Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[O:20][N:19]=1)[CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:10])=[O:9].C([Li])CCC.C[O:31][B:32](OC)[O:33]C>C1COCC1>[B:32]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[O:20][N:19]=1)[CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:10])=[O:9])([OH:33])[OH:31]
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Temperature: -95 °C
Reaction time: 0.17 h

Procedure:
To a solution of the title compound of step C (22.16 g, 52.85 mmol) in 264 ml THF at -95° C., n-butyl lithium (2M solution in pentane, 29.07 ml, 58.14 mmol) was added. The mixture was stirred at -95° C. for 10 minutes and trimethylborate (6.59 g, 63.42 mmol) was added and stirred at -78° C. for 15 minutes. The cold bath was removed and the mixture was warmed to room temperature slowly and stirred at room temperature for 0.5 hr. The mixture was then cooled to 0° C. and 100 ml 3N HCl was added dropwise. After stirring for 30 minutes, the mixture was extracted with CH2Cl2 (300 ml, 100 ml). The combined organic extracts were washed with 30 ml brine, dried and concentrated to give 2-borono-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide as a gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[C:20]([C:28]1[CH:29]=[C:30]([C:33](O)=[O:34])[NH:31][CH:32]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:33]([C:30]1[NH:31][CH:32]=[C:28]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:29]=1)=[O:34]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(c1ccccc1)c1c[nH]c(C(=O)O)c1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cc(C(=O)c2ccccc2)c[nH]1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-benzoyl-1H-pyrrole-2-carboxylic acid. MS: 457.4 (M+H).
Reaction SMILES: [F:1][C@@H:2]1[C:23]2[C@:18]([CH3:25])([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:4]([C@H:5]3[C@:14]([CH3:26])([CH2:15][CH2:16]2)[C@@H:8]([C:9](=[O:13])[C:10]([OH:12])=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[F:1][C@@H:2]1[C:23]2[C@:18]([CH3:25])([CH:19]=[CH:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:4]([C@H:5]3[C@:14]([CH3:26])([CH2:15][CH2:16]2)[C@@H:8]([C:9](=[O:13])[C:10]([OH:12])=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)C(=O)O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)C(=O)O

Procedure:
A solution of 1.0 g. of the butyl ester of 6α-fluoro-3,20-dioxo-16α-methyl-4-pregnene-21-oic acid in 30 ml. of benzene is combined with 1.0 g. of 2,3-dichloro-5,6-dicyanobenzoquinone and heated to the boiling point for 24 hours. The solution is then filtered and concentrated under vacuum. The residue is chromatographed with an acetone/hexane gradient on silica gel. After recrystallization from acetone/hexane, 465 mg. of the butyl ester of 6α-fluoro-3,20-dioxo-16α-methyl-1,4-pregnadiene-21-oic acid is obtained as a viscous oil. [α]D25 = + 108° (chloroform). UV: ε241 = 17,900 (methanol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[O:40]1CCCC1>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:40])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(Cl)cn5)n4)c3CO)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(Cl)cn5)n4)c3CO)ncc2c1

Procedure:
1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-chloro-pyridin-2-ylamino)-1H-pyrazole-4-carbonitrile (111 mg, 0.204 mmol) and dihydrogen tris(dimethylphosphinito)hydroplatinate (10.5 mg, 0.025 mmol) were taken up in tetrahydrofuran (3.8 ml) and water (0.38 ml). The material was stirred and heated to reflux (oil bath) for 1 hour. The mixture was cooled to ambient and the volatiles were stripped (rotary evaporator). The crude remainder was purified by preparative thin layer chromatography (2 plates, eluting first with 7% methanol in methylene chloride and then re-developing again with 7% methanol in methylene chloride). The product band was collected, providing the desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-chloro-pyridin-2-ylamino)-1H-pyrazole-4-carboxylic acid amide as an off-white powder (70 mg). LC/MS calc'd for C28H25ClFN7O3 (m/e) 561.99, obs'd 562 (M+H, ES+).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15]([F:18])(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=O.[ClH:21]>CC(C)=O>[ClH:21].[F:18][S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][NH:5][CH2:6]2)=[CH:11][CH:10]=1)(=[O:16])=[O:17]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)F)cc2C1)C(F)(F)F
Agent: Cl
Solvent: CC(C)=O
Product: O=S(=O)(F)c1ccc2c(c1)CNCC2

Procedure:
A solution of 5.0 g. (0.06 mole) of 2-trifluoroacetyl-7-fluorosulfonyl-1,2,3,4-tetrahydroisoquinoline and 100 ml. of acetone and 50 ml. of 6 N hydrochloric acid was stirred at room temperature overnight. The solution was concentrated, taken up in water, extracted with chloroform, concentrated and the water azeotropically removed. The resultant solid was recrystallized from methanol to give 7-fluorosulfonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 230°-232° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cccc1OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C=O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of (3-(benzyloxy)-2-methylphenyl)methanol (228 mg) in DMSO (5.0 mL) was added 2-iodoxybenzoic acid (280 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (200 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[N:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:5].[Cl:16][C:17]1[CH:18]=[C:19]([C:23]2[S:24][CH:25]=[C:26](CO)[N:27]=2)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[C:4]([C:6]1[N:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH2:11][C:26]1[N:27]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[S:24][CH:25]=1)=[O:9])#[N:5]
Reactant: COC(=O)c1cccnc1C#N
Reactant: OCc1csc(-c2cccc(Cl)c2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ncccc1C(=O)OCc1csc(-c2cccc(Cl)c2)n1
Yield: 25.3 %

Procedure:
Sodium methylate (0.11 g; 0.002 mole) is added to a solution of methyl 2-cyanonicotinate (3.24 g; 0.02 mole) and 2-(3-chlorophenyl)-4-(hydroxymethyl)thiazole (4.96 g; 0.022 mole) in toluene (100 cc). The methanol/toluene azeotrope is distilled off and the toluene is then evaporated off. The residue is treated with water. The precipitate formed is filtered off, washed with water and then dried. Compound 2 (1.8 g; 25% m.p. 130° C.) is obtained.
Reaction SMILES: [CH2:1]1[CH2:17][O:16][C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH2:4][CH2:5][CH2:6][N:7]=[N+]=[N-])[O:2]1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:17]1[CH2:1][O:2][C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([CH2:4][CH2:5][CH2:6][NH2:7])[O:16]1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4,4-Ethylenedioxy-4-phenylbutylazide (130.0 mg, 0.56 mmol) was dissolved in tetrahydrofuran (5 ml), and thereto were added water (0.01 ml, 0.56 mmol) and triphenylphosphine (146.2 mg, 0.56 mmol) in a tetrahydrofuran solution (2 ml) in sequential order at the same temperature, and thereafter, the solution was stirred at room temperature for 24 hours. The reaction solution was added to a saturated aqueous sodium hydrogencarbonate solution and then extracted by chloroform, to obtain an organic layer. The extracted organic was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant substance was purified by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained as a colorless oil (61.8 mg, 56.4% for 2 steps).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[C:2]=[S:3].[NH2:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)[O:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].CCN(CC)CC>CN(C1C=CN=CC=1)C.C1COCC1>[CH:4]1([NH:1][C:2](=[S:3])[NH:10][C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[O:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: S=C=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cccc(NC(=S)NC2CCCCC2)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of isothiocyanatocyclohexane (27) (0.16 mL, 1.17 mmol), tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) (0.282 g, 1.12 mmol), DMAP (0.024 g, 0.196 mmol) and Et3N (0.3 mL, 2.15 mmol) in anhydrous THF was stirred under argon at 50° C. for 24 h. The mixture was concentrated under reduced pressure. Purification by flash chromatography (30% to 60% EtOAc—hexanes gradient) gave tert-butyl 2-(3-(3-cyclohexylthioureido)phenoxy)ethylcarbamate (28) as a white solid. Yield (0.1917 g, 44%); 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.59 (br.d, J=7.6 Hz, 1H), 7.15 (t, J=8.2 Hz, 1H), 6.97 (br.t, J=5.5 Hz, 1H), 6.85-6.89 (m, 1H), 6.58-6.63 (m, 1H), 4.06 (br.s, 1H), 3.88 (t, J=5.9 Hz, 2H), 3.25 (q, J=5.7 Hz, 2H), 1.82-1.90 (m, 2H), 1.60-1.70 (m, 2H), 1.47-1.57 (m, 1H), 1.36 (s, 9H), 1.07-1.34 (m, 6H).
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[O:14]=[C:4]1[C:5]2[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[S:1][CH:2]=[CH:3]1
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano-[3,2-b]indol-4(5H)-one is alkylated with ethyl bromoacetate to give 6.0 g of product, mp 163°-165° C., after recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:19][C:20]([NH:22][CH2:23][CH:24]=[CH2:25])=[S:21])[CH:17]=[CH2:18]>>[ClH:1].[CH2:23]([N:22]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:21][C:20]1=[N:19][CH2:16][CH:17]=[CH2:18])[CH:24]=[CH2:25]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: C=CCNC(=S)NCC=C
Product: C=CCN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1CC=C
Product: Cl

Procedure:
5.2 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 2.5 g of 1,3-diallyl-thiourea were reacted according to the prescription given in Example 12, the end product was precipitated with diisopropyl ether and the oil obtained was crystallized with diethyl ether/ethyl acetate (1:1). Colorless solid body: melting point: 158° C. (decomposition).
Reaction SMILES: Cl.[C:2]([NH:6][SiH:7](NC(C)(C)C)[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])([CH3:4])[CH3:3].C(N[SiH2]N([SiH2]NC(C)(C)C)C(C)(C)C)(C)(C)C>>[C:9]([NH:8][SiH2:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N[SiH](NC(C)(C)C)NC(C)(C)C
Agent: CC(C)(C)N[SiH2]N([SiH2]NC(C)(C)C)C(C)(C)C
Agent: Cl
Product: CC(C)(C)N[SiH2]NC(C)(C)C

Procedure:
The product of the reaction was a BTBAS-containing crude liquid having a TBA.HCl salt contained therein. The liquid was analyzed by GC analysis and found to contain the following: 91.90% TBA, 7.34% BTBAS, 0.13% 3-aza-2,2,8,8-tetramethyl-5-oxa-4,6-disilanane, 0.012% tris(tert-butylamino)silane, 0.028% bis{[(tert-butyl)amino]silamethyl}(tert-butyl)amine, and 0.064% other impurities present in minor amounts.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][C@H:33]([CH3:35])[CH2:32][C@H:31]([NH:36]C(=O)OC(C)(C)C)[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.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>CN(C=O)C>[NH2:36][C@H:31]1[CH2:32][C@@H:33]([CH3:35])[CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30]1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(N)cnc3c2CCO3)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (13.7 mg, 0.0541 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (15.9 mg, 0.0456 mmol), and HATU (59.1 mg, 0.155 mmol), DMF (1.0 mL) was added followed by DIPEA (70.1 μL, 0.402 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (8.5 mg, 38%). LCMS calc. for C25H25F3N5O2 (M+H)+: m/z=484.2. found 484.2.
Reaction SMILES: Cl.C(O[C:5](=[NH:16])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].[CH3:19][C:20]1[CH:21]=[C:22]([C:26]([NH:28][NH2:29])=[O:27])[O:23][C:24]=1[CH3:25]>C(Cl)(Cl)Cl>[NH2:16][C:5](=[N:29][NH:28][C:26]([C:22]1[O:23][C:24]([CH3:25])=[C:20]([CH3:19])[CH:21]=1)=[O:27])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1cc(C(=O)NN)oc1C
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)NN=C(N)CS(=O)(=O)c2ccccc2)oc1C
Yield: 85 %

Procedure:
A suspension of 1.18 g (0.004 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 15 ml chloroform was treated with 6 ml 1N aqueous sodium hydoxide. The mixture was extracted with dichloromethane. The extracts were combined and dried with magnesium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 0.68 g (0.004 mol) 4,5-dimethyl-furan-2-carboxylic acid hydrazide in 10 ml chloroform for 24 hours at reflux temperature. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 19/1 gave 1.14 g (76%) 4,5-dimethyl-furan-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide as white crystals with mp. 197-199° C., MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([C:10]([OH:12])=O)[CH2:5][C:4]([F:7])([F:6])[C:3]1([F:9])[Cl:8].S(Cl)([Cl:15])=O>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][C:2]1([C:10]([Cl:15])=[O:12])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:8])[F:9]
Reactant: CC1(C(=O)O)CC(F)(F)C1(F)Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C(=O)Cl)CC(F)(F)C1(F)Cl
Yield: 75.4 %

Procedure:
One drop of dimethylformamide is added to a mixture of 91.2 g (0.45 mol) of 1-methyl-2,3,3-trifluoro-2-chlorocyclobutane-1-carboxylic acid and 450 ml of chloroform. After this, 80.3 g (0.675 mol) of thionyl chloride are added dropwise at 25°-30° C. with stirring, and the stirred mixture is heated to the boil. After 6 hours the mixture is cooled, the solvent is stripped off, and the residue is subjected to fractional distillation under reduced pressure. 75 g (75% of theory) of 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carbonyl chloride are obtained in form of a liquid of boiling point 65°-70° C. at 20 mbar. ##STR60##
Reaction SMILES: C=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:11]3[N:31]=[CH:32][CH:33]=[C:10]3[N:9]=2)[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.O.[O-:43]S([O-])(=S)=O.[Na+].[Na+]>O1CCOCC1.O=[Os](=O)(=O)=O>[CH3:30][Si:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][O:24][CH2:23][N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[C:12]1[N:11]2[N:31]=[CH:32][CH:33]=[C:10]2[N:9]=[C:8]([CH:5]2[CH2:4][CH2:3][C:2](=[O:43])[CH2:7][CH2:6]2)[CH:13]=1
Reactant: C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=S([O-])([O-])=S
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To 5-(4-methylenecyclohexyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (4.60 g, 9.41 mmol) in dioxane (50 mL) was added OsO4 (2.5 w % in tBuOH, 5 mol %), 2,6-Lutidine (4.37 mL, 37.6 mmol) and H2O (10 mL). The resulting mixture was stirred at room temperature for 20 min, then NaIO4 (8.05 g, 37.6 mmol) was added and the reaction mixture was stirred at room temperature overnight. LCMS showed very good conversion to the desired product (491). Na2S2O3 (sat.) was added and the mixture was stirred for 10 min. Dioxane was removed and the residue was extracted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.15 in 20% EtOAc) to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone as a colorless oil (3.37 g, 73%).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43]N)=[CH:39][CH:38]=1>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:40](=[CH:41][CH:42]=1)[NH:43][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1)=[C:21]2[CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:33])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3cccc([N+](=O)[O-])c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 555.2 (M+H)+.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:12][NH:11][CH2:10]1)(C(C)(C)C)(C)C.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)[CH2:15][CH2:14]1.CC([O-])(C)C.[Na+].O1CCOCC1>O>[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:11]3[CH2:10][CH:9]([OH:8])[CH2:12]3)=[CH:20][CH:19]=2)[CH2:14][CH2:15]1
Reactant: Ic1ccc(OCC2CC2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OC1CN(c2ccc(OCC3CC3)cc2)C1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
6.50 g (26.0 mmol) 3-(tert-butyldimethylsilyloxy)azetidine, 7.13 g (26.0 mmol) of 1-(cyclopropylmethoxy)-4-iodobenzene (WO2012/028676), 10.0 g (104 mmol) NaOtBu and 1.54 g (2.08 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2-(2-aminoethyl)-phenyl)-palladium (II) are added to 65 mL dioxane and stirred at 75° C. for 2.5 h under inert gas atmosphere. Water is added and the resulting mixture is extracted with EtOAc. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo. The resulting crude product is purified by HPLC (ACN/H2O/NH3).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:8]([C:18]([OH:20])=[O:19])=[CH:7][CH:6]=1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.Cl>ClCCCl>[C:24]([CH2:23][CH2:22][C:21]([C:13]1[CH:14]=[C:15]2[C:10]([C:9]3[C:8]([C:18]([OH:20])=[O:19])=[CH:7][CH:6]=[CH:5][C:17]=3[CH2:16]2)=[CH:11][CH:12]=1)=[O:27])([OH:26])=[O:25]
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc2c(c1)Cc1cccc(C(=O)O)c1-2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a dry argon-purged round bottom flask anhydrous AlCl3 (26.9 g, 0.202 mol) was suspended in anhydrous 1,2-dichloroethane (60 mL). 4-Fluorenecarboxylic acid (10.0 g, 0.048 mol) was added to the suspension. The reaction flask was placed in a room temperature bath and succinic anhydride (5.72 g, 0.057 mol) was carefully added. The reaction was stirred for five hours and then cooled to 0° C. The reaction was very carefully quenched by the slow portion-wise addition of 3 M HCl (Caution! The reaction can react violently when HCl is added too rapidly.) The final well mixed suspension was acidic and not reactive to additional HCl solution. The organic solvent was removed at reduced pressure and the product was filtered and washed well with water. The crude product was dissolved in warm NaOH solution (approximately <1M NaOH), filtered and precipitated with the addition of concentrated HCl. The product was filtered washed with water and then dried at reduced pressure in the presence of P2O5. The product was a pale yellow solid (14.3 g, 97%). 1H-NMR (d6-DMSO): δ (ppm) 8.4 (d, 1H, Ar); 8.2 (s, 1H, Ar); 8.0 (d, 1H, Ar); 7.8 (m, 2H, Ar); 7.5 (t, 1H, Ar); 4.1 (s, 2H, CH2); 2.6 (t, 2H, CH2) 2.5 (under DMSO, CH2).