Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])=O.[CH3:33][NH2:34].C(O)C>>[CH3:10][C:9]1[O:8][C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])=[N:6][C:5]=1[C:3](=[O:2])[NH:34][CH3:33]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)OC)c(C)o1
Reactant: CN
Solvent: CCO
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)NC)c(C)o1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-oxazole-4-carboxylic acid methyl ester (40 mg, 0.091 mmol) in a solution of methyl amine in ethanol (455 μL, 33% solution, 3.66 mmol) was stirred at 100° C. in a sealed tube. After 16 hours, the reaction was cooled to room temperature, vented, opened and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-8% methanol in methylene chloride to afford the title compound as white solid. MS m/z 437.63 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:45])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:44])[C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)=[CH:28][N:27]=2)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:45][N:17]1[C:18]2[C:23](=[CH:22][C:21]([O:25][C:26]3[N:27]=[CH:28][C:29]([NH:32][C:33](=[O:44])[C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:36][CH:35]=4)=[CH:30][CH:31]=3)=[CH:20][CH:19]=2)[CH:24]=[C:16]1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15]
Reactant: Cn1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc2cc(Oc3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cn3)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C(=O)N2CCNCC2)cc2cc(Oc3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cn3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To 4-{1-methyl-5-[5-(4-trifluoromethylbenzoylamino)-pyridin-2-yloxy]-1H-indole-2-carbonyl}piperazine-1-carboxylic acid tert-butyl ester (2.75 g, 4.41 mmol) was added trifluoroacetic acid (16 mL) under ice cooling. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated under reduced pressure. The residue was made alkaline with 5 M NaOH, and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 2.03 g of the title compound as a yellow amorphous powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33](=[N:35]O)[NH2:34])[CH:32]=1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33]2[N:34]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[CH3:7])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=3)[O:20][N:35]=2)[CH:32]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c([N+](=O)[O-])c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 8 (132 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 80/20) followed by crystallisation from ethyl acetate/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=[O:16]>C(#N)C.Cl[Pd]Cl>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[C:9]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A solution of PdCl2 (0.066 g, 0.373 mmol) in 200 ml of acetonitrile was heated to reflux. To this solution was added 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 1.4 g, 5 mmol) portion by portion slowly so that no cloudiness of the solution occurred. After the addition, the reaction was kept at reflux for another 10 min. Then the mixture was cooled to room temperature and filtered. The filtrate was treated with 5 g of 3-mercaptopropyl functional silica gel with stirring for 30 min and filtered. The filtrate was concentrated and the residue was recrystallized from EtOAc/Hexane to give 0.84 g (60%) of 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde, analytical dada identical as in Ex-57D.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO>[F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH2:33])[CH2:10][CH2:9]2
Reactant: [BH3-]C#N
Reactant: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Yield: 49.7 %

Procedure:
To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one (1 g, 2.39 mmol) in CH3OH (10 mL) were added ammonium acetate (1.84 g, 23.9 mmol) and sodium cyanoborohydride (NaCNBH3; 0.44 g, 7.17 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium bicarbonate (satd aq NaHCO3) solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (500 mg, crude): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.71 (s, 2H), 4.78 (m, 1H), 4.2 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 1.60 (m, 2H); ESIMS m/z 419.02 ([M+H]+); IR (thin film) 2924, 1552, 1112, 807 cm−1.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([CH2:22][N:23]([CH3:25])[CH3:24])[CH:21]=1)[C:15](OC)=[O:16]>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH2:15][OH:16])[CH:19]=[C:20]([CH2:22][N:23]([CH3:24])[CH3:25])[CH:21]=1
Reactant: COC(=O)c1cc(Br)cc(CN(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)Cc1cc(Br)cc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
1.0M Diisobutylaluminum hydride in hexanes (6.2 mL, 6.2 mmol) was added dropwise to a solution of methyl 3-bromo-5-[(dimethylamino)methyl]benzoate (0.50 g, 1.8 mmol, from Step A) in tetrahydrofuran (10 mL) at −78° C. After stirring for 2 hours, the mixture was quenched with saturated potassium sodium tartrate solution and was allowed to warm to room temperature. Ethyl acetate was added and the mixture was then stirred until a biphasic solution formed. The ethyl acetate layer was washed with water (3×), followed by brine, was dried over sodium sulfate and concentrated to give a light yellow oil (0.41 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.41 (dd, J=1.7 Hz, 1H), 7.37 (dd, J=1.8 Hz, 1H), 7.24 (dd, J=1.4, 0.7 Hz, 1H), 4.65 (s, 2H), 3.37 (s, 2H), 2.22 (s, 6H). LCMS (M+H)+: 244.0, 246.0.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:13][CH2:14][OH:15])[C:11]=1[NH2:12].C(N(CC)CC)C.[C:23]([O:27][C:28]([NH:30][C:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=NS(C(F)(F)F)(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:12][C:11]1[N:10]([CH2:13][CH2:14][OH:15])[N:9]=[CH:8][C:7]=1[NH:6][C:31]([NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: Nc1cnn(CCO)c1N
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn(CCO)c1N
Yield: 62.5 %

Procedure:
To a suspension of 4,5-diamino-1-(2-hydroxyethyl)pyrazole sulfuric acid salt (50.0 g) in chloroform (500 ml) were added 4-(dimethylamino)pyridine (2.54 g), triethylamine (116 ml) and 1,3-bis(tert-butoxycarbonyl)-2-(trifluoromethanesulfonyl)guanidine (106 g). The mixture was stirred under reflux for 2 hours. After cooling on an ice bath, the reaction mixture was washed successively with water, 4% aqueous citric acid solution, water and aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixed solvent of ethyl acetate (50 ml) and diethyl ether (200 ml) to give 5-amino-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-1-(2-hydroxyethyl)pyrazole (50 g) as a solid.
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][C:19](I)([F:21])[F:20])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[Cl-].[Li+]>CN(C)C=O>[F:20][C:19]([F:21])=[CH:18][C:15]([F:16])([F:17])[CH2:14][C:1]([F:2])([F:3])[C:4]([F:5])([F:6])[C:7]([F:8])([F:9])[C:10]([F:13])([F:12])[F:11]
Reactant: FC(F)(I)CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: FC(F)=CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 140 °C

Procedure:
A round-bottomed flask was charged with a mixture of C4F9—CH2CF2—CH2CF2—I (180 g, 0.38 mol) and lithium chloride (23.9 g, 0.56 mol) in anhydrous N,N-dimethylformamide (DMF, 160 ml) solvent. The mixture flask was vigorously stirred throughout the reaction. A vacuum was applied (220-240 mm Hg) and the mixture was slowly heated up to 140° C. over the course of 1-2 hrs. A volatile component was distilled off during this heating period. It was collected in a cold trap. Redistillation afforded the desired 1,1,3,3,5,5,6,6,7,7,8,8,8-tridecafluoro-1-octene [C4F9—CH2CF2—CH═CF2] product as a clear colorless liquid having a boiling point 80-82° C. at 230 mm Hg. The yield was 86 grams (65.4%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[CH3:20])#[N:14].CN(C)[CH:23]=[O:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.O1CCCC1.O>[CH:23]([C:17]1[S:16][C:15]([C:13]#[N:14])=[C:19]([CH3:20])[CH:18]=1)=[O:24]
Reactant: CN(C)C=O
Reactant: Cc1ccsc1C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: Cc1cc(C=O)sc1C#N
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
112 ml (179 mmol) of a 1.6-molar solution of n-butyllithium in n-hexane were added in the course of 20 minutes to a solution of 25.1 ml (179 mmol) of diisopropylamine in 400 ml of tetrahydrofuran cooled to −78° C. The solution was allowed to come to −35° C., then cooled again to −78° C., and a solution of 20.0 g (162 mmol) of 2-cyano-3-methylthiophene in 80 ml of tetrahydrofuran was slowly added dropwise at this temperature. During this process, the color of the solution changed to dark red. Stirring was continued for 45 minutes, 63 ml (811 mmol) of dimethylformamide were slowly added dropwise, and the mixture was stirred for another 30 minutes. For work-up, a solution of 27 g of citric acid in 160 ml of water was added at −70° C. The mixture was concentrated on a rotary evaporator, 540 ml of saturated sodium chloride solution were added, and the batch was extracted three times using in each case 250 ml of diethyl ether. The combined organic extracts were dried over magnesium sulfate. After the desiccant had been filtered off, the solvent was distilled off under a water pump vacuum and the residue was purified by column chromatography (eluant hexane/ethyl acetate 4/1). This gave 23 g (94%) of the title compound. 1H NMR (270 MHz, DMSO-d6): δ=2.4 (s, 3H), 8.0 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].O>N1C=CC=CC=1>[C:1]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]1=[O:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCn1ccc(=O)[nH]c1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=c1ccn(CCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 50 °C
Yield: 24.1 %

Procedure:
Trityl chloride (0.358 g, 1.28 mmol) was added to a solution of 1-(4′-aminobutyl)uracil (contaminated by 11% 1,3-bis(4′-aminobutyl)uracil) (0.168 g) in anhydrous pyridine (15 mL). The reaction mixture was heated at 50° C. for 44 h, left to cool to room temperature, poured into cold water (50 mL) and extracted with DCM (3×25 mL). The organic extracts were washed with brine (40 mL), dried over Na2SO4 and concentrated in vacuo. Further purification was carried out by silica gel column chromatography, using Jones Chromatography Isolute SI columns with a gradient elution of 0→5% CH3OH in CHCl3. The fractions with Rf=0.51 (10% CH3OH/CHCl3) gave the title compound as a white crystalline solid (94 mg, ca 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)Cc1cccc(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
3-chlorophenylacetic acid (20.90 g, 122.52 mmol) and NBS (23.50 g, 133.14 mmol) were dissolved in carbon tetrachloride (300 mL), then BPO (300 mg) was added, the resulting reaction was heated to reflux under a sunlamp for 5 hours, then cooled to room temperature, filtered and concentrated to give the desired α-bromo-3-chlorophenylacetic acid. 5.00 g of this acid was then reacted with 3,4-dimethyl benzenethiol (2.85 g, 20.62 mmol) and sodium hydride (60% oil dispersion, 4.50 g, 87.50 mmol) to yield Intermediate 3, which was used in the next synthetic step without further purification.
Reaction SMILES: C1COCC1.Br[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[F:12][C:13]1[N:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:17][N:18]=1
Reactant: Fc1ccc([Mg]Br)cn1
Reactant: Brc1cccs1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccs2)cn1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
In a separate reaction vessel, under a nitrogen atmosphere were added NiCl2(dppp) (0.02 equiv, 0.60 g) and THF (50 ml). 2-Bromothiophene (8.1 g, 4.81 ml, 50 mmol, 1 equiv.) was added and the resulting solution stirred for 2 min. To the resulting mixture was then added the mixture prepared in STEP A above, over about 30 min at 0° C., then allowed to warm to room temperature, with stirring. To the resulting mixture was then added diethylether, then cooled to 0° C. and treated with 1N HCl. The resulting mixture was extracted with diethylether (3×), the layers separated, the organic layer dried over MgSO4, then filtered and the filtrate evaporated to yield 2-fluoro-5-(thiophen-2-yl)pyridine as a liquid residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[OH-].[K+].[CH3:14]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:14])[CH:7]=[CH:6]2
Reactant: CI
Reactant: COc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of 5-methoxyindole (1 g, 6.8 mmol) in 8 mL of DMF were added potassium hydroxide (0.92 g, 2.4 eq.) and methyl iodide (1 mL, 16 mmol). The resulting mixture was stirred at room temperature overnight. After removing volatile, the residue was diluted with EtOAc and washed with water (4×). The organic layer was dried and concentrated to afford 0.9 g (82%) 5-methoxy-1-methylindole. MS (EI): (M++1) 162.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6]C(OCC2C=CC=CC=2)=O)[CH2:4][N:3]1[C:17]([NH:19][S:20]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=[O:22])=[O:21])=[O:18].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[H][H].N1CCC1=O>C(#N)C.[Pd]>[NH2:6][C@H:5]1[CH2:4][N:3]([C:17]([NH:19][S:20]([NH:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)(=[O:22])=[O:21])=[O:18])[C:2]1=[O:1]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)Nc2ccncc2)C1=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C1CCN1
Solvent: CC#N
Product: N[C@H]1CN(C(=O)NS(=O)(=O)Nc2ccncc2)C1=O
Reaction time: 0.5 h

Procedure:
(S)-2-Oxo-3-[[(phenylmethoxy)carbonyl]amino]-N-[[(4-pyridyl)amino]sulfonyl]-1-azetidinecarboxamide (2.1 g; see example 36) was suspended in 25 ml of acetonitrile and 3 g (3.6 ml) of bis(trimethylsilyl)acetamide was added with stirring. After a few minutes a clear solution was formed. This solution was added to a suspension of 1 g of 10% palladium on charcoal in 25 ml of acetonitrile, through which hydrogen was passed for 30 minutes prior to the addition of the solution of the starting azetidinone. Hydrogenation was complete after 70 minutes. The catalyst was removed by filtration. On addition of 1 ml of methanol the title compound crystallized from the solution; yield 1.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[OH-].[K+:25]>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[K+:25]
Reactant: Cc1cccc(Cl)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1Cn1nc(C)c2ccc(CC(=O)[O-])cc21

Procedure:
To a solution of the compound [102] (33.1 mg) in ethanol (3.0 mL) was added an aqueous solution of 1N-potassium hydroxide (0.1 mL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (35.5 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:29]2[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH2:30]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]=[N+:27]=[N-:28])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:29]2[CH2:30][CH2:31][C:32]([CH3:35])([CH3:36])[CH2:33][CH2:34]2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]2[CH:42]=[C:41]([Si:38]([CH3:40])([CH3:39])[CH3:37])[N:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2cc([Si](C)(C)C)nn2)CC1

Procedure:
A solution of 3-[(trans-4-azido-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4,4-dimethyl-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (0.90 g, 1.7 mmol) in trimethylsilylacetylene (1.2 ml, 6.8 mmol) was treated in microwave at 120° C. for 2 h. The mixture was concentrated under reduce pressure and the residue purified by silica gel column chromatography (1% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to obtain 5-(4,4-Dimethyl-cyclohexyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(4-trimethylsilanyl-[1,2,3]triazol-1-yl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (1.1 g, 58%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=O)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[S:26])[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2c(c1)C1CCCC1C(=O)N2
Product: COc1ccc2c(c1)C1CCCC1C(=S)N2
Yield: 70.7 %

Procedure:
Analogously to Example 4, 8-methoxy-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (8 mg, 0.37 mmol) is reacted with Lawesson's reagent (404 mg, 1.0 mmol) to form 61 mg (71%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH:24]([CH3:27])[CH2:25][CH2:26][C:10]=3[N:9]=2)[CH:7]=1.[CH2:29]([N:31](CC)CC)C.CN.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21]([NH:31][CH3:29])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH:24]([CH3:27])[CH2:25][CH2:26][C:10]=3[N:9]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1C(C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid (20 mg, 0.05 mmol, 1 eq) in DMF (2 ml) was added triethylamine (8 μl, 0.05 mmol, 1.1 eq) followed by methylamine (250 μl, 3.89 mmol, 2M solution in THF, 10 eq). To the suspension was added a solution of PyBOP (40 mg, 0.08 mmol, 1.5 eq) in DMF (1 ml) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (100% ethylacetate) to afford 4-[2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-N-methyl-nicotinamide, 47 (12 mg, 58%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[Br:15]Br>CC(O)=O>[Br:15][CH:3]1[CH2:4][CH2:5][C:6]2[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][C:10]=2[C:2]1=[O:1]
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1nc2c(s1)C(=O)C(Br)CC2
Temperature: 75 °C

Procedure:
N-(7-Oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (Stage T.4, 2.286 g, 10.87 mmol) was dissolved in AcOH (60 ml), then bromine (1.74 g, 10.87 mmol) dissolved in AcOH (10 mL) were slowly added and the RM was heated to 75° C. for 20 h. The color changed from red to beige. The mixture was evaporated and the residue was dissolved in MeOH (10 mL) and precipitated with H2O. The mixture was filtered and dried on HV. The crude material was chromatographed with MPLC C18 H2O 0.1% TFA/CH3CN 0.1% TFA, gradient 0-50%. Fractions containing the product were neutralized with NaHCO3, extracted with EtOAc and lyophilized from dioxane to give of the title compound as a white solid (M+H=291; M−H=289; tR 4.29 (Method F)). 1H-NMR (d6-DMSO, 600.13 MHz) 12.75 (s, 1H) 4.95 (t, 1H), 2.95-2.84 (m, 2H), 2.62-2.52 (m, 1H), 2.40-2.30 (m, 1H), 2.20 (s, 3H).