Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (101 mg, 0.54 mmol) and 1-iodo-3-(trifluoromethyl)benzene (0.09 mL, 0.62 mmol) according to the general procedure IC to give 119 mg (67%) of an yellow oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.58 (EtOAc:hexanes, 2:5); 1HNMR (CDCl3) δ 7.77 (s, 1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.48-7.43 (m, 3H), 7.21-7.18 (m, 2H), 3.67 (s, 3H), 3.00-2.94 (t, 2H, J=7.8 Hz), 2.67-2.61 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 141.4, 134.6, 131.8, 128.8, 128.4, 128.3, 128.3, 124.7, 124.6, 124.6, 124.3, 120.5, 90.8, 87.5, 51.6, 35.3, 30.8; ESI-MS m/z 355.1 (MNa+).
Reaction SMILES: Cl[C:2](OCC)=O.[OH-].[Na+].[CH3:9][NH:10][CH2:11][CH:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:15]=1)[OH:13]>O.C(Cl)(Cl)Cl>[CH3:9][N:10]([CH3:2])[CH2:11][CH:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:15]=1)[OH:13]
Reactant: CCOC(=O)Cl
Reactant: CNCC(O)C1=CC2(CCCC2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CC(O)C1=CC2(CCCC2)c2ccccc21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (0.7 g) and sodium hydroxide (0.3 g) dissolved in water (10 ml) are added to 2-methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol (1.3 g) in chloroform (25 ml). The mixture is stirred vigorously for 2 hours at about 10° C. The chloroform layer is separated, washed with water and dried. The solvent is removed in vacuo and the residual crude 2-(N-ethoxycarbonyl-N-methylamino)-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is dissolved in tetrahydrofuran (75 ml) and added to lithium aluminium hydride (2.0 g) in tetrahydrofuran (25 ml). The mixture is refluxed for 3 hours, and the excess of hydride is destroyed with a slight excess of saturated aqueous sodium sulphate solution. The inorganic salt precipitate is filtered off and washed with tetrahydrofuran. The combined filtrate and washings are dried over sodium sulphate and the solvent is removed under reduced pressure. The crude title compound is dissolved in acetonitrile and treated with a slight excess of oxalic acid dissolved in acetonitrile. The slowly depositing hydrogen oxalate is collected by filtration and recrystallization from acetonitrile; m.p. 133°-134° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19](O)/[C:20](/[CH3:33])=[CH:21]/[CH2:22]C(C)C(C)(O[SiH3])C(C)(C)C)=[C:16]([O:35][CH3:36])[C:15]([CH3:37])=[C:14]2[C:10]=1[C:11](=[O:38])[O:12][CH2:13]2)(C(C)(C)C)([CH3:3])[CH3:2].C(O)(=O)[C:40]([CH3:43])([CH3:42])[CH3:41]>C(OCC)(OCC)(OCC)C.CCOCC>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:33])/[CH:21]([CH2:22][CH2:17][CH2:9][O:8][Si:1]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:3])[CH3:2])[CH2:10][C:11]([O:12][CH2:13][CH3:14])=[O:38])=[C:16]([O:35][CH3:36])[C:15]([CH3:37])=[C:14]2[C:10]=1[C:11](=[O:38])[O:12][CH2:13]2)([C:20]([CH3:21])([CH3:33])[CH3:19])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)O
Reactant: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC(O)/C(C)=C/CC(C)C(C)(O[SiH3])C(C)(C)C)C(=O)OC2
Agent: CCOC(C)(OCC)OCC
Solvent: CCOCC
Product: CCOC(=O)CC(CCCO[Si](C)(C)C(C)(C)C)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reaction time: 0.5 h
Yield: 276.5 %

Procedure:
(E)-7-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-1-tert-butyldimethyl-silyloxy-6-hydroxy -5-methylhept-4-ene (4.74 g) was dissolved in triethyl orthoacetate (76 ml) and pivalic acid (171 mg) was added. The solution was placed in an oil bath preheated to 130° C., and stirred for 2 1/2 hrs. After cooling, the reaction was diluted with ether, washed with 1N NaHSO4 (3×), saturated sodium bicarbonate, brine, and dried. The solvent was evaporated and the resulting oil chromatographed on silica gel (20% ethyl acetate in hexanes) to give ethyl (E) 6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy -7-methyl-3-oxoisobenzofuran -5-yl)-3-(3-tert -butyldimethylsilyloxypropyl) -4-methylhex-4-enoate (2.94 g), a compound of Formula 802.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=1>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:20][C:21]3[CH:22]=[C:23]([C:35]([F:36])([F:37])[F:38])[C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#Cc1ccc(-c2ccc(N)cc2C(F)(F)F)cc1
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(NC(=O)Cc3ccc(-n4cnc5ccccc54)cc3)cc2C(F)(F)F)cc1

Procedure:
The title compound is prepared as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid (Step 20.1) and 4′-amino-2′-trifluoromethyl-biphenyl-4-carbonitrile. Title compound: ES-MS: 496.9 [M+H]+; single peak at tR=4.37 min (System 1); Rf=0.12 (CH2Cl2/MeOH, 96:4).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:27]1([C:26]2[C:21]([N:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[N:22][CH:23]=[CH:24][N:25]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2N2CCCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(N2CCNCC2)c(N2CCCCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
Add trifluoroacetic acid (1.00 mL, 13.24 mmol, 10 eq) to a solution of 3′-piperidin-1-yl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.46 g, 1.32 mmol, 1 eq) in DCM (10 mL) then stir the mixture at room temperature for 4 hr. Concentrate the reaction mixture, then dissolve in methanol and load on to a 10 g SCX-2 ion exchange cartridge (pre-washed with methanol). Wash with one column volume of methanol then elute with one column volume of 3.5 M ammonia in methanol. Concentrate to give 3′-piperidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.317 g, 0.97%). MS (m/z): 248.2 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:23])[C:10]3[C:15]([O:16][C:17]=2[C:18]=1[O:19][CH2:20][CH:21]=[CH2:22])=[CH:14][CH:13]=[CH:12][CH:11]=3)C=C.[C:24]1(OC2C=CC=CC=2)[CH:29]=CC=C[CH:25]=1>>[CH2:29]([C:18]12[C:5](=[O:4])[CH:6]3[CH:7]=[C:8]4[C:17]1([CH:21]([CH2:22]3)[CH2:20][O:19]2)[O:16][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:9]4=[O:23])[CH:24]=[CH2:25]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccc2c(=O)c3ccccc3oc2c1OCC=C
Product: C=CCC12OCC3CC(C=C4C(=O)c5ccccc5OC431)C2=O
Temperature: 25 °C
Yield: 12 %

Procedure:
A stirred solution of 3,4-bis-allyloxy-xanthen-9-one (236.4 mg, 0.767 mmol) and diphenyl ether (3.0 mL) was refluxed in an oil bath at 190° C. for 11 h. The solution was cooled to room temperature and product was purified twice by flash column chromatography (dichloromethane) to yield 28.0 mg (12%) of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.95 (dd, J1=7.69 Hz, J2=1.65, 1H), 7.56 (ddd, J1=8.17 Hz, J2=7.07, J3=1.58, 1H), 7.34 (d, J=7.14Hz, 1H), 7.08 (m, 1H), 5.22 (m, 1H), 4.69 (m, 1H), 4.53 (m, 1H), 3.91 (d, J=7.97 Hz, 1H), 3.53 (ddd, J1=6.11 Hz, J2=3.43, J3=2.06, 1H), 2.82 (dd, J1=13.33 Hz, J2=5.35, 1H), 2.63 (m, 1H), 2.51 (dd, J1=13.60 Hz, J2=9.48, 1H), 1.90 (m, 1H), 1.78 (ddd, J1=12.22 Hz, J2=10.38, J3=2.39, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl.Cl[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1
Reactant: O=C1CNCCN1
Reactant: ClCCc1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(CCc2ccccn2)CCN1
Yield: 33.2 %

Procedure:
Piperazinone (2.2 g, 22 mmol), 2-(2-chloroethyl)pyridine hydrochloride (3.9 g, 22 mmol) and i-Pr2NEt (5.67 g, 7.6 mL, 44 mmol) were heated at reflux for 16 h. The mixture was concentrated, and the residue was purified by column chromatography (80 g ISCO column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 90% methylene chloride) to provide the title compound (1.5 g, 33%) as a yellow solid; ESI MS m/z 206 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:16][CH2:15][CH2:14][C:13]3[C:8](=[N:9][N:10]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:11](=[O:17])[CH:12]=3)[C:6]=2[CH:7]=1.CC(C)=[O:27].O.O.O.Br[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:16](=[O:27])[CH2:15][CH2:14][C:13]3[C:8](=[N:9][N:10]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)[C:11](=[O:17])[CH:12]=3)[C:6]=2[CH:7]=1
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(Cl)ccc1SCC2
Reactant: CC(C)=O
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(Cl)ccc1S(=O)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2.4 g of 10-chloro-2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, prepared in Example 11 in 25 ml of water and 300 ml of acetone is added 2.8 g of sodium hypobromite trihydrate. The mixture is stirred for 18 hours at room temperature and concentrated under reduced pressure. To the residue is added water, the precipitated crystals are collected by filtration and recrystallized from dimethylformamide-water to give 1.0 g of 10-chloro-2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]-pyridazin-3(2H)-one 7-oxide, melting at 239°-241° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH3:8][C:9]([CH3:13])=[CH:10][CH:11]=[CH2:12].P(Cl)(Cl)(Cl)=O>[Zn].CCOCC>[Cl:1][C:2]1([Cl:7])[CH:11]([CH:10]=[C:9]([CH3:13])[CH3:8])[CH2:12][C:3]1=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CC=C(C)C
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)=CC1CC(=O)C1(Cl)Cl

Procedure:
The first step of Example 1 was repeated employing as the reactants, 5.6 ml trichloroacetyl chloride (50 mmol), 5 g (60 mmol) 4-methyl-1,3-pentadiene, 4.6 ml (50 mmol) phosphoryl chloride, 5 g (78 mmol) zinc and 500 ml ether. The yield was 6.8 g. or 71% theoretical, boiling at 65°-67° C. at 0.2 torr.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:5]3[C:4]=2[CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]([N:18]=[CH:21][N:22]([CH3:24])[CH3:23])=[O:17])[N:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=NC(=O)c1cn2c(n1)-c1cc(Cl)ncc1OCC2

Procedure:
A mixture of 10-chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-2-carboxamide (1.290 g, 4.875 mmol) and 1,1-Dimethoxy-N,N-dimethylmethanamine (3.238 mL, 24.37 mmol) in 70 ml of toluene was heated under reflux for 1 hour. After cooling the product precipitated from the reaction mixture, collected, washed with ethyl ether and dried on air. Weight 0.705 g (85%). MS (ESI+): 320.1
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:19]([F:22])([F:21])[F:20])=[C:7]([CH:18]=1)[C:8]([O:10]CC1C=CC=CC=1)=[O:9])#[N:2].[H][H]>[Pd].CO>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:19]([F:20])([F:21])[F:22])=[C:7]([CH:18]=1)[C:8]([OH:10])=[O:9]
Reactant: N#Cc1ccc(C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCc1ccc(C(F)(F)F)c(C(=O)O)c1
Reaction time: 8 h
Yield: 50 %

Procedure:
Combine benzyl 5-cyano-2-(trifluoromethyl)benzoate (3.9 g, 12.78 mmol, 1.0 equiv), palladium (10 wt % on carbon, 400 mg, 0.38 mmol, 0.03 equiv), and methanol (128 mL), and purge the mixture with hydrogen. Stir overnight under a hydrogen atmosphere. Filter the mixture through a pad of diatomaceous earth, and then rinse the pad with hot methanol (3×150 mL) to bring through precipitated product. Concentrate the filtrate under reduced pressure to give the title compound (1.4 g, 50%). MS (m/z) 220 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[C:8]([NH:13][CH3:14])=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].C(O[C:22](=[O:24])[CH3:23])(=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[C:8]([N:13]([CH3:14])[C:22](=[O:24])[CH3:23])=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CNc1ncccc1C(=O)c1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C)c1ncccc1C(=O)c1cccc(Cl)c1
Yield: 90 %

Procedure:
Acetic anhydride (40 ml) solution containing 3-(3-chlorobenzoyl)-2-methylaminopyridine (3.16 g, 13 mmol) was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (benzene-ethyl acetate) to give N-[3-(3-chlorobenzoyl)-2-pyridyl]-N-methylacetamide (3.34 g, 90%).
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.Cl.Cl.[CH3:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([O:27][CH2:28][C:29]3[C:30]([Cl:54])=[C:31]([S:36]([N:39]4[CH2:43][CH2:42][CH2:41][C@H:40]4[C:44]([NH:46][CH2:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[O:45])(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=3[Cl:35])[CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[ClH:35].[ClH:1].[CH3:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([O:27][CH2:28][C:29]3[C:30]([Cl:54])=[C:31]([S:36]([N:39]4[CH2:43][CH2:42][CH2:41][C@H:40]4[C:44]([NH:46][CH2:47][CH:48]4[CH2:49][CH2:50][N:51]([C:9](=[O:11])[C:8]5[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:13][CH:12]=5)[CH2:52][CH2:53]4)=[O:45])(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=3[Cl:35])[CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: NN=Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(S(=O)(=O)N4CCC[C@H]4C(=O)NCC4CCNCC4)c3Cl)c2n1
Agent: Cl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(S(=O)(=O)N4CCC[C@H]4C(=O)NCC4CCN(C(=O)c5ccc(C=NN)cc5)CC4)c3Cl)c2n1

Procedure:
By following a procedure analogous to Example 23, starting from 4-(aminoiminomethyl)benzoic acid hydrochloride and 1-[[3-[(2-methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[(piperidin-4-yl)methyl]-2(S)-pyrrolidinecarboxamide dihydrochloride, the expected product is obtained in the form of a powdery white solid (yield=39%) after purification by means of reversed phase chromatography on RP18-grafted silica gel using a water/acetonitrile/hydrochloric acid mixture (63/32/1; v/v/v) as the eluent.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:9]([CH2:10][CH:11]=O)=[CH:8][N:7]=[C:6]2[N:13]([S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:5]=12.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH4-].[Na+]>ClCCCl>[Cl:3][C:4]1[C:9]([CH2:10][CH2:11][NH:2][CH3:1])=[CH:8][N:7]=[C:6]2[N:13]([S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:5]=12
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(CC=O)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: CNCCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
Methylamine gas was bubbled into a solution of 2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetaldehyde (1.45 g, 4.16 mmol) in DCE (50 mL) for about 10 min. NaBH(OAc)3 (1.69 g, 7.97 mmol) was added and the mixture was stirred at rt. After about 45 min, the mixture was concentrated under reduced pressure then dissolved in MeOH (25 mL) and treated with NaBH4 (0.236 g, 6.24 mmol). After about 10 min, the mixture was concentrated under reduced pressure then partitioned between DCM (50 mL), saturated aqueous NaHCO3 (20 mL) and water (30 mL). The layers were separated then the aqueous layer was extracted with DCM (20 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified by preparative reverse phase HPLC (Table 2, Method i). The desired fractions were collected then most of the MeCN was removed under reduced pressure. The solution was basified with saturated aqueous NaHCO3 and the solids were collected by filtration to give 2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylethanamine (0.67 g, 44%): LC/MS (Table 2, Method a) Rt=1.88 min; MS m/z 364 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@H:7]([O:8][C:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:29])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: O=C1CCC(=O)O1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1[C@H](OC(=O)CCC(=O)O)O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Artemisinin (500 mg) and cation exchange resin (1 g) are stirred in tetrahydrofuran (10 ml) at room temperature for 5 minutes. Sodium borohydride (250 mg) is added slowly for 10 minutes and the reaction mixture is stirred for about 30 minutes at room temperature (20-35 degree C.). After completion of the reaction succinic anhydride (250 mg) and triethylamine (0.7 ml) are added at room temperature and the reaction mixture is stirred further for 1 hours at room temperature. The resin is filtered. After usual workup and column chromatography of the crude product (710 mg), 480 mg of pure artesunic acid (yield=96% w/w) is obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=C(OC)C=C2C=1C=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: N#Cc1c[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2c(C#N)c[nH]c2c1

Procedure:
3-(3-Cyano-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester CLII was prepared from 6-bromo-1H-indole-3-carbonitrile using the procedure described above for preparation of 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester CXVI (Example 25).
Reaction SMILES: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1.[CH3:39][Si:40]([CH3:73])([CH3:72])[CH2:41][CH2:42][O:43][CH2:44][N:45]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:46]1[N:51]2[N:52]=[CH:53][CH:54]=[C:50]2[N:49]=[C:48]([CH:55]2[CH2:60][CH2:59][C:58](=[CH:61][C:62]#[N:63])[CH2:57][CH2:56]2)[CH:47]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(=CC(OCC)=O)CC2)C=1>>[CH3:72][Si:40]([CH3:39])([CH3:73])[CH2:41][CH2:42][O:43][CH2:44][N:45]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:46]1[N:51]2[N:52]=[CH:53][CH:54]=[C:50]2[N:49]=[C:48]([CH:55]2[CH2:60][CH2:59][CH:58]([CH2:61][C:62]#[N:63])[CH2:57][CH2:56]2)[CH:47]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=CC#N)CC2)nc2ccnn12
Agent: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)CC2)nc2ccnn12

Procedure:
2-(4-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetonitrile substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[I-].[CH3:13][O:14][CH2:15][CH2:16][CH2:17][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:17][CH2:16][CH2:15][O:14][CH3:13])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(Br)nc1C=O
Agent: [I-]
Product: COCCC=Cc1nc(Br)ccc1OC

Procedure:
1.5 mmol of 6-bromo-3-methoxypyridine-2-carbaldehyde and (3-methoxypropyl)triphenyl-phosphonium iodide [133622-76-1] are reacted in analogy to building block 24a. The title compound is identified by means of the Rf.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH:24][C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[N:23]=3)[CH:20]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}carbamate (1.5 g, 4.39 mmol) in N,N-dimethylacetamide (5.0 mL) was added cyclopropanecarbonyl chloride (480 μL, 5.27 mmol) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.79 g, 99%) as a pale-yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.[OH-].[Na+].O>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12](=[O:14])/[CH:13]=[CH:20]/[C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)/C=C/c1ccc(C(C)C)cc1
Reactant: O=Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(/C=C/C(=O)/C=C/c2cccs2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
A mixture of 7.9 grams (0.042 mol) of E-4-(p-isopropylphenyl)-3-butene-2-one, 4.7 grams (0.042 mol) of 2-thiophene carboxaldehyde, 2 mL of 10% sodium hydroxide, 30 mL of water, and 75 mL of ethanol was stirred at ambient temperature for 15 hours. The product was collected by filtration and air dried to give 10.2 grams (86% of theoretical yield) of E,E-1-(p-isopropylphenyl)-5-(2-thienyl)-l,4-pentadien-3-one as a yellow solid. Melting point was determined to be 100°-101° C. Proton nuclear magnetic resonance (1H NMR) was conducted in CDCl3 : d 7.84 (d, 1H, J=16 Hz), 7.69 (d, 1H, J=16 Hz) , 7.53 (AA'BB', 2H) , 7.39 (m, 1H) , 7.32 (m, 1H), 7.25 (AA'BB', 2H) , 7.06 (dxd, 1H, J= 3.6, 5 Hz), 6.96 (d, 1H, J=16 Hz), 6.87 (d, 1H, J=16 Hz), 2.90 (septet, 1H, J=7 Hz), 1.23 (d, 6H, J=7 Hz). Infrared spectroscopy was conducted using a KBr pellet: 2960, 1650, 1585, 1180, and 705 cm-1. Field desorption mass spectral analysis (FDMS) was consistent with the proposed formula (C18H18OS) m+ /z 316.