Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].CN1CCNCC1.[F:22][C:23]1[CH2:28][CH2:27][CH:26]([C@H:29]2[CH2:34][CH2:33][C@H:32]([C:35](OC)=[O:36])[CH2:31][CH2:30]2)[CH2:25][CH:24]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[F:22][C:23]1[CH2:28][CH2:27][CH:26]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH:35]=[O:36])[CH2:31][CH2:30]2)[CH2:25][CH:24]=1
Reactant: COC(=O)[C@H]1CC[C@H](C2CC=C(F)CC2)CC1
Agent: CN1CCNCC1
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C[C@H]1CC[C@H](C2CC=C(F)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8.9 ml of sodium bis(2-methoxyethoxy)-aluminum hydride and 9 ml of toluene were cooled to 0° C. while gassing with nitrogen and treated within 30 minutes with a solution of 4.15 ml of 1-methylpiperazine in 20 ml of toluene. This solution was stirred at 0° C. for a further 30 minutes and subsequently added dropwise within 45 minutes to a solution, cooled to -50° C., of 3.0 g of methyl trans-4-(4-fluoro-cyclohex-3-enyl)cyclohexanecarboxylate in 40 ml of toluene. After stirring at -50° C. for 2 hours the reaction mixture was treated with 20 ml of ethanol and poured into a 10% sodium tartrate solution. The organic phase was extracted twice with water. The aqueous phase was extracted twice with ether and the organic phases were combined, dried over magnesium sulphate, filtered and the filtrate was evaporated. The residue was purified on silica gel (5% ethyl acetate/cyclohexane) and gave 1.77 g of trans-4-(4-fluoro-cyclohex-3-enyl) cyclohexanecarbaldehyde.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]1
Reactant: OC1CCNCC1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(I)cc2c(N2CCC(O)CC2)c1S(C)(=O)=O
Yield: 62.1 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), 4-hydroxypiperidine (87 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 0.5 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, and the residue directly purified by chromatography on silica gel in dichloromethane/methanol 20:1. One obtained a yellow oil which was triturated with ethyl acetate and the resulting white crystals were filtered off. One obtained 218 mg (62%) of white crystals. MS: m/z=447 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]#[N:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N+:9]2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]#[N:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2[n+]([O-])n1-c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99877.6 %

Procedure:
To a stirred solution of the crude intermediate 2-(4-chlorophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carbonitrile 1-oxide (23 g, 0.06 mmol) in chloroform (230 mL) was added phosphorus trichloride (23 mL) and the reaction mixture was then heated at 60° C. After 2 h, the reaction was cooled to RT and ice-water added (ca. 200 mL). The organics were extracted into DCM (3×200 mL), dried (Na2SO4) and concentrated in vacuo to give (v) (20.3 g, 92%), which was used unpurified in subsequent steps. ESI-MS m/z calculated for [M+H]+: 339.1. found: 339.0. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.92-7.81 (m, 2H), 7.69-7.57 (m, 3H), 2.42-2.29 (m, 1H), 1.14-1.03 (m, 2H), 0.82-0.72 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH2:13][O:12][C:9]=3[CH:10]=2)[C:5](=[O:16])[NH:4][N:3]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH2:13][O:12][C:9]=3[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:18][CH2:19][CH2:20][Cl:21])[N:3]=1
Reactant: ClCCCBr
Reactant: Cc1n[nH]c(=O)c2cc3c(cc12)OCCO3
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nn(CCCCl)c(=O)c2cc3c(cc12)OCCO3

Procedure:
1-[4-Methyl-6,7-ethylenedioxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane was prepared analogous to Example 1 (a) by reaction of 4-methyl-6,7-ethylenedioxy-1(2H)-phthalazinone with 1-bromo-3-chloro-propane in dimethylformamide. Rf -value (chloroform/methanol = 19/1) : 0.9.
Reaction SMILES: C(N(CC)CC)C.C(OP(C#N)(=O)OCC)C.[NH2:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][N:24]2[C:33]3[C:28](=[C:29]([CH2:36][CH:37]4[S:41][C:40](=[O:42])[NH:39][C:38]4=[O:43])[CH:30]=[CH:31][C:32]=3[O:34][CH3:35])[CH2:27][CH2:26][C:25]2=[O:44])=[CH:21][CH:20]=1.[CH:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][C:48]=1[C:57](O)=[O:58]>C(OCC)(=O)C.O.CN(C=O)C>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:29]([CH2:36][CH:37]2[S:41][C:40](=[O:42])[NH:39][C:38]2=[O:43])=[C:28]2[C:33]=1[N:24]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:57]([C:48]3[CH:49]=[CH:50][C:51]4[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:47]=3)=[O:58])=[CH:46][CH:45]=1)[C:25](=[O:44])[CH2:26][CH2:27]2
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(N)cc1)C(=O)CC2
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(NC(=O)c3ccc4ccccc4c3)cc1)C(=O)CC2
Reaction time: 16 h
Yield: 76.9 %

Procedure:
0.52 g of triethylamine and 0.42 g of diethylphosphoro cyanidate (DEPC) were added with ice cooling to a DMF solution (14 ml) of 0.7 g of 5-[1-(4-aminobenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione and 0.59 g of 2-naphthoic acid, followed by stirring for 16 hours. Water and ethyl acetate were added to the reaction liquid, and the insoluble matter thus formed was collected by filtration. The collected insoluble matter was dissolved in a dichloromethane-methanol mixed solvent and concentrated. The residue was washed with diethylether and diisopropyl ether. The residue was dried under reduced pressure, giving 0.74 g (77% yield) of 5-{8-methoxy-1-[4-(2-naphthoylamino)benzyl]-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidin-2,4-dione as a white amorphous solid.
Reaction SMILES: S([C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)(C1C=CC(C)=CC=1)(=O)=O.[C-:26]#[N:27].[K+].[Cl-].[Na+].O.O>CS(C)=O>[C:26]([C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:12]1)#[N:27]
Reactant: Cc1ccc(S(=O)(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)C2)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#C[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 70.6 %

Procedure:
3-Tosyl-Cbz-(R)-pyrrolidine (20.4 g, 0.05 mol) was dissolved in DMSO (54 mL), followed by the addition of KCN (5.3 g, 0.08 mol). The reaction mixture was stirred for 5 h at 80° C. The solution was cooled to room temperature and brine/H2O (90 mL) (1/1, v/v) was added. The aqueous solution was extracted with ethyl acetate. The organic extracts were dried over MgSO4, and concentrated. The crude product was purified by column chromatography eluting with ethyl acetate/hexanes (1/1, v/v) to afford 8.13 g (65% yield) of the desired product as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=[CH:13][CH:12]=2)[C:5]([CH2:31][CH2:32][CH3:33])=[N:4]1)[CH3:2].C[N+]1([O-])CCOCC1.C(#N)C>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:3]1[C:7]([CH:8]=[O:9])=[C:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][S:24]([C:27]([F:29])([F:28])[F:30])(=[O:25])=[O:26])=[CH:15][CH:16]=2)[C:5]([CH2:31][CH2:32][CH3:33])=[N:4]1)[CH3:2]
Reactant: CCCc1nn(CC)c(CO)c1Cc1ccc(-c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCCc1nn(CC)c(C=O)c1Cc1ccc(-c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Yield: 70.1 %

Procedure:
Tetra-n-propylammonium perruthenate (46 mg) was added to a mixture of the product of Example 86 (630 mg), N-methylmorpholine N-oxide (0.46 g) and 4A molecular sieves (2.5 g) in dichloromethane (10 ml) and dry acetonitrile (10 ml) and the reaction left for 5 min. The reaction was filtered, solvent removed in vacuo and the residue adsorbed onto silica. The material was purified by chromatography eluting with System A (4:1) to give the title compound as a yellow gum (0.44 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)CCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)C(=O)CCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-butanoyl-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32](=[O:44])([O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[O:33][CH:34](I)[CH3:35].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:34]([O:33][C:32]([O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:44])[CH3:35])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(I)OC(=O)OC1CCCCC1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)OCC1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: -5 °C
Yield: 52.9 %

Procedure:
In 30 ml of N,N-dimethylformamide is dissolved 4.76 g of sodium 7β-[2-(2-aminothiazol-4-yl]acetamido]-3-acetoacetoxymethylceph-3-em-4-carboxylate and the solution is cooled to -5° C. With stirring, to the solution is added dropwise 5.0 g of 1-iodoethyl cyclohexyl carbonate, followed by stirring for further 5 minutes. The reaction mixture is poured into a mixture of 300 ml of ethyl acetate and 200 ml of ice water and the organic layer is separated. The aqueous layer is extracted with 200 ml of ethyl acetate. The organic layers are combined and washed with 150 ml each portion of ice water (three times) and saturated aqueous sodium chloride (three times) and then dried over anhydrous magnesium sulfate. The solution is then distilled off under reduced pressure and isopropyl ether is added to the residue. The resultant white powder is collected by filtration, washed with isopropyl ether and dried to obtain 3.3 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[CH2:3]1.Cl[C:14]1[N:19]=[C:18]2[N:20]([CH3:34])[C:21](=[O:33])[N:22]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[C:23](=[NH:24])[C:17]2=[CH:16][N:15]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[N:22]1[C:23](=[NH:24])[C:17]2[C:18](=[N:19][C:14]([NH:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[CH2:3][N:2]([CH3:1])[CH2:11][CH2:10]4)=[N:15][CH:16]=2)[N:20]([CH3:34])[C:21]1=[O:33]
Reactant: CN1CCc2cc(N)ccc2C1
Reactant: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: CN1CCc2cc(Nc3ncc4c(=N)n(-c5c(Cl)cccc5Cl)c(=O)n(C)c4n3)ccc2C1

Procedure:
28 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2-methyl-1,2,3,4-tetrahydroisoquinolin-6-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichlorophenyl)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 7 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23](C2CCCCO2)[N:22]=[CH:21]3)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH:33]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH2:34].C(N(CC)CC)C.Cl>CN(C=O)C.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:23]1[C:24]2[C:20](=[CH:19][C:18](/[C:8](/[C:5]3[CH:6]=[CH:7][C:2](/[CH:34]=[CH:33]/[S:35]([NH2:38])(=[O:37])=[O:36])=[CH:3][CH:4]=3)=[C:9](/[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)\[CH2:10][CH3:11])=[CH:26][CH:25]=2)[CH:21]=[N:22]1
Reactant: CC/C(=C(/c1ccc(Br)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Reactant: C=CS(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC/C(=C(/c1ccc(/C=C/S(N)(=O)=O)cc1)c1ccc2[nH]ncc2c1)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of (E)-5-(1-(4-bromophenyl)-2-phenylbut-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.1 g, 0.25 mmol), ethenesulfonamide (80 mg, 0.74 mmol), Pd(Ph3P)2Cl2 (18 mg, 0.025 mmol), triethylamine (0.25 g, 2.5 mmol) in DMF (1.25 mL) was degassed with 3 vacuum/nitrogen cycles, heated at 100° C. overnight, and then cooled to room temperature. The reaction mixture was diluted with water, extracted with EtOAc, washed with water, brine, dried over sodium sulfate, and filtered. The filtrate was concentrated down to give a residue that was redissolved in EtOH (2.5 ml). HCl (0.5 mL, 1.25 N HCl in ethanol) was added, and the mixture was heated at 80° C. for 1 h, diluted with water, and then extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a RP-C18 column using 30-100% acetonitrile in water in the presence of 0.1% TFA to afford the title compound. LCMS: 430 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C)C=O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1c2ccccc2Oc2ccccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
A solution of phenoxazine (10 g, 54.6 mmol) in dry dimethyl formamide (15 ml) was added slowly to a stirred ice cooled suspension of sodium hydride (60% dispersion in oil) (2.88 g, 60.1 mmol) in dimethyl formamide (10 ml), under an atmosphere of nitrogen. The mixture was stirred at 80° C. for 2 h and cooled to 0° C. and ethyl bromoacetate (12.78 g, 76.50 mmol) was added dropwise and stirring was continued for 12 h at 25° C. (TLC monitored). Water (50 ml) was added and the aqueous phase extracted with ethyl acetate (2×75 ml). The combined organic phases were washed with water (50 ml), brine (5 ml), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel (100-200 mesh) using a mixture of benzene and petroleum ether (1:1) to afford the title compound (5.7 g, 39%) as a pale bluish green solid. mp: 96-97° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:15]([CH3:29])[O:14][N:13]=1>N1C=CC=CC=1>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]4[C:12]([CH3:11])=[N:13][O:14][C:15]=4[CH3:29])=[CH:24][CH:23]=3)(=[O:26])=[O:27])=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cnc(C2CC2)nc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2cnc(C3CC3)nc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To a solution of 2-cyclopropylpyrimidin-5-amine (50 mg, 0.370 mmol) in pyridine (1 mL) stirred in air at room temperature was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (123 mg, 0.407 mmol). The reaction mixture was stirred at 20° C. for 30 minutes, to ensure dissolution and then left to stand overnight. The solvent was evaporated in vacuo to give the crude product which was purified by mass directed autoprep (formic acid modifier) to give the title product (74.5 mg). LCMS (2 min, formic) Rt 0.94 min, m/z (ES+) 401 (M+H).
Reaction SMILES: [CH2:1]([C:3]([OH:10])([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[CH:11]12[CH2:17][CH:14]([CH:15]=[CH:16]1)[CH2:13][CH:12]2[CH2:18][CH2:19][C:20](OC)=[O:21]>>[CH:11]12[CH2:17][CH:14]([CH:15]=[CH:16]1)[CH2:13][CH:12]2[CH2:18][CH2:19][C:20]([O:7][CH2:6][CH2:5][CH2:4][C:3]([CH2:8][CH3:9])([OH:10])[CH2:1][CH3:2])=[O:21]
Reactant: COC(=O)CCC1CC2C=CC1C2
Reactant: CCC(O)(CC)CCCO
Product: CCC(O)(CC)CCCOC(=O)CCC1CC2C=CC1C2
Yield: 91 %

Procedure:
By following the procedure of Synthesis Example 2 except that 4-ethyl-1,4-hexanediol was used instead of 4-methyl-1,4-pentanediol and methyl 3-(5-norbornen-2-yl)propionate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 4-ethyl-4-hydroxyhexyl 3-(5-norbornen-2-yl)propionate. Yield 91%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=[CH:13][C:12]=1[N+:24]([O-])=O.O.[Cl-].[NH4+]>C(O)C.ClCCl.[Fe]>[NH2:24][C:12]1[CH:13]=[N:14][N:15]([CH2:16][CH2:17][O:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:11]=1[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[C:7]#[N:8]
Reactant: COc1ccc(C#N)cc1-c1c([N+](=O)[O-])cnn1CCOC[Si](C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(C#N)cc1-c1c(N)cnn1CCOC[Si](C)(C)C
Temperature: 75 °C
Reaction time: 6 h
Yield: 86.7 %

Procedure:
To a solution of 4-methoxy-3-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)benzonitrile (900 mg, 2.4 mmol) in 25 mL ethanol was added 50 mL water, ammonium chloride (636 mg, 12 mmol), and iron powder (806 mg, 14 mmol). The reaction mixture was stirred at 75° C. for 6 hours. After cooling to room temperature, the reaction was diluted with dichloromethane and filtered through a celite pad, rinsing with more dichloromethane. The filtrate was added to 150 mL saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to yield 717 mg (84%) of 3-(4-amino-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)-4-methoxybenzonitrile, which was carried forward without purification. LCMS (ESI) m+H=375.1.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])=[CH:4][CH:3]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].N1CCC[C@H]1C(O)=O>[Cu]I.CS(C)=O>[CH3:29][S:30]([C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])=[CH:4][CH:3]=1)(=[O:32])=[O:31]
Reactant: CS(=O)[O-]
Reactant: O=C1N(Cc2ccc(Br)o2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)o1
Temperature: 100 °C
Reaction time: 72 h
Yield: 71.6 %

Procedure:
A mixture of 1′-[(5-bromo-2-furyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.70 g, 1.59 mmol), sodium methanesulfinate (85%, 0.23 g, 1.91 mmol), copper (I) iodide (0.04 g, 0.22 mmol), L-proline (0.04 g, 0.35 mmol) and dimethyl sulfoxide (4.00 mL) was heated at 100° C. After 3 days, the reaction mixture was cooled down to ambient temperature, quenched with water (50.0 mL) and extracted with ethyl acetate (3×40.0 mL). The combined organic layers was washed with brine (2×50.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate:hexane (30-50%) to afford the title compound (0.50 g, 71%): mp 177-179° C.; 1H NMR (300 MHz, CDCl3) δ 7.29 (t, 1H), 7.19 (d, 1H), 7.12-7.04 (m, 2H), 6.94 (d, 1H), 6.50 (s, 1H), 6.42 (d, 1H), 6.11 (s, 1H), 5.86 (s, 2H), 5.00 (ABq, 2H), 4.79 (ABq, 2H), 3.11 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 155.9, 154.5, 149.1, 149.1, 142.4, 141.1, 131.9, 129.1, 124.2, 124.1, 119.0, 118.4, 109.9, 108.7, 102.9, 101.6, 93.7, 80.3, 58.2, 43.4, 37.2; MS (ES+) m/z 440.0 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C2C=CC(C([O:23][C@@H:24]3[CH2:32][C@@H:27]4[O:28][C:29](=[O:31])[CH2:30][C@@H:26]4[C@H:25]3[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=O)=CC=2)C=CC=CC=1.CC(C)=O.C(=O)=O.CO>C1(C)C=CC=CC=1>[OH:23][C@@H:24]1[CH2:32][C@@H:27]2[O:28][CH:29]([OH:31])[CH2:30][C@@H:26]2[C@H:25]1[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CO
Product: OC1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](O)C[C@@H]2O1
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1.5 M solution of Diisobutylaluminum hydride in toluene (12.6 mL, 18.9 mmol) was added dropwise to a stirred solution of a compound [9a] (4.1 g, 7.2 mmol) in toluene (60 mL) at −70-−80° C. (acetone/dry ice bath). The mixture was stirred for 1 hour at the same temperature. Methanol (50 mL) was added dropwise to the stirred mixture at −70-−80° C. and the cooling bath was removed. The mixture was stirred for 1 hours at room temperature, filtered and evaporated under reduced pressure. A solution of the residue in dichloromethane (150 mL) was washed with brine (2×10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 1:2 v/v) to obtain compound [11a] (2.53 g, 90% yield).