate prepared in Example I, above, in 30 ml. of ethanol was catalytically reduced over 50 mg. of pre-reduced platinum oxide. The theoretical amount of hydrogen was taken up over a 3 hr. period. The catalyst was removed by filtration and the alcohol was removed at reduced pressure. The residue, 1.5 g. (100%) could be used directly without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:10]([Br:11])=[C:9]([Br:12])[NH:8][N:7]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([N:7]1[C:6]([Br:5])=[C:10]([Br:11])[C:9]([Br:12])=[N:8]1)([O-:4])=[O:2]
Reactant: Brc1n[nH]c(Br)c1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])n1nc(Br)c(Br)c1Br
Temperature: 15 °C
Reaction time: 2 h

Procedure:
HNO3 (d=1.50 g/ml; 18 ml, 0.429 mol) was added dropwise over 10 minutes to a solution of 3,4,5-tribromopyrazole (1) (50 g, 0.164 mol) in glacial acetic acid (750 ml) while maintaining the temperature at 15° C. Acetic anhydride (250 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. Once the reaction was complete, the reaction mixture was poured onto crushed ice (1 kg). After stirring for 1 hour, the crude product was filtered off and then washed with demineralized water (2×60 ml) to give crude 1-nitro-3,4,5-tribromopyrazole. The water (24.6 ml) contained in the wet product was removed by heating a solution of the product in toluene (750 ml) at reflux in a Dean-Stark apparatus. The toluene solution was maintained at reflux for a further 30 minutes until a TLC (eluent:toluene) showed that the rearrangement of the 1-nitro-3,4,5-tribromopyrazole (Rf=0.77), the intermediate formed, into 3,5-dibromo-4-nitropyrazole (2) (Rf=0.05) was complete. The solution was concentrated to a residual volume of 150 ml and then allowed to cool to 60° C., followed by addition of hexane (275 ml). The solution was cooled to 0–5° C. for 1 hour and the 3,5-dibromo-4-nitropyrazole (2) (29.1 g, 65%) was recovered by filtration and drying under vacuum in the form of a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=1)[CH3:2].[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][NH:30][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCc1ccccc1
Product: CCOc1cc(CNCCc2ccccc2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 99 %

Procedure:
The compound of example 224 step 1 was reductively aminated with phenethylamine using procedures similar to those previously described to afford the title compound in 99% yield.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.[Cl:20][C:21]1[C:28]([CH3:29])=[C:27]([C:30]2[CH:34]=[CH:33][NH:32][N:31]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].CC(OC(/[N:41]=N/C(OC(C)C)=O)=O)C.Cl>CCOC(C)=O.O>[NH2:41][CH2:2][C@H:1]([N:32]1[CH:33]=[CH:34][C:30]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:20])[C:28]=2[CH3:29])=[N:31]1)[CH3:6]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: Cc1c(-c2cc[nH]n2)ccc(C#N)c1Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccn([C@H](C)CN)n2)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 20 h
Yield: 29.3 %

Procedure:
N-t-BOC-(R)-1-Amino-2-propanol (3.22 g, 18.4 mmol) and triphenylphosphine (4.82 g, 18.4 mmol) were dissolved in EtOAc (10 ml) and added to a solution of 2-chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.00 g, 9.2 mmol) in EtOAc (20 ml). Reaction mixture was cooled down to 0° C. and DIAD (3.62 ml, 18.4 mmol) was added slowly by syringe. After 20 h of reaction time at RT, water (10 ml) and conc. HCl (5.58 ml, 184 mmol) were added, and the reaction was stirred another 20 h. Reaction mixture was diluted with water, washed with DCM, and the organic phase was extracted twice with diluted HCl. Combined water phases were washed twice with DCM, made alkaline (pH 12) by adding 50% NaOH solution, and extracted twice with DCM. Combined organic phases were dried over Na2SO4 and evaporated to yield 0.74 g (29%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.43 (d, 3H), 2.57 (s, 3H), 4.29-4.38 (m, 1H), 4.70-4.85 (m, 2H), 6.63 (d, 1H), 7.69 (dd, 1H), 7.82 (dd, 1H), 7.89 (d, 1H). m/z [274.8+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][CH:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])=[CH:18][C:17]=1[F:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)c1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (79 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-fluorophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (55 mg, yield 46%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[N:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.[BH4-].[Na+].CC(O)(C)C>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[NH2:8])=[CH:12][CH:11]=1
Reactant: N#Cc1cnccn1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: NC(c1ccc(Cl)cc1)c1cnccn1
Temperature: 60 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
Pyrazine-2-carbonitrile (10.5 g, 100 mmol) was dissolved in PhMe (100 mL) at 0° C. and 4-chlorophenyl magnesium bromide (100 ml, 1.0 M in Et2O, 100 mmol) was added portion-wise over 5 min. The reaction mixture was stirred for 6 h and NaBH4 (7.58 g, 201 mmol) and tBuOH (100 mL) were added. The reaction mixture was warmed to 60° C. for 18 h and quenched with 1 M aq NaOH solution. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (DCM:EtOH:NH3 200:8:1 to 50:8:1) to give the title compound as a brown oil (7.46 g, 34%). MS (ESI+) m/z=220.0 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]>C(O)=O>[C:10]([O:9][CH:8]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])(=[O:3])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: CCOC(OCC)OC(C)=O
Yield: 54.5 %

Procedure:
Acetic anhydride (550 g), formic acid (275 g) and triethyl orthoformate (740 g) were reacted as is described in DeWolfe, Synthesis, 1974, 153-172 (scaled up five fold). The product had a b.p. of 77°-78° C. at 25 mm/Hg, and was obtained in a yield of 54.5%.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][C:16]([C:17](OC(C)(C)C)=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:48][NH:49][S:50]([NH2:53])(=[O:52])=[O:51].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>ClCCl.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][C:16]([C:17]([NH:53][S:50](=[O:52])(=[O:51])[NH:49][CH3:48])=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Reactant: CNS(N)(=O)=O
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNS(=O)(=O)NC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of tert-butyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate (0.50 g, 1.30 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (5.0 mL). The resulting mixture was stirred for 30 minutes and then concentrated in vacuo. The residue was treated with methanol (20 mL) and concentrated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (20 mL), treated with carbonyl diimidazole (0.42 g, 2.60 mmol), and refluxed under nitrogen for 30 min. The reaction mixture was cooled to ambient temperature and added (methylsulfamoyl)amine (0.43 g, 3.90 mmol) and 1,8-diazabicycloundec-7-ene (0.58 mL, 3.90 mmol). The reaction mixture was refluxed under nitrogen for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with 1 M aqueous hydrochloric acid solution (2×30 mL) and brine (30 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.12 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.65 (br s, 1H), 8.46 (d, J=2.3 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.58-7.51 (m, 1H), 3.92 (s, 2H), 2.52-2.48 (m, 3H), 2.07-1.98 (m, 1H), 1.97-1.90 (m, 3H), 1.72-1.55 (m, 12H), 0.98-0.90 (m, 2H), 0.77-0.70 (m, 2H); MS (ES+) m/z 420.2 (M+1).
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][N:21]=[C:20]3[N:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:30]=[CH:31][C:19]=23)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.C1COCC1>[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]3[N:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:30]=[CH:31][C:19]=23)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3c(N4CCC[C@H](NC(=O)OC(C)(C)C)C4)c(C(=O)O)cnc32)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Water (5 mL) and lithium hydroxide (1.5 g, 63 mmol) were added to a solution of ethyl 4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.9 g, 3.7 mmol) in MeOH (5 mL) and THF (5 mL). The mixture heated at 50° C. with stirring for 2 h. The mixture was allowed to cool to room and concentrated under reduced pressure. The residue was neutralized with 2N HCl and extracted twice with EtOAc. The organic extract was dried with Na2SO4 and concentrated under reduced pressure to give the sub-title compound (1.6 g (89%). LCMS calc. for C25H32N5O5 (M+H)+: m/z=482.2. Found: 482.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1B1OC(C)(C)C(C)(C)O1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.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>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: Cn1cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Oc1ccccc1Br
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: [K+]
Solvent: ClCCCl
Product: Cn1cccc1-c1ccccc1O
Temperature: 80 °C
Yield: 33.7 %

Procedure:
1-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole (5.0 g, 24 mmol), tetrakis(triphenylphosphine)palladium (0) (1.4 g, 1.2 mmol), 2-bromophenol (4.2 g, 24 mmol), and potassium carbonate (24 mL of 2.0 M, 48 mmol) were combined in 1,2-dichloroethane (291 mL). The mixture was heated at 80° C. for 16 h. The mixture was cooled to 25° C. before it was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, and concentrated. Column chromatography (0-100% ethyl acetate/hexanes) on the residue gave 2-(1-methylpyrrol-2-yl)phenol (1.4 g, 34%). ESI-MS m/z calc. 173.2, found 174.2 (M+1)+; Retention time: 1.76 minutes (3 min run).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:20]=[CH2:21])[C@H:12]([CH3:22])[N:11]1[C:23](=[O:33])[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:34].[Na+].OO>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:20]([OH:34])[CH3:21])[C@H:12]([CH3:22])[N:11]1[C:23](=[O:33])[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dissolve 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (477 mg, 0.95 mmol) in THF (9.5 mL). Cool to 0° C. Add BH3 (1.9 mL, 1.89 mmol, 1M in THF). Stir 4 h at room temperature. Cool to 0° C. Add NaOH (3.8 mL, 3 M in water) and H2O2 (0.58 mL, 30% wt/wt % in water). Stir overnight at room temperature. Add ethyl acetate, wash with saturated NaHCO3 solution and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-60%) to give 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (mixture of diastereomers) as a white foam (92 mg, 0.19 mmol). MS (m/z): 522 (M+1); and 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one as a white foam (254 mg, 0.49 mmol). MS (m/z): 522 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:27][C:24]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)=[O:28]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 84.1 %

Procedure:
To a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid methyl ester (4.436 g, 11.25 mmol) in tetrahydrofuran (50 mL) and water (25 mL) was added lithium hydroxide monohydrate (2.30 g, 54.81 mmol). The reaction mixture was stirred at ambient temperature for 23 h and the pH of the solution was adjusted to ˜3 with concentrate hydrochloric acid (5.3 mL) at 0° C. The mixture was concentrated. Ethyl acetate (100 mL) was added to the residue and the product was precipited. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to afford the title compound (3.60 g). The aqueous layer was extracted with ethyl acetate, dried over Na2SO4 and concentrated to give the second portion of title compound (0.463 g). The total amount of product was 4.063 g (95% yield).