Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32](B4OC(C)(C)C(C)(C)O4)=[CH:33][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl.C1C[O:50][CH2:49][CH2:48]1.CO>>[C:49]([C:32]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]3[C:16]([C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:43])=[CH:5][CH:6]=4)=[N:11][C:12]=2[CH:33]=1)=[CH:17][C:18]1[C:19]([CH3:27])([CH3:28])[CH2:20][CH2:21][C:22]([CH3:25])([CH3:26])[C:23]=1[CH:24]=3)(=[O:50])[CH3:48]
Reactant: COC(=O)c1ccc(C2=Nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc2c(c1)N=C(c1ccc(C(=O)O)cc1)c1cc3c(cc1N2C)C(C)(C)CCC3(C)C
Reaction time: 12 h

Procedure:
A solution of 4-[5,7,7,10,10-pentamethyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-7,8,9,10-tetrahydro-5H-5,13diazabenzo[4,5]cyclohepta[1,2-b]naphthalen-12-yl]benzoic acid methyl ester (19) (R4=CH3, Z=H, R5=CH3, 0.90 mmol) in THF/MeOH (3:1, 4 mL) is treated with 1 N NaOH (1 mL) and the mixture is stirred for 12 h. The mixture is poured into 1 N HCl and extracted with EtOAc. The extract is washed with brine, dried over MgSO4 and evaporated in vacuo. The resulting solids are collected by filtration and washed with ether/hexane (1:10) to give the benzoic acid (20) (R4=CH3, Z=H, R5=CH3) as yellow solid:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:50][N:51]1[C:60]2[C:55](=[CH:56][N:57]=[C:58]([CH3:61])[CH:59]=2)[CH:54]=[C:53]([C:62]2[CH:63]=[C:64]([NH:69]/[C:70](/[NH2:73])=[N:71]/O)[CH:65]=[CH:66][C:67]=2[CH3:68])[C:52]1=[O:74]>CN(C=O)C>[CH3:50][N:51]1[C:60]2[C:55](=[CH:56][N:57]=[C:58]([CH3:61])[CH:59]=2)[CH:54]=[C:53]([C:62]2[CH:63]=[C:64]([NH:69][C:70]3[N:71]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[O:9][N:73]=3)[CH:65]=[CH:66][C:67]=2[CH3:68])[C:52]1=[O:74]
Reactant: O=C(O)c1ccccn1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4ccccn4)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Yield: 33 %

Procedure:
To a solution of picolinic acid (1.35 g, 11 mmol), HATU (4.18 g, 11 mmol) and DIPEA (2.09 mL, 12 mmol) in dry DMF (50 mL) at rt in the presence of anhydrous Na2SO4 (7 g, 50 mmol) was added 17 (3.37 g, 10 mmol) slowly. The consumption of 17 was determined to be completed by LC/MS. Additional anhydrous DMF (50 mL) was added and the mixture was heated at 100° C. for 16 h. Solid was filtered off and most of DMF was removed under vacuum. The residue was partitioned between a mixture of water (200 mL), aqueous Na2CO3 (2 M, 20 mL), EtOAc (300 mL) and MeOH (30 mL). The organic phase was washed further with water (2×50 mL). After drying and removal of EtOAc, the residue was treated with mixtures of DCM/MeOH (30 mL/3 mL) and washed with DCM to yield A52 as a solid precipitate (1.4 g). The mother liquor was purified by silica gel chromatography (8% MeOH in DCM) to remove most impurities. Most fractions containing product were combined to obtain solid product which was further trituated in ACN (60 mL) and washed several time with ACN to give 0.9 g of product A52. Fractions containing some product but more impurities were combined to get a crude residue which was purified with preparative HPLC to recover an additional 0.3 g A52. All three batches of 1,7-dimethyl-3-(2-methyl-5-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A52) had identical NMR and LC/MS. 1H NMR (400 MHz, d6-DMSO) δ 10.1 (s, 1H), 8.83 (m, 2H), 8.18 (dt, J=8.8, 1 Hz, 1H), 8.1 (td, J=7.7, 1.7 Hz, 1H), 7.97 (s, 1H), 7.71 (ddd, J=7.6, 4.8, 1.2 Hz, 1H), 7.47 (dd, J=8.3, 2.4 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 3.66 (s, 3H), 3.34 (s, 3H), 2.01 (s, 3H). MS m/z 425.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CNc1ccc(-c2ccc(F)cc2)nc1
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ccc(-c2ccc(F)cc2)nc1)N1CCCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 46.3 mg (0.54 mmol) of piperidine. Yield: 6 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].C1CCN2C(=NCCC2)CC1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1>C(Cl)Cl>[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:8]2[S:7](=[O:13])(=[O:12])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:10](=[O:11])[CH2:9]2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: BrCc1ccc(CBr)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(CBr)cc3)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the title B compound in Example 9, 2,4-dimethoxybenzyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 6.98 mmol) in CH2Cl2 (100 mL) is treated with DBU (1.06 g, 6.98 mmol). α, α′-Dibromo-p-xylene (9.2 g, 34.9 mmol) is added and the mixture is stirred at RT for 16 h. The mixture is filtered and the filtrate is concentrated to 20 mL. The mixture is chromatographed on silica gel using CH2Cl2 as the eluent. The residual α, α′-dibromo-p-xylene is removed from the product by triturating with Et2O to afford 5-(4-bromomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid: [M+H]+=469.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:25][CH2:24][CH2:23][C@H:2]1[C:3]([NH:5][C@H:6]([C:12]([NH:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10])=[O:4]>CO.[Pd]>[NH:1]1[CH2:25][CH2:24][CH2:23][C@H:2]1[C:3]([NH:5][C@H:6]([C:12]([NH:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10])=[O:4]
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1

Procedure:
5.50 Grams of Z-Pro-Gln-NHNHBoc was dissolved in 50 ml of methanol and was catalytically reduced by using palladium as the catalyst to obtain H-Pro-Gln-NHNHBoc.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN1CCCC1=O.[Cu]>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([O:1][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=[CH:5][N:4]2[CH:8]=1
Reactant: Cc1cn2cccc(O)c2n1
Reactant: Brc1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cn2cccc(Oc3ccccc3)c2n1

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (14.8 g), bromobenzene (15.7 g), copper powder (1.0 g) and powdered potassium hydroxide (5.6 g) in N-methyl pyrrolidone was heated under reflux for 4 hrs. The solvent was removed by distillation and the residue suspended in dichloromethane, washed with 10% sodium hydroxide solution and the dichloromethane was evaporated to give 2-methyl-8-phenoxyimidazo[1,2-a]pyridine. Treatment of this compound in accordance with Examples 10 and 11 yields the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[C:9][Si](C)(C)C)=[CH:6][CH:5]=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH3:9]
Reactant: Cc1ncccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cccnc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
First, 2-methyl-3-((trimethylsilyl)ethynyl)pyridine (22.6 g, 119 mmol) was dissolved in tetrahydrofuran (dehydrated)(200 ml). To the mixture, tetrabutyl ammonium fluoride (1N tetrahydrofuran solution) (150 ml, 150 mmol) was added. The mixture was stirred at room temperature for one hour. The reaction mixture was partitioned by ethyl acetate and a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed twice with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and distilled by a rotary evaporator. To the obtained fraction, 10% palladium/carbon (900 mg) was added and stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtrated through anhydrous magnesium sulfate and cerite. To the filtrate, 10% palladium/carbon (810 mg) was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtrated through anhydrous magnesium sulfate and celite and thereafter the filtrate was concentrated to obtain the title compound (7.25 g, yield: 51.1%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[CH:14][N:4]2[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:18][CH2:17][CH2:16][NH:15][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][N:13]=[CH:14][N:4]3[N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NCCCN1CCCC1
Reactant: Clc1nn2cnnc2c2c1CCCC2
Product: c1nnc2c3c(c(NCCCN4CCCC4)nn12)CCCC3

Procedure:
A solution of 5.0 g of 6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine in 25 ml of 1-(3-aminopropyl)pyrrolidine was heated at reflux for 15 hours. Excess amine was removed by distillation and the resulting residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated. The brown residue obtained was triturated with ether and the resulting solid was recrystallized from toluene to give 6-[3-(1-pyrrolidinyl)propylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 169°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]#[N:18].[CH3:20][S:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[C:17]([C:10]1[CH:11]=[C:12]([C:14]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:30][CH:29]=2)=[O:16])[S:13][C:9]=1[S:8][C:7]1[C:6]([Cl:19])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])#[N:18]
Reactant: N#Cc1cc(C(=O)O)sc1Sc1c(Cl)cncc1Cl
Reactant: CS(=O)(=O)c1ccc(N)cc1
Product: CS(=O)(=O)c1ccc(NC(=O)c2cc(C#N)c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-cyano-thiophene-2-carboxylic acid (47 mg, 0.14 mmol) from step C of example 203 and 4-methylsulfonylaniline (26.0 mg, 0.15 mmol). The crude material was purified by reverse phase HPLC and the title compound was obtained as a yellow solid (3.5 mg, 5% yield). MS m/z: 484.94, 485.94 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([NH2:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([NH:23][C:26](=[O:28])[CH3:27])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Solvent: c1ccncc1
Product: CC(=O)NC(C)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1

Procedure:
A solution of 1-({trans-4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexyl}oxy)propan-2-amine (373 mg) and acetic anhydride (0.51 mL) in pyridine (4 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (NH, hexane/ethyl acetate). The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (265 mg) as white crystals.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8](C2C=CC(O)=CC=2)([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].CC(C1C=CC=CC=1)=C.C1(C(C)C)C=CC=CC=1>[C].[Pd]>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1CCC(c2ccc(O)cc2)(c2ccc(O)cc2)CC1
Agent: [Pd]
Agent: C=C(C)c1ccccc1
Agent: [Na+]
Solvent: CC(C)c1ccccc1
Product: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 90.3 %

Procedure:
Into a 300-ml stainless steel autoclave were charged 19.6 g (0.060 mole) of 4,4-bis(4-hydroxyphenyl)cyclohexanecarboxylic acid methyl ester, 2.9 g (0.072 mole) of sodium hydroxide, 21.3 g (0.18 mole) of α-methylstyrene, 0.4 g of 5% palladium-carbon catalyst, and 100 g of cumene. The reaction was conducted in the same manner as described in Example 1. The resulting reaction mixture was worked up in the same manner as described in Example 1 to obtain 11.6 g 4'-hydroxy-biphenyl-4-carboxylic acid in the form of white crystals. This product contained practically no impurities, and its yield as corrected for its purity was 90%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=O)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.O.[C:23]1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[CH2:23])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: Cc1ccccc1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@H]12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CS(C)=O
Solvent: O
Product: C=C1CC[C@@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C
Temperature: 65 °C

Procedure:
—Lithium amide (6.6 g) was added to a suspension of methyltriphenylphosphonium bromide (113 g) in dry toluene (300 ml) and dry dimethyl sulfoxide (24 ml). The reaction mixture was heated to 65° C. for 30 min. After cooling to 35-40° C., a solution of (14β)-3-methoxyestra-1,3,5(10)-trien-17-one [Johnson, W. S. et al, J. Am. Chem. Soc. 79, 2005 (1957); 30 g] in dry toluene (225 ml) was added and the mixture was heated at 60° C. for 22 h. Then it was cooled and poured into water. The product was extracted into ethyl acetate; the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. In order to achieve complete conversion of starting material, the procedure was repeated. The triphenylphosphine oxide was removed by addition of diethyl ether and filtration. Column chromatography of the crude product afforded (14β)-3-methoxy-17-methyleneestra-1,3,5(10)-triene (26 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:41]1([S:47](Cl)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:41]1([S:47]([CH:2]([NH2:1])[C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]3[O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:5][CH:4]=2)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CN)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(N)S(=O)(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of 47 mg (0.105 mmol) of tert-butyl (3RS,4RS)-4-(4-aminomethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 2 ml of methylene chloride was treated with 18 μl (1 2.7 mg, 0.1 26 mmol, 1.2 eq.) of triethylamine and cooled to 0° C. 15 μl (20.4 mg, 0.116 mmol, 1.1 eq.) of benzenesulphonyl chloride were added dropwise, the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. There were obtained 47 mg of crude tert-butyl (3RS,4RS)-4-[4-(phenylsulphonyl-amino-methyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, which was used in the following step without further purification and characterization.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1.C(=O)=O.CC(O)C>[CH3:17][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: O=C=O
Agent: [Li+]
Solvent: CI
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottom flask was charged THF (8 mL). The flask was flushed with argon, sealed, and fitted to balloon containing argon. The flask was cooled to −78° C. in dry ice/IPA bath. To this solution was added ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-5a, 2.28 g, 10.64 mmol) in 8 mL THF. The resulting solution was allowed to remain at −78° C. while LiHMDS (1.0 M in THF, 12.34 mmol, 12.34 mL) was added dropwise. Upon completion of addition, the solution was allowed to warm to 0° C. in ice bath. The reaction was stirred at 0° C. for one hour, at which point it was cooled back to −78° C. in dry ice/IPA bath. At this point, iodomethane (750 μL, 12.02 mmol) in THF (8 mL) was added dropwise. The reaction was allowed to gradually warm to room temperature as it was stirred overnight. After 18 hours, the reaction was quenched with sat NH4Cl(aq) and extracted with Et2O (x2). The combined organic extracts were washed with H2O (x1), saturated brine (x1), and dried over Na2SO4 and the residue were purified via silica gel chromatography to yield the title compound as a clear oil. Yield=1.44 g.
Reaction SMILES: [Cl:1]C1C(F)=C(C=C(Cl)C=1F)C(F)=O.ClC1C(F)=C(F)C(F)=C(C=1)C(F)=O.ClC1C(Cl)=C(Cl)C(Cl)=C(C=1)C(Cl)=O.[F-].[K+].FC1C=C(F)C(F)=CC=1C(O)=O.[Cl:54][C:55]1[C:56]([F:66])=[C:57]([CH:61]=[C:62]([F:65])[C:63]=1[F:64])[C:58](O)=[O:59].S(Cl)(Cl)=O>S1(CCCC1)(=O)=O>[Cl:54][C:55]1[C:56]([F:66])=[C:57]([CH:61]=[C:62]([F:65])[C:63]=1[F:64])[C:58]([Cl:1])=[O:59]
Reactant: O=C(F)c1cc(Cl)c(F)c(Cl)c1F
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)c1Cl
Agent: O=C(F)c1cc(Cl)c(F)c(F)c1F
Agent: O=C(O)c1cc(F)c(F)cc1F
Solvent: O=S1(=O)CCCC1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F

Procedure:
The benzoyl halides (1) used as starting materials for this synthetic route are prepared as follows: 3,5-dichloro-2,4-difluorobenzoyl fluoride (boiling point 97°/20 mbar; nD20 =1.5148) and 5-chloro-2,3,4-trifluorobenzoyl fluoride (boiling point (68°-70°/20 mbar; nD20 =1.4764) are obtained together by heating tetrachlorobenzoyl chloride with potassium fluoride in sulpholane at elevated temperatures: ##STR18## The chlorination of 2,4,5-trifluorobenzoic acid in chlorosulphonic acid leads to 3-chloro-2,4,5-trifluorobenzoic acid which is reacted as the crude product with thionyl chloride to give 3-chloro-2,4,5-trifluorobenzoyl chloride (boiling point 94°/18 mbar; nD20 =1.5164): ##STR19##
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:41])[CH:13]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][O:30][Si](C(C)C)(C(C)C)C(C)C)=[CH:25][CH:24]=3)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[OH:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH:13]([C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[O:41])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:28][CH:27]=1
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propylcarbamate (E138) in THF at 0° C. was added TBAF, and the solution was stirred for 45 min at 0° C. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 6% MeOH/CH2Cl2) gave pure tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH3:20])([CH3:19])[C:17](=N)[N:16]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=3)[C:15]2=[S:34])=[CH:10][CH:9]=1)(C)(C)C.C[OH:37].O>Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH3:20])([CH3:19])[C:17](=[O:37])[N:16]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:31])([F:33])[F:32])[CH:23]=3)[C:15]2=[S:34])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C2(C)C)cc1
Reactant: CO
Agent: Cl
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(N)cc1
Temperature: 25 °C

Procedure:
The mixture of 2c (0.15 g, 0.3 mmol) in HCl aq, 3N. (1 ml) and methanol (4 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (5 ml) and extracted with dichloromethane (8 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane/acetone, 9:1) to yield 4-[3-(4-aminophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 2d, [RD9] (0.118 g, 0.29 mmol, 97%) as a yellow solid.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>>[CH3:20][N:21]([CH2:1][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH2:22][CH2:23][OH:24]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Reactant: CNCCO
Product: CN(CCO)C[C@@H]1Cc2ccccc2CN1

Procedure:
Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (58 mg, 0.22 mmol) and 2-(methylamino)ethanol (21.4 μL, 0.27 mmol) provided a crude oil which was used without purification in the preparation of Example 114. MS(ESI+) m/z 221.1 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[NH2:19][C:20]1[C:24]([Br:25])=[CH:23][NH:22][N:21]=1>>[Br:25][C:24]1[CH:23]=[N:22][N:21]2[C:3]([CH:2]([F:18])[F:1])=[CH:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[N:19][C:20]=12
Reactant: Nc1n[nH]cc1Br
Reactant: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(Br)cnn12
Yield: 92.9 %

Procedure:
Prepared from 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (example C.2 step 1) (21.40 g, 80 mmol) and commercially available 3-amino-4-bromopyrazole (13.29 g, 80 mmol) as described in example C.1, step 2a to give 3-bromo-7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (29.14 g, 92%) as a yellow solid. MS (ISP) 392.0 [(M+H)+], 394.0 [(M+2+H)+].