Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1.BrC1N=C(C[N:37]2[CH2:47][CH2:46][C:40]3([NH:44][C:43](=[O:45])[O:42][CH2:41]3)[CH2:39][CH2:38]2)C=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:37]3[CH2:38][CH2:39][C:40]4([NH:44][C:43](=[O:45])[O:42][CH2:41]4)[CH2:46][CH2:47]3)[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1
Reactant: O=C1NC2(CCN(Cc3cccc(Br)n3)CC2)CO1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C=O)n3)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCC5(CC4)COC(=O)N5)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to Example 106 Step 2 using 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-formyl-2-pyridinyl)amino)-3-thiophenecarboxamide (19.5 mg, 0.05 mmol) and 8-[(6-bromopyridin-2-yl)methyl]-3-oxa-1,8-diazaspiro[4.5]decan-2-one (7.6 mg, 0.05 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:19][OH:20]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCCCOCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Butoxypentyl)-4-piperidone oxime is prepared from 1-(5-butoxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]O)[CH:26]=[CH:27][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: OCc1cccc(F)c1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4cccc(F)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 21.7 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3-fluorophenyl)-methanol (134 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (100 ml), and the DCM layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (45 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][Cl:31])=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1.[CH3:32][O:33][CH2:34][C:35]#[CH:36].C(NC(C)C)(C)C>[Cu]I.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:36]#[C:35][CH2:34][O:33][CH3:32])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][Cl:31])=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1
Reactant: C#CCOC
Reactant: CC(C)Oc1cc(OCCCCl)cc2ncnc(Nc3c(Cl)cc(I)c4c3OCO4)c12
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)cc(OC(C)C)c23)c2c1OCO2
Temperature: -10 °C

Procedure:
A mixture N-(5-chloro-7-iodo-1,3-benzodioxol-4yl)-7-(3-chloropropoxy)-5-isopropoxyquinazolin-4-amine (1.313 g, 1:1 wt.:wt. mixture with triphenylphosphine), 3-methoxy-prop-1-yne (0.19 ml), palladium(II) bis-triphenylphosphine dichloride (0.080 g) and copper (I) iodide (0.022 g) was taken up into ethyl acetate (15 ml) and cooled to −10° C. This was set to stir rapidly and then diisopropylamine (0.32 ml) was added and the reaction was stirred cold for 45 minutes before being warmed to room temperature and left to stir for a further 90 minutes. The reaction mixture was then filtered through Celite under suction (washing the Celite with a further portion of ethyl acetate) then the combined filtrate solutions were evaporated under reduced pressure to leave a brown gum. The gum was then purified by column chromatography on silica using diethyl ether as eluent. There was thus obtained the title compound (as a 1:1.3 wt.:wt. mixture with triphenylphosphine) (1.056 g) as a yellow solid; NMR Spectrum: (CDCl3) 1.53 (d, 6H), 2.30 (quin, 2H), 3.45 (s, 3H), 3.76 (t, 2H), 4.25 (t, 2H), 4.35 (s, 2H), 4.83 (sept, 1H), 6.10 (s, 2H), 6.49 (d, 1H), 6.85 (d, 1H), 7.06 (s, 1H), 8.52 (s, 1H), 9.42 (s, 1H)—triphenylphosphine 7.46 (m, 6H), 7.54 (m, 3H), 7.67 (m, 6H);
Reaction SMILES: [CH3:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O-:12])=[O:11])=[CH:3]1.[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([S:24]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:21][C@H:20]1[CH2:44][CH:45]1[NH:49][C:48](=[O:50])[NH:47][C:46]1=[O:51])=[O:18])[CH:14]=[CH2:15]>>[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([S:24][C:3]2[C@H:2]([CH3:1])[C@@H:6]3[C@@H:7]([C@H:8]([OH:9])[CH3:7])[C:8](=[O:9])[N:5]3[C:4]=2[C:10]([O:12][CH2:3][CH:2]=[CH2:1])=[O:11])[CH2:21][C@H:20]1[CH2:44][CH:45]1[NH:49][C:48](=[O:50])[NH:47][C:46]1=[O:51])=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1NC(=O)NC1=O
Reactant: CC1C=C(C(=O)[O-])N2C(=O)C[C@@H]12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3NC(=O)NC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 31 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (220 mg, 0.440 mmol) and (2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)-4-tritylthiopyrrolidine diastereomer B (220 mg, 0.406 mmol, compound of Reference Example 29) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer B (70 mg, yield: 31%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:13][C@H:14]1[CH2:19][O:18][CH2:17][CH2:16][NH:15]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][C@@H:14]2[CH3:13])[N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Methyl 2,6-dichloropyrimidine-4-carboxylate (5.00 g) was dissolved in DCM (120 mL). (3S)-3-Methylmorpholine (2.49 g) dissolved in triethylamine (3.70 mL) and DCM (10 mL) was added dropwise to the solution over 10 minutes. The reaction was left to stir at room temperature for 1 hour then the mixture concentrated in vacuo and dissolved in DCM (300 mL). The organics were washed with water (150 mL) and dried (MgSO4). The crude material was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (3.15 g) as a white solid.
Reaction SMILES: [F:1][C:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3].C1C(=O)N([I:36])C(=O)C1.C(O)(C(F)(F)F)=O>CC#N>[F:1][C:2]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:36])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([F:4])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
(R)-4-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (865 mg, 2.22 mmol) and NIS (550 mg, 2.45 mmol, 1.1 eq.) were dissolved in CH3CN (5 mL). Then CF3COOH (76 mg, 0.67 mmol, 0.3 eq.) was added to the mixture dropwise at 0° C. The mixture was warmed to 15° C. and stirred for another 1 h. Then the mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using PE/EA (1/1) as eluent to give the title compound as a slight red solid (1.02 g, 90%). EDI-MS (M+1): 515.8. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, 1H), 7.73 (d, 2H), 7.48 (dd, 1H), 7.18 (d, 1H), 6.49 (s, 1H), 4.45-4.40 (m, 2H), 4.33-4.30 (m, 1H), 2.27-2.25 (m, 2H), 2.03-2.01 (m, 2H), 1.84 (s, 3H), 1.65-1.24 (m, 8H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[NH:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[N+:9](=[C:11]1[N:15]=[N:14][N:13]=[C:12]1[C:16]([NH2:18])=[O:17])=[N-:10].C>C(O)C>[CH2:1]([N:5]([C:6](=[NH:8])[CH3:7])[N:10]=[N:9][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16]([NH2:18])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=C1N=NN=C1C(N)=O
Reactant: CCCCNC(C)=N
Solvent: CCO
Product: CCCCN(N=Nc1[nH]nnc1C(N)=O)C(C)=N

Procedure:
5.7 g. of N-butyl-acetamidine are dissolved in 300 ml of anhydrous ethanol, whereupon 7 g. of 5-diazo-1,2,3-triazole-4-carboxamide are added at 25° C. within half an hour. After 3 hours the solution is clarified with activated charcoal and evaporated in vacuo. The residual thick oil is admixed with 40 ml of anhydrous ethylacetate and the crude product (9.7 g. melting at 150° C. decomposition) is recrystallized from a mixture of 110 ml of acetone and 40 ml of anhydrous ethanol. Thus 6.1 g. of 5-[3-n-butyl-3-(alpha-iminoethyl)-1-triazeno]-1,2,3-triazole-4-carboxamide melting at 159°-160° C. (decomposition) are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[O:14]=[S:15]1(=[O:32])[CH2:20][CH2:19][N:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:17]2=[N:16]1.O>CS(C)=O>[CH:9]1([CH2:8][O:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]3[C:17]4=[N:16][S:15](=[O:32])(=[O:14])[CH2:20][CH2:19][N:18]4[CH:21]=[CH:22][CH:23]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: ICC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OCC4CCCC4)cc3)C2=N1
Temperature: 130 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A mixture of potassium carbonate (450 mg), (iodomethyl)cyclopentane (684 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) in DMSO (5 mL) was stirred at 130° C. for 2 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with Et2O to give the title compound (311 mg) as a pale yellow solid. The solid was crystallized from CH3CN-IPE to give a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].C([Li])(C)(C)C.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[B:16]([OH:19])[OH:17]
Reactant: COc1cc(C)ccc1Br
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
To a cooled (−78° C.) solution of 1-bromo-2-methoxy-4-methylbenzene (0.5 g; 2.49 mmol) in dry THF (12.5 mL) under argon atmosphere was added dropwise a tert-butyllithium solution (1.6M in pentane) (3.65 mL; 5.47 mmol). After 10 min, trimethyl borate (0.424 mL; 3.73 mmol) was added dropwise as a neat liquid and the reaction was stirred at −78° C. for 1 h. The reaction was allowed to warm up to room temperature and was stirred for another 1 h. The mixture was quenched with a saturated solution of ammonium chloride and the mixture was concentrated under reduced pressure. The residue was acidified with a solution of hydrochloric acid 2N and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was precipitated out off a mixture of dichloromethane-heptane, filtered, washed with heptane and dried under reduced pressure to afford 0.095 g (23%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5]CC)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][CH:2]([C:3](=[O:5])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccccc1

Procedure:
Prepared according to Procedure A using diethyl 2-methylmalonate (24.485 g, 141 mmol), aniline (9.00 mL, 99 mmol) and pyridine (16 mL) to afford product as a colorless oil after purification by chromatography on silica gel, eluting with EtOAc gradient in hexane. 1H NMR (400 MHz, chloroform-d) δ ppm 8.66 (1H, br. s.), 7.55 (2H, d, J=7.8 Hz), 7.33 (2H, t, J=8.0 Hz), 7.13 (1H, t, J=7.4 Hz), 4.20-4.33 (2H, m), 3.46 (1H, q, J=7.2 Hz), 1.56 (3H, d, J=7.4 Hz), 1.26-1.39 (3H, m).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8].I[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(O)C>[CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:8][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CCCI
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NCCCC(=O)OC
Temperature: 45 °C
Yield: 26.3 %

Procedure:
A solution of L-leucyl-L-phenylalanine N-methylamide (1.19 g) in ethanol (24 ml) was treated with methyl 4-iodobutyrate (0.93 g); the resulting colourless solution was heated to 45° C. over 16 h. The crude product was purified by flash silica chromatography, eluting with ethyl acetate/heptane (1:1 to 5:1), to furnish the title compound as an off-white solid (0.42 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[C:24]4[CH2:25][C:26]([CH3:29])([CH3:28])[O:27][C:23]=4[C:22]([O:30][CH3:31])=[CH:21][CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:32]1(=[O:38])[NH:36][C:35](=[O:37])[CH2:34][CH2:33]1>>[CH3:31][O:30][C:22]1[C:23]2[O:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]=2[C:19]([C:13]2[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:36]4[C:32](=[O:38])[CH2:33][CH2:34][C:35]4=[O:37])[CH2:10][CH2:9]3)[N:12]=2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A5) and succinimide as starting compounds.
Reaction SMILES: [NH2:1][C:2]1([C:9]#[N:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.ClCCCl.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2C(=O)C3(CCOCC3)N(CCCC(O)=O)[C:24]2=[O:40])=[CH:19][C:18]=1[C:41]([F:44])([F:43])[F:42])#[N:16]>C(N(CC)CC)C>[NH:10]=[C:9]1[C:2]2([CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[NH:1][C:24](=[O:40])[N:23]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([C:41]([F:42])([F:43])[F:44])[CH:19]=1
Reactant: CN1CCC(N)(C#N)CC1
Reactant: N#Cc1ccc(N2C(=O)N(CCCC(=O)O)C3(CCOCC3)C2=O)cc1C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN1CCC2(CC1)NC(=O)N(c1ccc(C#N)c(C(F)(F)F)c1)C2=N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Using the procedure of Stage 2 of Example 20, 153 mg of the product of Stage 1 of Example 20, 1.5 ml of 1,2-dichlorethane and 0.1 ml of triethylamine were reacted and the solution was placed in an ice-cooled water bath. 1 ml of the product of Example 7 of European Patent Application EP 0,494,819 was added and the mixture was allowed to return to ambient temperature. The reaction medium stood for one hour, was dried and the residue was purified on silica with methylene chloride-methanol: 7-3 as eluant to obtain 277 mg of the expected product (white crystals) melting at 199°-200° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[S:15](Cl)(=[O:18])(=[O:17])[OH:16].CCN(C(C)C)C(C)C>ClCCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:15]([OH:18])(=[O:17])=[O:16])[C:12]([OH:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)CCCSSc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Yield: 48.7 %

Procedure:
4-(pyridin-2-yldisulfanyl)butanoic acid (102 mg, 0.445 mmol) was coevaporated with 1,2-dichloroethane, (2×6 ml) (to remove moisture) and re-dissolved in 6 ml of 1,2-dichloroethane. The resulting solution was then placed in a preheated oil bath (75-80° C.). To this solution, sulfurochloridic acid (100 μL, ˜3 eq) was added and the resulting mixture was stirred for 5˜8 min. DIPEA (117 μL, 1.5 eq) was then added (to precipitate the product) and the resulting mixture was stirred for 5 min. Another portion of sulfurochloridic acid (40 ul, 1.33 eq) was added and the mixture was stirred for ˜15 min, followed by addition of DIPEA (63 μL, 0.81 eq) and stirred for 5 min. A third portion of sulfurochloridic acid (40 ul, 1.33 eq) was added and the mixture was stirred for 15˜20 min. The resulting mixture was removed from the oil bath and cooled (on ice bath). Aqueous NaOH (0.5 M) or concentrated Na2CO3 was added to raise the pH ˜12 and the reaction mixture was stirred for 10 min. The organic phase was separated, washed with water (2×10 ml), and neutralized with H3PO4 to pH 7. The organic phase was then concentrated to ˜5 ml and acidified with HCl to pH ˜4. The crude product was purified by passing through a C-18 column using eluting with a gradient of 100% water (containing 0.5% HAc) to 75% of water (containing 0.5% HAc)/25% of MeOH. Fractions containing the desired product (eluted out at 5˜10% of MeOH) were pooled, evaporated to afford 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (67 mg, 0.217 mmol, 48.7% yield). 1H NMR (D2O) 8.41 (dd, 1H, J=1.5, 4.9 Hz), 7.89 (m, 2H), 7.31 (m, 1H), 3.75 (dd, 1H, J=5.1, 9.6), 2.97 (m, 1H), 2.82 (m, 1H), 2.28 (m, 2H); 13C NMR 176.60, 160.28, 150.60, 140.27, 123.39, 122.92, 69.07, 37.56, 29.45; ESI MS m/z-307.8 (M-H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:8]1[NH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:7]=1[CH2:6]2.[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][C:30](Cl)=[O:31].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([N:9]1[C:8]2[C:20]3[C:5]([CH2:6][C:7]=2[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:10]1)=[CH:4][C:3]([O:2][CH3:1])=[C:22]([O:23][CH3:24])[CH:21]=3)=[O:31]
Reactant: COC(=O)CCC(=O)Cl
Reactant: COc1cc2c(cc1OC)-c1[nH]nc(Nc3cccc(F)c3)c1C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)n1nc(Nc2cccc(F)c2)c2c1-c1cc(OC)c(OC)cc1C2

Procedure:
To a mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (0.50 g, 1.5 mmol), 3-Chlorocarbonyl-propionic acid methyl ester (Compound 26a) (0.277 g, 1.8 mmole) and DMF (1.5 mL) was added Duisopropylethylamine (DIEA) (0.52 mL, 3.0 mmole) at room temperature with stirring. The reaction was stirred at room temperature over night. The reaction was quenched with water and extracted with EtOAc. The solvent was removed via rotovap and the crude material was prepped on the reverse phase HPLC. Lyophilization gave the title compound as-a white powder. MS m/z 439.9 (M+H)+;
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.[C:14]([O-:17])(=[O:16])[CH3:15].[Na+]>CC(O)=O>[C:14]([O:17][CH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Br)c(COC(C)=O)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
To a solution of methyl 4-bromo-3-(bromomethyl)benzoate obtained in step 1 (6.5 g; 21 mmol) in AcOH (32.5 mL) was added sodium acetate (3.46 g; 42 mmol) and the reaction mixture was stirred at 100° C. for 12 hours. After concentration in vacuo, the residue was partitioned between EtOAc and water. The organic layer was washed with 5% aq. NaHCO3 then brine, dried over MgSO4 and concentrated in vacuo. Purification by silica column chromatography (c-hexane/EtOAc, 5/1) afforded the title compound as a white solid (4.78 g, 79%). 1H NMR (DMSO-d6) δ 8.03 (m, 1H), 7.85-7.84 (d, J=1.3 Hz, 1H), 5.18 (s, 2H), 3.87 (s, 3H), 2.11 (s, 3H). HPLC (Method A) Rt 4.37 min (purity 98.1%).
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@H:8]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:9]=[CH:10]2>C(OCC)C>[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@H:8]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[NH:9][C@H:10]2[CH3:1]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2C=N1
Reactant: C[Mg]Cl
Solvent: CCOCC
Product: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(Br)cccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 170.8 %

Procedure:
Add methylmagnesium chloride (0.66 L, 1.99 mol, 3M in THF) to a solution of (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4 dihydroisoquinoline (93.5 g, 0.24 mol) in diethyl ether (2.8 L) at −65° C. in an appropriate vessel. Then heat the reaction mixture to 20° C. over 2 hours and stir. After 16 hours, cool the mixture to 0° C. and quench the reaction with saturated aqueous ammonium chloride solution (2.5 L) and extract with ethyl acetate (2.5 L) and filter the mixture. Wash the combined organic extracts with brine (1 L), dry over anhydrous magnesium sulfate and concentrate under reduced pressure to give the crude title compound as an oil. Combine the oil with crude products from substantially same reactions run with 48 mmol and 229 mmol of [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane and purify them by silica gel chromatography eluting with ethyl acetate in hexanes (gradient 5-65% ethyl acetate) to give the title compound (151 g, 0.41 mol). MS (m/z): 370.1 (M+1 (79Br)), 372.1 (M+1 (81Br)).