Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.CN(C)C.[H][H]>[Pd].CO>[CH3:2][C:3]1[CH:4]=[C:5]([C:12]([F:13])([F:14])[F:15])[CH:6]=[C:7]([NH2:9])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(C(Cl)Cl)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CN(C)C
Solvent: CO
Product: Cc1cc(N)cc(C(F)(F)F)c1
Yield: 83 %

Procedure:
At room temperature, 32.3 gms of crude nitrated product from Example V was added to a mixture of 150 ml MeOH and 30 gms (2.5 eq) of trimethylamine. The dark solution was charged with 1.6 gms of 50% wet 5% Pd/C catalyst and hydrogenated for 48 hours at 60° C. with hydrogen at 4 atms. The final solution was concentrated by distilling about half of the MeOH, diluted with 250 ml H2O and washed 3 times with 100 ml CH2Cl2. All of the organic extractions were combined, dried (Na2SO4), filtered and concentrated to 24 gms of a dark liquid which was Kugelrohr distilled at 95°-110° C./32 mm to 17.6 gms of light yellow colored crystals of 3-methyl-5-amino benzotrifluoride; mp 27°-28° C. (83% yield).
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C)C=O>[C:26]([O:25][C:24]([N:23]([CH2:22][C:9]1[CH:8]=[C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[N:11]([S:12]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])(=[O:13])=[O:14])[CH:10]=1)[CH3:31])=[O:30])([CH3:27])([CH3:28])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2C2=CCCCC2)c1
Reaction time: 3 h

Procedure:
tert-Butyl ((5-(cyclohex-1-en-1-yl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7d (100 mg, 0.22 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (146 mg, 0.45 mmol) and ethyl bromoacetate (102 mg, 0.67 mmol), and then the reaction solution was stirred for 3 h. The reaction solution was concentrated under reduced pressure, 50 mL of water was added, and the reaction solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product ethyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(cyclohex-1-en-1-yl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 8a (99 mg, a light yellow oil) in 81% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([O:42][CH3:43])=[C:31]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:31]1[CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=[CH:29][C:30]=1[O:42][CH3:43])(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (example B.7) (439 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (300 mg, 49%). MS (ISP) 541.3 [(M+H)+]; mp 209-213° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:8]I>ClCCCl>[OH-:5].[CH3:1][N+:2]1([CH3:8])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CN1CCOCC1
Reactant: CI
Solvent: ClCCCl
Product: C[N+]1(C)CCOCC1
Product: [OH-]
Yield: 323.5 %

Procedure:
To a stirred solution of N-methylmorpholine (10.0 g) in 1,2-dichloroethane (125 mL) at room temperature there was added methyl iodide (14.1 g). The colorless precipitate that formed was filtered and was washed sequentially with 1,2-dichloroethane and petroleum ether. The solid was dried in air at room temperature to afford 21.3 g of product. A sample of this product (1.0 g) was dissolved in deionized water (2 mL) and was passed through a column of strongly basic ion-exchange resin (available under the trade designation DOWEX 1X2-100 from Dow Chemical Co., Midland, Mich.) that had been washed sequentially with 10 g of a 10% aqueous solution of NaOH and 200 mL of deionized water. The sample was washed from the column with 25 mL of deionized water. The eluted solution was concentrated to dryness using a rotary evaporator and was further dried using a vacuum oven at 50° C. overnight to give the product as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[Li].N.[CH2:12](Br)[CH:13]=[CH2:14]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH2:14][CH:13]=[CH2:12])[CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: C=CCBr
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC1CC(C)(C)CCC1=O
Temperature: -33 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution of 4,4-dimethyl-2-cyclohexen-1-one (500 mg) in dry tetrahydrofuran (2 ml) was added to a well stirred solution of lithium (141 mg) in liquid ammonia (5 ml), The mixture was stirred at -33° C. for 1 hr. And then, to this solution allyl bromide (2.4 g) was added, and stirred for 30 min. The reaction was quenched by addition of methanol, and the ammonia was allowed to evaporate. The residue was diluted with water, and extracted with diethyl ether. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue with silica gel column chromatography (using n-hexane:ethyl acetate=30:1 as an eluent) gave 4,4-dimethyl-2-(2-propenyl)cyclohexanone (345 mg, 52% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:33]=[N:32][CH:31]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 189.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC (Condition 4) tR=5.49 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=493.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.64 (m, 1H) 1.76-1.92 (m, 1H) 2.14-2.28 (m, 1H) 2.88-3.02 (m, 1H) 3.11-3.40 (m, 5H) 4.60 (t, J=1.00 Hz, 1H) 7.67 (d, J=8.60 Hz, 2H) 7.79-7.85 (m, 1H) 7.90 (d, J=8.60 Hz, 2H) 8.06 (d, J=1.96 Hz, 1H) 8.50 (s, 1H) 8.57 (d, J=2.74 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.26 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:31]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[O:32])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2ccc(-c3cccc(NC(=O)C4CCC4)c3)nn12
Reaction time: 4 h
Yield: 25.7 %

Procedure:
To a solution of 7.0 g of 3-methyl-6-(3-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 6 ml of N,N-diisopropylethylamine and 4.0 g of cyclobutane carboxylic acid chloride. This solution was stirred for 4 hours, washed with 200 ml of saturated aqueous sodium bicarbonate, dried and evaporated in vacuo. A small amount of dichloromethane was added and the mixture warmed to give 2.45 g of crystals. A second crop (3.5 g) was recovered from the mother liquor. Recrystallization from dichloromethane-hexane gave the desired compound as white crystals, mp 242°-245° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=O.CCN=C=NCCCN(C)C.Cl.[CH2:45]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.O>[CH2:45]([N:52]1[CH2:57][CH2:56][N:55]([C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[C:21]([F:20])([F:32])[F:31])=[O:26])[CH2:54][CH2:53]1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(Cc2ccccc2)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
HOBt (4.26 g, 31.5 mmol) and DIEA (10.19 g, 78.89 mmol) were added to a stirred solution of 2-trifluoromethylbenzoic acid (5 g, 26.3 mmol) in DMF (20 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (12.6 g, 65.7 mmol) followed by 1-benzyl-piperazine (5.56 g, 31.55 mmol) were then added. The reaction mixture was stirred at room temperature overnight, then diluted with water and the product extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh with (30% ethyl acetate in hexane) to afford 8.6 g (93%) of (4-benzyl-piperazin-1-yl)-(2-trifluoromethyl-phenyl)-methanone. 1H NMR: (DMSO-d6): δ 7.8 (m, 2H), 7.6 (t, 1H), 7.4 (d, 1H), 7.3 (m, 5H), 3.6 (m, 2H), 3.5 (s, 2H), 3.1 (m, 2H), 2.4 (m, 1H), 2.3 (m, 2H), 2.2 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10]O)=[CH:8][CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:5]=1.O=S(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][CH2:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl

Procedure:
0.311 g (1.046 mmol) of the above prepared [2-methoxymethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was dissolved in 4 ml of CH2Cl2 and treated at 0C. with 0.15 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at ambient temperature for 60 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents produced 0.330 g of pure title compound as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH:10]1([C:13]#[N:14])[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:10]1([C:13]#[N:14])[CH2:12][CH2:11]1
Reactant: N#CC1CC1
Reactant: BrCc1cccc(Br)c1
Product: N#CC1(Cc2cccc(Br)c2)CC1

Procedure:
Prepared according to the procedure described in Example 240, Step 1, using 1-bromo-3-bromomethyl-benzene and cyclopropanecarbonitrile.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]([OH:10])[C:7]2[S:11][CH:12]=[CH:13][C:6]=2[CH2:5]1)[CH:2]=[CH2:3].[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[ClH:14].[CH2:1]([N:4]1[CH2:9][CH:8]([O:10][C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[C:20]([Cl:21])[CH:19]=2)[C:7]2[S:11][CH:12]=[CH:13][C:6]=2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1Cc2ccsc2C(O)C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: C=CCN1Cc2ccsc2C(Oc2ccc(Cl)c(Cl)c2)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 5-allyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 16) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][CH2:18][CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Reaction time: 4 h
Yield: 87.3 %

Procedure:
Palladium on carbon (10 wt. %, 3 mg) was added to a solution of {4-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-butoxy}-acetic acid methyl ester (9.5 mg, 0.024 mmol) in MeOH (2.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 4 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 8.2 mg (86%) of the title compound.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C1(C)C=CC=CC=1.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[S:22])=[CH:17][CH:16]=1.Cl>C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[S:22])=[CH:23][CH:24]=1
Reactant: O=C(O)CCS
Reactant: S=C=NCc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(O)CCSC(=S)NCc1ccc(Cl)cc1

Procedure:
To a solution of 1.06 g. of 3-mercaptopropionic acid in 5 ml. of toluene and 2.0 g. of triethylamine, there was added with cooling 1.83 g. of p-chlorobenzylisothiocyanate. Two phases formed. The mixture was acidified with 1-N hydrochloric acid and extracted with chloroform. The chloroform phases were washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile, and 2.1 g. of 3-{[(p-chlorobenzyl)thiocarbamoyl]thio}-propionic acid having a melting point of 126°-127° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[C:13]([CH:21]=[O:22])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O1CC[CH2:35][CH2:34]1>C(N(CC)CC)C.[Cu](I)I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:34][CH3:35])=[CH:17][CH:18]=3)[C:13]([CH:21]=[O:22])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cc(Br)ccc32)cc1
Reactant: C1CCOC1
Reactant: C#CCCCCCCCC
Agent: I[Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1ccc2c(c1)c(C=O)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 168 h
Yield: 50.8 %

Procedure:
To a degassed mixture of 1-(4-methylphenylsulfonyl)-5-bromoindole-3-carboxaldehyde (36.9 g), 1-decyne (16.8 g), in dry triethylamine (200 ml) and dry tetrahydrofuran (150 ml) was added, l mole percent of copper (II) iodide and 2 mole percent of bis(triphenylphosphine)palladium (11) chloride. The reaction mixture was stirred at 65° C. for 7 days. The solution was evaporated, and the residue was flash chromatographed (silica gel:4:1, dichloromethane:heptane). The appropriate fractions were collected and evaporated. The residue was recrystallized from hexane to give 23.1 g (50.8%) of product, mp 84-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][N:9]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:6]2=[N:7][CH:8]=1.[Cl:30][C:31]1[CH:36]=[C:35](I)[CH:34]=[C:33]([Cl:38])[N:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.CCO.O.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>[Cl:30][C:31]1[CH:36]=[C:35]([C:11]2[C:5]3[C:6](=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH:10]=2)[CH:34]=[C:33]([Cl:38])[N:32]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: COc1cnc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COc1cnc2c(c1)c(-c1cc(Cl)nc(Cl)c1)cn2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 56 %

Procedure:
A suspension of Example 149c (0.150 g, 0.362 mmol), 2,6-dichloro-4-iodopyridine (0.099 g, 0.362 mmol), dichlorobis(triphenylphosphine)palladium(II) (10.17 mg, 0.014 mmol) and 1M sodium carbonate (0.290 mL, 0.290 mmol) in dimethoxyethane/EtOH/water (7:2:3, 2.5 mL) was degassed and heated at 80° C. overnight. After cooling, the suspension was diluted with water and extracted with EtOAc (2×). The suspension in the aq. layer was filtered, washed with water, and dried to give 88.0 mg of the title compound
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].S(=O)(=O)(O)O.[OH2:32].OO.[CH3:35]O>>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([CH2:35][OH:32])[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: OO
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CO
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Camptothecin (3.00 g, 8.61 m-mol) was suspended in methanol (90 ml) and then dissolved therein by addition of 75% sulfuric acid (75 ml) and 75 ml of water. To the solution was added FeSO4. 7H2O (40 g, 0.143 mol) and then was added dropwise under ice-cooling and agitation 30% hydrogen peroxide (15 ml) over 2 hours. After addition of the hydrogen peroxide, the reaction mixture was stirred for 14 hours at room temperature and poured into ice water (1 l). The yellowish brown solid precipitated was collected by filtration and dried under reduced pressure whereby 2.5 g of 7-hydroxymethylcamptothecin were obtained. The filtrate was extracted with chloroform (250 ml×4) thereby obtaining 200 mg of crude crystals of the product. 2.7 Grams (82.9%) in toto of 7-hydroxymethylcamptothecin were obtained, which was identified to be the same product as obtained in Example 1 by way of IR-absorption spectra and thin layer chromatography.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[C:23](O)=[O:24])=[CH:7][CH:6]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:48][O:49][C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[NH2:52].Cl>O.CN(C=O)C>[CH3:48][O:49][C:50](=[O:55])[C:51]([CH3:54])([NH:52][C:23]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[O:12][CH2:11][C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:27])([F:26])[F:1])=[CH:6][CH:7]=1)=[O:24])[CH3:53]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to 115 mg 1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carboxylic acid in 2 mL of abs. DMF 82 mg EDC, 45 mg 1-hydroxybenzotriazole and 49 mg N,N-diisopropylethylamine were added. After 30 min at 0° C. 56 mg of 2,2-dimethylglycine methyl ester hydrochloride and 49 mg N,N-diisopropylethylamine were added. The mixture was stirred for 16 h at room temperature. The mixture was poured into cold water, acidified to pH 3 with 2M HCl, extracted with ethyl acetate, washed with sat. sodium hydrogen carbonate solution and brine, dried over magnesium sulphate, filtrated and concentrated in vacuo to provide 124 mg of 2-methyl-2-({1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carbonyl}-amino)-propionic acid methyl ester.
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][NH:20][C:24](=[O:25])[CH2:23][C:21]#[N:22])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: NC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC(=O)NC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanamine (40.0 mg, 0.148 mmol), 2-cyanoacetic acid (15.0 mg, 0.178 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (68.0 mg, 0.178 mmol) in N,N-dimethylformamide (2 mL) were mixed with N,N-diisopropylethylamine (57.0 μL, 0.326 mmol) and stirred at room temperature for 16 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/acetone=1/1→2/3 (v/v)) to give the title compound as a colorless solid (11.4 mg, yield 23%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][S:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)[N:9]2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.CC(C)=[O:33].C1COCC1.[OH2:40]>[Os](=O)(=O)(=O)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[CH2:11][S:12](=[O:33])(=[O:40])[CH2:13][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[N:9]2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[CH:15][CH:16]=1
Reactant: CC(C)=O
Reactant: O
Reactant: CC(C)(C)c1ccc(N2C(c3ccc(Br)cc3)CSCC2c2ccc(Br)cc2)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N2C(c3ccc(Br)cc3)CS(=O)(=O)CC2c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of Example 159D (850 mg, 1.56 mmol) in mixture of acetone (15 mL), water (5 mL) and THF (5 mL) was added a solution of osmium tetroxide (2.5% in tert-butanol, 0.587 mL, 0.047 mmol) and the mixture was stirred at room temperature for 1.5 hr. The solution was then diluted with water and extracted with EtOAc, the organic extract dried, filtered and concentrated to afford 900 mg (100%) of the title compound. MS (ESI) m/z 578 (M+H)+.