Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=1[CH2:31][CH2:32][CH3:33].[H-].[Na+].[I-].[Na+]>CN(C)C=O>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=3[CH:15]=2)=[C:22]([CH2:31][CH2:32][CH3:33])[C:23]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CC1(C(=O)O)CCc2cc(O)ccc2O1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2)CCC(C)(C(=O)O)O3)ccc(C(C)=O)c1O
Yield: 68.9 %

Procedure:
The procedure of Example 7 was employed to alkylate 0.9 g of the ethyl ester of racemic-3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acid with 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone (1.5 g), using sodium hydride (12.16 mmole), and sodium iodide (10 mmoles), in N,N-dimethylformamide. After saponification with lithium hydroxide monohydrate (1.5 g), the crude product was purified by chromatography on silica gel. There was obtained 1.16 g (68.9%) of racemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylic acid as an off-white solid mp 108°-110.5° C.
Reaction SMILES: [S:1]1[C:5]2[C:6]([CH2:10][C:11]([OH:13])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH2:20])[S:18][CH:19]=1>>[S:1]1[C:5]2[C:6]([CH2:10][C:11]([NH:20][C:17]3[S:18][CH:19]=[C:15]([Br:14])[C:16]=3[C:21]3[NH:25][N:24]=[CH:23][N:22]=3)=[O:13])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1cccc2ncsc12
Product: O=C(Cc1cccc2ncsc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(benzo[d]thiazol-7-yl)acetic acid (25.5 mg, 0.13 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (22.3 mg, 0.093 mmol) according to protocol A. The crude product was purified by prep HPLC. LCMS Retention time (min)=4.075, method [7], MS (ESI) 421.9 (M+H). 1H NMR (CDCl3) δ 12.39 (s, 1H), 9.02 (s, 1H), 8.22, (d, J=6.6 Hz, 1H), 7.65-7.61 (m, 1H), 7.54 (s, 1H), 7.55-7.49 (m, 1H), 6.90 (s, 1H), 4.19 (s, 2H).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25]>>[OH:28][C:27]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:24](=[O:25])[C:23]=1[S:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH3:14]
Reactant: COc1ccccc1SC(C(=O)O)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: COc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2-methoxyphenyl)thio]propanedioic acid (1.51 g, 5.07 mmol). m.p. 208°-209° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 6.74 (dd, 1H), 6.82 (d, 1H), 6.86 (s, 1H), 6.97 (d, 1H), 7.08 (t, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]I.[CH3:17][O:18][CH2:19][CH2:20][NH:21][CH3:22].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][N:21]([CH2:20][CH2:19][O:18][CH3:17])[CH3:22]
Reactant: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Reactant: CNCCOC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COCCN(C)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 70 °C
Reaction time: 16 h
Yield: 492.8 %

Procedure:
A mixture of (S)-2-tert-butoxycarbonylamino-4-iodobutyric acid methyl ester (0.200 g, 0.58 mmol), (2-methoxyethyl)-methylamine (0.062 g, 0.70 mmol), and triethylamine (0.41 mL, 2.9 mmol) in dioxane (1 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in dichloromethane (20 mL). The solution was washed with water (3×10 mL), brine (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The tan oil was chromatographed eluting with ether to provide 0.87 g of pale yellow oil (49% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][OH:21].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][O:21][C:22]([CH2:23][CH3:24])=[O:25]
Reactant: Cc1cc2c(cc1C)C(CCO)N(c1cccnc1)C2=O
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Yield: 70.6 %

Procedure:
A solution of 5,6-dimethyl-2-(3-pyridyl)-3-(2-hydroxyethyl)isoindolin-1-one (50 mg, 0.18 mmol), propionyl chloride (16 mg, 0.18 mmol) and triethylamine (18 mg, 0.18 mmol) in dichlorometane was stirred at 25° C. for 3 hrs. The reaction solution was washed with water, dried, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 43 mg of the title compound.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[OH:9].CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.[OH2:27].CO>C(OCC)(=O)C.Cl[Cu]>[CH3:10][C:1]1[CH:6]=[C:5]([CH:4]=[C:3]([CH3:8])[C:2]=1[OH:9])[CH:7]=[O:27]
Reactant: O
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: Cl[Cu]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C=O)cc(C)c1O
Temperature: 25 °C
Reaction time: 9 h
Yield: 6278.4 %

Procedure:
A mixture of 13.622 g(100 mmol) of mesitol, 285 mg (1.26 mmol) of neocuproine hydrate, 503 mg (5.0 mmol) of CuCl and 120 mL of methanol was stirred at ambient temperature for 9 hours under an oxygen blanket. The reaction mixture was then diluted with ethyl acetate and filtered. The methanol was stripped off and the residue diluted with additional ethyl acetate. The solution was washed twice with a 1% solution of ethylenediaminetetraacetic acid trisodium salt (EDTA-Na3.2H2O), water and brine, dried over MgSO4 and concentrated. There was obtained 13.92 g of an orange-gold solid which was shown by 1H NMR and GC to contain 11.88 g (79.2% yield) of 3,5-dimethyl-4-hydroxybenzaldehyde (DMHB).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[C:23]#[N:24])=[N:9]S(C(C)(C)C)=O)[CH:5]=[CH:6][CH:7]=1.I[C:26]1[CH:27]=[C:28]([C:34]([F:37])([F:36])[F:35])[C:29]([O:32][CH3:33])=[N:30][CH:31]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:26]3[CH:31]=[N:30][C:29]([O:32][CH3:33])=[C:28]([C:34]([F:37])([F:36])[F:35])[CH:27]=3)[C:16]3[C:17](=[C:18]([F:22])[CH:19]=[CH:20][CH:21]=3)[C:23]([NH2:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1ncc(I)cc1C(F)(F)F
Product: COc1ncc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1C(F)(F)F
Yield: 71 %

Procedure:
The title compound was synthesized as described for Example 14i in 71% yield, starting from N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (815 mg, 2 mmol) and 5-iodo-2-methoxy-3-(trifluoromethyl)pyridine (606 mg, 2 mmol).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH2:37]>C(Cl)Cl>[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH:37][C:8]([C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1)=[O:10]
Reactant: O=C(O)c1cc(I)ccn1
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc(I)ccn1
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
To a solution of 4-iodo-picolinic acid (1.41 g, 5.66 mmol) in CH2Cl2 (35 mL) at room temperature under N2 is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.62 g, 8.49 mmol) and 1-hydroxybenzotriazole (HOBt) (0.077 g, 0.57 mmol). The solution is stirred for 5 minutes and glycine methyl ester hydrochloride (1.07 g, 8.49 mmol) is added and the reaction is stirred 16 hours. The reaction volume is concentrated under reduced pressure and the crude material was partitioned between EtOAc and 1M K2CO3. The aqueous phase is removed and the organic phase washed with H2O, sat. NaCl, dried (MgSO4), filtered and concentrated under reduced pressure to afford a brown oil which is purified over silica (EtOAc:heptane gradient 1:4) to afford 0.805 g (44% yield) of the desired product as a colorless solid. HPLC-MS: m/z 321 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.N1CCCCC1.[CH2:34]([OH:39])[CH2:35][CH2:36][C:37]#[CH:38].Cl>[Cu]I>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:38]#[C:37][CH2:36][CH2:35][CH2:34][OH:39])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: C#CCCCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Product: OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
To 3.3 g (7.72 mmol) Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester in 20 ml piperidine 447.0 mg (3.9 mmol) tetrakis(triphenylphosphine)palladium and 73.6 mg (3.9 mmol) CuI were added. At 80° C. 1.43 ml (15.45 mmol) 4-pentyn-1-ol were added slowly, and the solution was stirred for an additional hour. The cooled solution was added to ice water, acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 30:1 yielded 2.7 g (96%) 5-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol as orange oil, MS: 361(M).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.O1[CH2:14][CH2:13][NH:12]C1=O>ClCCl.O1CCOCC1>[ClH:1].[NH2:12][CH2:13][CH2:14][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1NCCO1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCNc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 3-chloroaniline (30 mL) in 500 mL of dichloromethane at 0° C. was added dropwise a solution of 4 N HCl in 1,4-dioxane (80 mL). The solution was warmed to room temperature, then concentrated to dryness in vacuo to provide a white powder. A mixture of this powder with 2-oxazolidinone (24.6 g) was heated under nitrogen atmosphere at 160° C. for 10 hours, during which the solids melted, and gas evolution was observed. The reaction was allowed to cool, forming the titled compound as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[S:41](Cl)(=[O:43])=[O:42])[CH:34]=[CH:33][CH:32]=1>>[C:25]1([S:22]([NH:21][C:3]2[CH:4]=[C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][S:41]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:40]=2[N:31]=[CH:32][CH:33]=[CH:34]3)(=[O:42])=[O:43])(=[O:24])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1cccc2cccnc12)c1ccccc1

Procedure:
N-[2-[(Phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-8-quinolinesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 8-quinolinesulfonylchloride (54 mg, 0.239 mmol) according to general method 3 to give 50 mg of a purple solid. MS (posES-FIA) m/z=Found: 524.2. Calcd: 524.13. 1H NMR δ 9.34 (dd, 1H), 8.79 (dd, 1H), 8.37 (dd, 1H), 8.25 (dd, 1H), 7.92 (dd, 1H), 7.73 (t, 1H), 7.57-7.40 (m, 5H), 7.17 (d, 1H), 6.71 (dd, 1H), 6.14 (d, 1H), 3.23-3.08 (m, 8H).
Reaction SMILES: C(O)(C)C.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][CH:7]=1.[O:19]1[CH2:21][C@@H:20]1[CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33]>O>[OH:19][C@H:20]([CH2:21][NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:10][CH:11]=1)[CH2:22][N:23]1[C:24](=[O:33])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]1=[O:32]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Solvent: CC(C)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1
Temperature: 27.5 °C

Procedure:
In a four neck round bottom flask charged Isopropyl alcohol (135 ml), 4-(4-aminophenyl) morpholin-3-one (10 g), 2-[(2s)-oxiran-2yl methyl]-1H-isoindole-1,3(2H)dione ((11.6 g) and water (15 ml) at 25 to 30° C. Slowly heated the reaction mixture to reflux and maintained for 24 h at reflux temperature. Reaction mass is cooled to 25 to 30° C. after completion of the reaction. Reaction mass then maintained at 25 to 30° C. for 30 minutes. Finally obtained solid is filtered off and washed by isopropyl alcohol (25 ml)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10](=[O:27])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[CH:15][C:14](Cl)=[N:13][CH:12]=1)([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.CCOC(C)=O>[C:5]([O:9][C:10](=[O:27])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[CH:15][C:14]([N:1]=[N+:2]=[N-:3])=[N:13][CH:12]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cnc(N=[N+]=[N-])cc1Nc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Sodium azide (1.51 g, 23.2 mmol) was added to a suspension of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid tert-butyl ester (40) (3.23 g, 7.73 mmol) in DMF (60 mL). The reaction mixture was heated to 80° C. and stirred for 16 hours. After cooling to room temperature, the reaction was diluted with EtOAc and washed with water, saturated NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated. Purification by flash column chromatography using the Biotage system (CH2Cl2) (repeated) provided the desired product (41) (1.41 g, 43%).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Li+].[CH2:11](Br)[CH2:12][C@H:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:14]>C(OCC)C.C1COCC1.[Cu](Cl)Cl>[CH3:14][C@@H:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:12][CH2:11][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)=CCC[C@H](C)CCBr
Reactant: Cl[Mg]C1CCCCC1
Agent: Cl[Cu]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)CCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A flask was charged with 100 mL of dry THF and cooled to 0° C. To this flask was added 103 mL (205 mmol) of 2 M cyclohexylmagnesium chloride in diethylether. Then 2.30 g (17 mmol) copper (II) chloride was taken up in 60 mL of THF and added as a slurry to the Grignard reagent. To this mixture was added 0.73 g (17.1 mmol) lithium chloride, and the mixture was stirred at 0° C. for 30 minutes. Then 13.5 mL (68.4 mmol) of (S)-citronellyl bromide was added, and the mixture was stirred 2 hours at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of sat. aq. NH4Cl until bubbling ceased. The THF was removed under reduced pressure. The residue was taken up in water and extracted with diethyl ether. The combined ether layers were dried over MgSO4. The drying agent was removed by filtration. The solvent was removed under reduced pressure to yield 11.48 g (76% yield) of a clear oil. The crude long-chain alkyl was not readily characterized, and was carried on without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:16]O)=[CH:14][CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:32]([CH2:16][C:15]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[N:12]=[CH:13][CH:14]=1)=[N+:33]=[N-:34]
Reactant: CS(=O)(=O)c1ccc(-n2nccc2CO)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2nccc2CN=[N+]=[N-])cc1
Reaction time: 8 h

Procedure:
To a solution of [2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-methanol (4 mmol) and diphenylphosphoryl azide (0.95 mL, 4.4 mmol, 1.1 equiv) in THF (10 mL) at rt was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL, 4.4 mmol, 1.2 equiv). The resulting solution was stirred overnight, concentrated and chromatographically purified (15% ethyl acetate in hexanes) to give 5-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (0.344 g, 31% based on 4-(methylsulfonyl)phenylhydrazine hydrochloride, LCMS: (MH)+=278.0 (rt=1.36 min) and 3-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (75 mg, 7% based on 4-(methylsulfonyl)phenylhydrazine hydrochloride, LCMS: (MH)+=278.0 (rt=1.48 min)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:12][N:13]([CH3:40])[CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[CH:22][C:21]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:40][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][N:17]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][N:23]=1)[C:7](=[O:8])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: CN(C)CCCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)N(CCCN(C)C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A solution of 6.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane is added to a solution of 2 mmol of 10-[[6-[3-(dimethylamino)-propylamino]-3-pyridinyl]carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 5 ml of diisopropylethylamine in 75 ml of dichloromethane. The solution is stirred 16 hours at room temperature, washed with water, dried (MgSO4) and the solvent removed. The residue is purified by column chromatography over silica gel with 30% methanol in chloroform as eluent to give 0.75 g of solid; mass spectrum (CI) 525 (M+1).
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)[CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([CH3:31])[CH:29]=3)[N:24]([CH2:32][C:33]([OH:35])=[O:34])[C:23]=2[CH3:36])(=O)=[O:20])=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([CH3:31])[CH:29]=3)[N:24]([CH2:32][C:33]([O:35][CH2:1][CH3:2])=[O:34])[C:23]=2[CH3:36])=[O:20])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2c(c1)c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(S(=O)c2ccc(Cl)cc2)c2cc(C)ccc21
Reaction time: 1 h

Procedure:
MCPBA (1.07 g) was added to a solution of example 1 part a) (1.79 g) in dichloromethane (20 ml) at 0° C. The reaction mixture was stirred for 1 h, after which further mCPBA (53 mg) was added and stirred for a further 30 min. The reaction mixture was allowed to reach room temperature and the sub-title compound was obtained as a white solid after filtration (0.68 g). Used directly in the next step without further purification.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=2[O:2]1.[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A mixture of (3,4-methylenedioxyphenyl)acetic acid (4.64 g, 25.74 mmol) in dry DMF (40 mL), cesium carbonate (9.2 g, 25.74 mmol) and methyl iodide (3.7 g, 26.0 mmol) in dry DMF (40 mL) was stirred at room temperature for 3h. At the end of this period, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated NaHCO3, water, brine and then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to provide pure methyl (3,4-methylenedioxyphenyl)acetate as an oil (4.38 g).
Reaction SMILES: [CH2:1]([C:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[N:7]2[N:6]=[C:5]1[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:39].[Na+].OO>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH2:9][CH:8]3[C:4]([CH2:1][CH2:2][CH2:3][OH:39])([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:5]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:6][N:7]3[C:12]=2[CH:13]=1
Reactant: C=CCC1(c2ccccc2)C(C(=O)N(C)OC)=NN2c3cc(Cl)ccc3OCC21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCCO)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Allyl-8-chloro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-2; a racemic mixture, 0.26 g, 0.64 mmol) was dissolved in anhydrous THF (5 mL) and treated with a 0.5M solution of 9-BBN (5.1 mL, 2.6 mmol) and stirred at 50° C. for 2 h. The reaction was cooled to 0° C. and treated with 3N NaOH (1 mL) and 30% H2O2 in water (1 mL), and stirred an additional hour. Upon completion, the reaction was quenched with the addition of brine (5 mL), and extracted with EtOAc (3×10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude residue was subjected to flash column chromatography (ISCO Redisep 40 g SiO2 column, 0-100% EtOAc/hexanes gradient) to provide pure 8-chloro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-3; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=2.1 Hz 1H), 7.43-7.24 (m, 5H), 6.83 (d, J=8.5, 2.1 Hz, H), 6.77 (d, J=12.5 Hz, 1H), 3.99 (dd, J=10.5, 3.5 Hz, 1H), 3.91 (s, 3H), 3.76 (br s, 1H), 3.56 (dd, J=11.0, 3.7 Hz, 1H), 3.32 (s, 3H), 2.93 (t, J=10.7 Hz, 1H), 2.59 (dt, J=12.2, 4.9 Hz, 1H), 2.42 (dt, J=12.2, 4.6 Hz, 1H), 1.90-1.60 (m, 4H); MS (M+H+, C22H24ClN3O4) 430.4 found 430.9 required.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](C(O)=O)=[CH:13][N:12]=[C:11]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:25](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([NH2:25])=[CH:13][N:12]=[C:11]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 66 °C
Yield: 40 %

Procedure:
4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 2-e, (200 mg, 0.68 mmol) was dissolved in THF (20 ml) and treated with Et3N (204 mg, 2.02 mmol) and DPPA (204 mg, 0.74 mmol). The mixture was heated at 66° C. for 12 hours. Then water was added and the resulting mixture was continued to stir at reflux for 2 h. After that the mixture was concentrated under vacuum. The residue was diluted with aq. K2CO3 followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel column with the eluent of dichloromethane/methanol=50/1 (Rf=0.7) to provide compound 2-f (72 mg, 40%).