Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]4[CH:37]5[CH:33]([NH:34][C:35](=[O:38])[NH:36]5)[CH2:32][S:31]4)=[C:20]([O:40]CC4C=CC=CC=4)[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]4[CH:37]5[CH:33]([NH:34][C:35](=[O:38])[NH:36]5)[CH2:32][S:31]4)=[C:20]([OH:40])[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1O
Yield: 63 %

Procedure:
{3-Benzyloxy-4-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-phenyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (389) (0.28 g, 0.422 mmol) was dissolved in TFA (2 mL) and thioanisole (0.4 mL) was added. The mixture was shaken at room temperature in a Teflon septum capped 40 mL I-Chem vial for 3 h. LC-MS indicated complete de-benzylation at this point. The mixture was diluted with water (15 mL) and a pink/orange precipitate formed. Collection by filtration under reduced pressure followed by rinsing with water followed by drying under high vacuum for 16 h gave the desired product (390) as a pink/orange powder (0.152 g, 0.266 mmol, 63% yield). LC-MS (ESI): (exact mass: 572.21) m/e=573.1 [M+1]+.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:13]C(=O)N(C)C)[CH:10]=2)[CH2:5]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])([O-])=O.[Cs+].[Cs+].Br[C:32]([CH3:41])([CH3:40])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].[BH4-].[Na+]>C1COCC1>[C:36]([O:35][C:33](=[O:34])[C:32]([CH3:41])([S:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH2:5][CH:4]([NH:3][CH3:1])[CH2:12]2)[CH3:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CN(C)C(=O)Sc1ccc2c(c1)CC(NC=O)C2
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CNC1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
To dimethylthiocarbamic acid S-(2-formylaminoindan-5-yl)ester (0.772 g; 2.9 mmol) in THF (9 mL) under N2 is added a solution of 1.0 M lithium aluminum hydride (9 mL) at 0° C. The reaction is warmed to RT then stirred at reflux for 24 h. The reaction is cooled to 0° C., quenched with H2O, and the solvent removed under reduced pressure. The residue is dissolved in MeOH (4 mL), to which is added Cs2CO3 (0.304 g; 0.93 mmol), tert-butyl 2-bromoisobutyrate (0.311 mL; 1.39 mmol), and NaBH4 (2.0 g; 52.8 mmol). The reaction mixture is stirred for 18 h, the removed under reduced pressure and the residue partitioned between EtOAc and H2O. The layers are separated, the aqueous phase extracted with EtOAc, the organic extracts combined, washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue is purified by flash chromatography (SiO2) eluting with a CH2Cl2-MeOH gradient to afford 0.186 g (20%) of 2-methyl-2-(2-methylaminoindan-5-ylsulfanyl)propionic acid tert-butyl ester as an oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:40]=3[N:39]=[CH:38][CH:37]=[CH:36]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Nc1cccc2cccnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc4cccnc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 100 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.10 g, 0.24 mmol) obtained in Example 19, step 4 and 8-aminoquinoline (0.069 g, 0.48 mmol), the title compound (0.125 g, 99%) was obtained.
Reaction SMILES: C(O[Si](OCC)(OCC)OCC)C.S(=O)(=O)(O)O.[Br:19][C:20]1[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[C:23]([NH2:24])=[C:22]([CH:30]([CH3:32])[CH3:31])[CH:21]=1.[C:33]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[K+]>>[C:34]1([C:33]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[N:24][C:23]2[C:25]([CH:27]([CH3:28])[CH3:29])=[CH:26][C:20]([Br:19])=[CH:21][C:22]=2[CH:30]([CH3:32])[CH3:31])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)c1cc(Br)cc(C(C)C)c1N=C(c1ccccc1)c1ccccc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
40.7 g (0.195 mol) of tetraethoxysilane and 0.5 mL of sulfuric acid were added to a flask equipped with a distiller, containing 43.9 g (0.169 mol) of 4-bromo-2,6-diisopropylaniline and 24.8 g (0.130 mol) of benzophenone under a nitrogen atmosphere. The mixture was reacted by heating at 160° C. for 2 days while removing formed ethanol using the distiller. After the reaction, the resultant product was cooled to room temperature. Then, 200 mL of 1.0 M aqueous solution of potassium hydroxide was added to the resultant product and stirred for 10 minutes to obtain yellow precipitates. The obtained precipitates were filtered off and dissolved in 300 mL of ethyl acetate, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain a yellow solid. Then, the yellow solid was recrystallized in hexane at −20° C. to obtain 42 g of N-diphenylmethylene-2,6-diisopropyl-4-bromoaniline compound.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][CH:4]([CH2:16][Br:17])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](O)=[O:14])=[N:11][CH:12]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:13](=[O:14])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH:4]([Br:3])[CH2:16][Br:17])=[CH:12][N:11]=1
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1ccc(CCC(Br)CBr)cn1
Temperature: 8 °C

Procedure:
According to the same method as Example 1 with cooling 30% aqueous methylamine solution (100 ml) was added to the chloroform solution (200 ml) of acid chloride prepared from 10 g of 5-(3,4-dibromobutyl)picolinic acid and 10 ml of thionyl chloride, and stirred at 8°C for an hour. Chloroform layer which was separated, was washed with 0.3% aqueous hydrochloride solution, 5% aqueous sodium bicarbonate solution, and then water. Chloroform was evaporated in reduced pressure to yield 8.7 g of crude product as oil. To purify the product, above crude product was chromatographed on silicagel using ethylacetate as developing solvent. The pure product was viscous oil and showed only one spot (Rf 0.60) on TLC (silicagel; ethylacetate, IR (liquid film) 1670 cm-1, UV λmaxMeOH 268 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)(=[O:27])=[O:26].CN(C=O)C.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:30][CH:31]=3)=[CH:21][N:22]=2)[N:19]=1
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A reaction vial was charged with (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 30 mg, 0.095 mmol), 4-(methylsulfonamido)benzoic acid (41 mg, 0.19 mmol), and 2(1H-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophophate methanaminium (HATU; 72 mg, 0.19 mmol). DMF (0.8 mL) was added to the mixture to make a solution. The reaction mixture was cooled in an ice bath for 10 minutes before DIEA (0.05 mL, 0.29 mmol) was added dropwise. After addition, reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water and brine (10 mL each), and concentrated. The crude material was purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(methylsulfonamido)benzamide as a yellowish solid (13 mg, 27% yield). MS (apci negative) m/z=511.4 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=1.N>>[Cl:33][C:28]1[CH:27]=[C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: Fc1ccc(Br)cc1Cl
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (described in Example 99) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-bromo-3-chloro-4-fluorobenzene in place of 4-bromothioanisole (yield: 330 mg, 58.8%). mp 205° C. 1H NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 7.17 (d, J=9 Hz, 2H), 7.23–7.31 (m, 1H), 7.28 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.65 (ddd, J=9 Hz, 3 Hz, 1.5 Hz, 1H), 7.85 (dd, J=9 Hz, 3 Hz, 1H), 7.93 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 489 (M+H)+, 508 (M+NH4)+. Anal. calc. for C23H15Cl2N2O3S: C, 56.44; H, 3.17; N, 5.73. Found: C, 56.37; H, 3.19; N, 5.64.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][C:10](=O)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[C:20]([CH:21]=O)=[CH:19][CH:18]=[CH:17][N:16]=1.[OH-].[K+]>C(O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CCNC(=O)OC(C)(C)C
Reactant: Nc1ncccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1ccc2cccnc2n1

Procedure:
A solution of 10-4 (10 g, 53.4 mmol), 2-amino-3-formylpyridine 1-3 (7.2 g, 64 mmol), 20% aq. KOH (1 mL), and ethanol (200 mL) was heated at reflux for 3 h. Evaporation of the solvents and flash chromatography (silica, 70 CHCl3 /28 EtOAc/2 MeOH) gave 10-5 as a solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@H:5]1[C:17]2[C:16]3[C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)#[N:2].[OH:33][Li].O.OO>CO>[C:1]([CH2:3][CH2:4][C@H:5]1[C:17]2[C:16]3[C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:21][CH2:20]4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:33])[NH2:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCC#N)CCC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCC(N)=O)CCC4)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of tert-butyl N-(4-[[(13S)-13-(2-cyanoethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (300 mg, 0.66 mmol, 1.00 equiv) in methanol (15 mL) was added LiOH.H2O (82 mg, 1.95 mmol, 3.00 equiv) and H2O2 (30%, 0.5 mL) at 0° C. and the resulting solution was stirred for 2 h at 30° C. The reaction was quenched with saturated aqueous sodium sulfite, extracted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 240 mg (77%) of tert-butyl N-(4-[[(13S)-13-(2-carbamoylethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:16])[CH2:4][CH:5]2[CH2:11][CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=12.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].[OH-].[Na+].Cl>O>[O:16]=[C:3]1[NH:2][N:1]=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]2=[CH:4]1
Reactant: O=C1CC2CCCc3ccccc3C2=NN1
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=c1cc2c(n[nH]1)-c1ccccc1CCC2
Temperature: 25 °C

Procedure:
Alternatively, a solution of 4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one (2.31 g, 10.74 mmol), sodium m-nitrobenzenesulfonate (2.48 g, 11 mmol), sodium hydroxide (1.86 g, 46.5 mmol) in water (80 mL) was heated under reflux for 1.5 h. The solution was cooled to ambient temperature, and then acidified with concentrated hydrochloric acid. The solid which precipitated was filtered off, washed with water and crystallized from ethanol to give 3-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine as tan crystals, 1.46 g; 1H NMR (DMSO-d6, 300 MHz) 13.04 (s, 1H), 7.25-7.45 (m, 4H), 6.78 (s, 1H), 2.49 (m, 2H), 2.35 (m, 2H), 2.04 (m, 2H) ppm; MS (ES) 213 (M+H).
Reaction SMILES: [N+]([O-])(O)=O.[O:5]([CH2:9][CH2:10][NH2:11])[N+:6]([O-:8])=[O:7].C(=O)(O)[O-].[Na+].[C:17]([O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])(=[O:19])[CH3:18]>O.C(Cl)(Cl)Cl>[C:17]([O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:11][CH2:10][CH2:9][O:5][N+:6]([O-:8])=[O:7])=[O:25])(=[O:19])[CH3:18]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cccc(C(=O)NCCO[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
18.6 g (0.110 mole) of 2-nitroxy-ethylamine nitrate at 0° C. were added to a solution of 40.7 g (0.458 mole) of sodium bicarbonate in 140 ml of water and 120 ml of chloroform. After stirring for 10 min, 22.5 g (0.113 mole) of 3-acetoxybenzoic acid chloride were dropped therein and the resulting mixture was stirred for one hour at 0° C. The reaction mixture was warmed to room temperature, the two phases were separated and the organic phase was washed with water and dried over sodium sulfate. The crude title product was obtained, which was recrystallized from ethyl ether. M.p. 89°-91° C. Yield 26.5 g.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].OO.C([O-])([O-])=[O:19].[Na+].[Na+]>CC(O)=O>[CH:1]([S:4]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)=[O:19])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(SC(C)C)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(S(=O)C(C)C)cc1
Yield: 65 %

Procedure:
A solution of ethyl 4-isopropylsulfanylbenzoate (350 mg, 1.6 mmol) and H2O2 (180 μL of 30% w/v, 1.6 mmol) in AcOH (2 mL) was stirred at ambient temperature for 3 h. The mixture was poured into sat. aq. Na2CO3 and the pH was adjusted to 10 with solid Na2CO3. The mixture was extracted with EtOAc (3×). The organics were combined and washed with sat. aq. Na2CO3, water (2×), then brine. The organic layer was dried over magnesium sulfate and was evaporated to dryness. The residue was purified by column chromatography (20-50% EtOAc in hexanes) to give ethyl 4-isopropylsulfinylbenzoate (65%). ESI-MS m/z calc. 240.1, found 241.3 (M+1)+. Retention time: 1.16 minutes (3 min run).
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][C:33]=1[C:41]([OH:43])=O.[NH2:44][C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][N:51]2[CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[CH:47][CH:46]=1>CN(C=O)C.ClCCl>[Cl:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][C:33]=1[C:41]([NH:44][C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][N:51]2[CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[CH:47][CH:46]=1)=[O:43]
Reactant: O=C(O)c1[nH]c2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(NC(=O)c3[nH]c4ccccc4c3Cl)cc21
Yield: 55 %

Procedure:
DIPEA (2.5 equiv.), EDCI (2.73 mmol, 1.2 equiv.) and HOBt (2.73 mmol, 1.2 equiv.) were added at 0° C. to a solution of 3-chloro-1H-indole-2-carboxylic acid (2.27 mmol, 1.0 equiv.) in DMF (6 ml), and the mixture was stirred for 15 min. tert-Butyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate A—for synthesis see above) (2.27 mmol, 1.0 equiv.) was dissolved in DMF (1 ml) and added, with stirring, and the reaction mixture was then stirred for 12 h at 25° C. The mixture was diluted with dichloromethane (50 ml), washed with sat. ammonium chloride solution (20 ml), water (20 ml) and sat. NaCl solution (20 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (10-15% ethyl acetate in hexane). Yield: 55%
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][CH:12]([C:13]([F:14])([F:15])[F:16])[C:17]([F:20])([F:19])[F:18]
Reactant: O=[N+]([O-])c1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
3-Chloro-2-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-5-nitropyridine (Preparation 51, 2.55 g, 7.9 mmol), ammonium chloride (2.50 g, 46.7 mmol) and iron powder (1.70 g, 30.4 mmol) were suspended in a mixture of ethanol (10 mL) and water (3 mL). The suspension was heated for 3 hours under reflux then allowed to cool to room temperature. The reaction mixture was filtered on a celite pad and washed with ethanol. The filtrate was concentrated in vacuo and the residue partitioned between water and EtOAc. The aqueous layer was further extracted with EtOAc (2×25 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 50% diethyl ether in heptane to afford the title compound as a light yellow oil (2.0 g, 87%).
Reaction SMILES: C(N(CC)CC)C.[C@@H:8]1([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.[CH3:25][O:26][C:27]1[CH:48]=[CH:47][C:30]([C:31](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1.CO>C1COCC1>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:31]([O:14][CH2:13][C@H:12]2[O:15][C@@H:8]([N:16]3[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]3=[O:18])[CH2:9][C@@H:10]2[OH:11])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:30]2[CH:47]=[CH:48][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 85.3 %

Procedure:
Triethylamine (10 ml) in 200 ml THF was injected into a solid mixture of 6.8 g (28.0 mmol) thymidine and 10.2 g (28.6 mmol) 4,4'-dimethoxytrityl chloride under nitrogen with stirring. The solution was stirred at room temperature for 2 hours. After completion of the reaction, 10 ml methanol was added to consume the excess DMTrCl. The mixture was stirred for 5 minutes and the solvent removed by rotary evaporation. The residue was dissolved in 250 ml of ethyl acetate and the solution was washed with saturated NaHCO3 and dried over MgSO4. The solid was recrystallized from ethyl acetate/hexane to obtain 13.0 g 5'-protected thymidine 16 (85.6%).: m.p. 124°-126° C.; 1H NMR (200 MHz, CDCl3) δ8.97 (s, 1H, NH), 7.60 (m, 1H, H-6), 6.72-7.42 (m, 13H, Ph), 6.42 (m, 1H, H-1'), 4.56 (m, 1H, H-3'), 4.05 (m, 1H, H-4'), 3.78 (s, 6H, OMe2), 3.41 (m, 2H, H-5'), 2.62 (m, 1H, OH), 2.46 (m, 2H, H-2'), 1.46 (s, 3H, Me); 13C NMR (50 MHz, CDCl3) δ163.0 (C-4), 157.6, 149.8 (C-2), 143.5, 135.0 (C-6), 134.7, 134.6, 129.4, 127.4, 127.3, 126.5, 112.8, 110.9 (C-5), 86.7 (C-4'), 86.2, 84.7 (C-1'), 72.5 (C-3'), 63.8 (C-5'), 55.5 (OCH3), 41.3 (C-2'), 12.5 (CH3).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([OH:16])=O)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]([NH2:32])([CH3:31])[CH3:30]>O1CCCC1.C(OCC)(=O)C>[CH3:3][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:16])[CH3:1]
Reactant: CC(C)N
Reactant: CC(C)Oc1c(C(=O)O)oc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)c1oc2ccccc2c1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 1.14 mmol) and 1,1'-carbonyldiimidazole (240 mg, 1.48 mmol) in 7 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and i-propylamine (0.58 mL, 6.84 mmol) is added and the reaction mixture is stirred at room temperature for 30 minutes. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:2 to 1:1) provides 3-(1-methylethoxy)-N-(1-methylethyl)-2-benzofurancarboxamide in 72% yield as a yellow oil.
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].S(=O)(=O)(O)O.C=C.OO.[C:15]([O-])(=O)[CH3:16].[Al+3:19].[C:20]([O-])(=O)[CH3:21].[C:24]([O-])(=O)[CH3:25]>O>[CH2:20]([P:2]([CH2:15][CH3:16])(=[O:4])[O-:3])[CH3:21].[Al+3:19].[CH2:24]([P:2]([CH2:15][CH3:16])(=[O:4])[O-:3])[CH3:25].[CH2:20]([P:2]([CH2:15][CH3:16])(=[O:4])[O-:3])[CH3:21]
Reactant: O=[PH2][O-]
Reactant: CC(=O)[O-]
Agent: C=C
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CCP(=O)([O-])CC
Temperature: 10 °C

Procedure:
1500 g (14 mol) of sodium hypophosphite monohydrate and 35 g of concentrated sulfuric acid were dissolved in 7.5 kg of water and used as initial charge in a 16 l jacketed pressure reactor composed of enameled steel. Once the reaction mixture had been heated to 10° C., ethylene was introduced by way of a reducing valve set to 6 bar until saturation had been reached in the reactor. A solution of 80 g (5 mol %) of hydrogen peroxide (33% by weight) in 300 g of water was metered in uniformly over a period of 6 h with constant stirring at an ethylene pressure of 6 bar and a temperature of from 100 to 110° C. After a continued reaction time of 1 h, depressurization of the reactor, and cooling to about 90° C., 746 g (4.67 mol of aluminum) of aluminum acetate in 2254 g of water were added within a period of 60 min. The resultant solid was then filtered off, washed with 2 l of hot water, and vacuum-dried at 130° C. Yield: 1721 g (93.5% of theory).