Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:20][C:21]1[C:30]([O:31][CH3:32])=[CH:29][C:24]2[NH:25][C:26](=[O:28])[S:27][C:23]=2[CH:22]=1>>[CH3:32][O:31][C:30]1[C:21]([NH:20][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:22][C:23]2[S:27][C:26](=[O:28])[NH:25][C:24]=2[CH:29]=1
Reactant: CN(C)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2sc3c(c12)CCC(C(=O)N(C)C)C3

Procedure:
30 mg (101 μmol) (RS)-4-chloro-N,N-dimethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 85a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 5.8 mg (12%) of the title compound.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[C:12]2[C:7](=[C:8]([CH2:13][CH:14]=[CH2:15])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=1.[Cl:18]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.P(O)(O)([O-])=O.[K+]>ClCCCl.ClC(Cl)C>[Cl:18][CH:5]1[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH:14]=[CH2:15])[C:4]1=[O:3]
Reactant: C=CCc1cccc2c1CC=C2O[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: C=CCc1cccc2c1CC(Cl)C2=O
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
8 g of 3-trimethylsilyloxy-7-(2-propenyl)-indene in 25 ml of 1,2-dichloroethane is cooled to 0° C.; 31 g of N-chlorosuccinimide in 80 ml of dichloroethane is introduced over 25 minutes, with agitation for 30 minutes at 0° C.; 0.6 g of N-chlorosuccinimide in 15 ml of dichloroethane and a few mg of paratoluene sulphonic acid are added. After 30 minutes of agitation at 0° C., the reaction mixture is poured over an iced aqueous solution saturated with monopotassium phosphate, with agitation for 16 hours at 20° C. After decanting and extracting with methylene chloride, the extracts are dried, and concentrated to dryness under reduced pressure. The residue is chromatographed on silica, eluting with a hexane-isopropyl ether mixture (7-3). The fractions recovered are concentrated and chromatographed again on silica, eluting with a hexane-isopropyl ether mixture (3-1) and 2.75 g of expected product is isolated.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:19]([NH:25][NH2:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1>C(O)(=O)C>[Cl:17][C:18]1[C:19]([N:25]=[N:26][C:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[OH:16])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: CC(=O)O
Product: Oc1c(N=Nc2ncc(Cl)cc2Cl)c2ccccc2c2ccccc12
Temperature: 105 °C

Procedure:
Next, a reaction flask was loaded with acetic acid (15 ml) and 9,10-phenanthrenequinone (5.0 g), and the temperature was raised to 105° C. with stirring to dissolve 9,10-phenanthrenequinone. To the resultant, the crystals of 3,5-dichloro-2-hydrazinopyridine (4.6 g) was added in 30 minutes. After stirring at 105 to 110° C. for one hour, the reaction mixture was filtrated. The filtrated crystals were washed with methanol, and then dried to give intended crystals (5.1 g).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]3[CH2:33][CH2:34][CH2:35]3)[N:27]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C3CCC3)n2)c(C(N)=O)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
In a 25 mL round bottom flask, a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclobutylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (112 mg, 233 μmol) in CH2Cl2 (5.0 mL) was treated with TFA (2.22 g, 1.5 mL, 19.5 mmol) and the mixture stirred to room temperature for 18 h. Solvents evaporated and residue purified by flash chromatography (spherical silica 20-45 μM, 80 g, Versaflash Supelco) eluting with 0 to 10% over 30 min (MeOH containing 10% NH4OH)/CH2Cl2 to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-cyclobutylpyridin-2-ylamino)pyridazine-3-carboxamide (48 mg, 126 μmol, 54.1% yield) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 11.43 (br. s., 1H), 8.45 (s, 1H), 8.03 (br. s., 1H), 7.51 (t, J=7.7 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.68 (d, J=7.9 Hz, 1H), 5.62 (d, J=8.3 Hz, 1H), 5.37 (br. s., 1H), 3.88 (br. s., 1H), 3.65 (quin, J=8.5 Hz, 1H), 3.22 (d, J=4.9 Hz, 1H), 2.27-2.51 (m, 4H), 1.99-2.22 (m, 1H), 1.94 (dd, J=11.1, 5.5 Hz, 1H), 1.07-1.84 (m, 10H); LC-MS 382.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18](SC)=[CH:17][CH:16]=3)=[CH:13][C:12]([CH:23]([F:25])[F:24])=[N:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:27]1C=CC=C(C(OO)=O)C=1.[S:37]([O-:41])([O-])(=[O:39])=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:37]([CH3:27])(=[O:41])=[O:39])=[CH:17][CH:16]=3)=[CH:13][C:12]([CH:23]([F:24])[F:25])=[N:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(SC)cc2)cc1Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl

Procedure:
To a solution of 1-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole (2.0 g) in dichloromethane (50 ml) was added portionwise m-chloroperbenzoic acid (2.3 g, 80% purity) at 5° C. with stirring. After being stirred at room temperature for 2 hours, the reaction mixture was treated with aqueous solution of sodium thiosulfate and then partitioned between dichloromethane and water. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After evaporation of the solvent, the crude solid was recrystallized from ethanol to give 1-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (1.8 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)=[C:8]([Cl:9])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1ccnc(Cl)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2c(Cl)ccnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 3-(bromomethyl)-2,4-dichloropyridine (1.41 g, 5.86 mmol) in anhydrous ethanol (20 mL) was added 6-methyl-2-sulfanylpyrimidin-4-ol (0.58 g, 4.09 mmol) and triethylamine (0.65 g, 6.43 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to precipitate the product. The white solid was filtered and washed with water and ether to provide 2-{[(2,4-dichloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.795 g, 45% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.31 (s, 3H), 4.68 (s, 2H), 6.04 (bs, 1H), 7.67 (d, J=5.3 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H); M+302.3.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=2[CH3:15])[O:4][N:3]=1.[H][H]>C(O)C.[Pt]=O>[CH3:15][C:8]1[CH2:9][CH2:10][CH2:11][C:12]([CH3:13])([CH3:14])[C:7]=1[C:5](=[O:4])[CH:6]=[C:2]([NH2:3])[CH3:1]
Reactant: [H][H]
Reactant: CC1=C(c2cc(C)no2)C(C)(C)CCC1
Agent: O=[Pt]
Solvent: CCO
Product: CC(N)=CC(=O)C1=C(C)CCCC1(C)C
Yield: 99.4 %

Procedure:
30.75 g (0.15 mole) of 3-methyl-5-[2,6,6-trimethyl-cyclohex-1-en-1-yl]-isoxazole were dissolved in 50 ml of dry ethanol and the solution was added to 1.396 g of a mixture of 82.9% of platinum oxide in 600 ml of ethanol, the said mixture having previously been subjected to a hydrogenation. The alcoholic solution was then subjected to a hydrogenation at ordinary temperature and pressure and, after absorption of one equivalent of hydrogen, was filtered through a "Celite" carrier. After having been concentrated under reduced pressure, the residual mixture was recrystallized from hexene containing traces of ethanol to yield 30.91 g (yield 100%) of 2,6,6-trimethyl-1-[3-amino-but-2-enoyl]-cyclohex-1-ene which exists in two interconvertible crystalline structures: m.p. 124.5°-125.0° and 135°-136°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[N:23]1([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCNCC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and piperazine to give 262. MS: (ESI+)=382.1
Reaction SMILES: CS(OCC)(=O)=O.C(#N)C.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C@@H:33]4[CH2:37][CH2:36][N:35]([CH:38](C)[CH3:39])[CH2:34]4)=[CH:28][CH:27]=3)[C:22](=[O:41])[CH:21]=2)=[N:16][CH:17]=1>C(Cl)(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C@@H:33]4[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34]4)=[CH:30][CH:31]=3)[C:22](=[O:41])[CH:21]=2)=[N:16][CH:17]=1
Reactant: CC(C)N1CC[C@@H](Oc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Agent: CCOS(C)(=O)=O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCN1CC[C@@H](Oc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
Ethyl methanesulfonate (0.45 mL) was added to acetonitrile solution of 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(3R)-3-pyrrolidinyl]oxy}phenyl)-1H-pyridin-2-one (1.65 g, Example 122), and stirred at 80° C. for 2 hours. Additional ethyl methanesulfonate (0.45 mL) was added and stirred at 80° C. for further 2 hours, followed by cooling to room temperature. Chloroform was added to the reaction liquid which then was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous potassium carbonate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (C-300; methanol:chloroform=1:100-1:10-1:4). The residue was crystallized from mixed solvent of ethyl acetate and heptane to provide the title compound (660 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4](Cl)=[O:5].[CH2:15]([NH:17][CH2:18][C:19]([CH2:25][NH:26][C:27]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]2[C:28]=1[CH:29]=[N:30][N:31]2[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)([OH:24])[C:20]([F:23])([F:22])[F:21])[CH3:16]>>[CH2:15]([N:17]([CH2:18][C:19]([CH2:25][NH:26][C:27]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]2[C:28]=1[CH:29]=[N:30][N:31]2[C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1)([OH:24])[C:20]([F:22])([F:23])[F:21])[C:4](=[O:5])[C:3]1[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:16]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1C(F)(F)F

Procedure:
Prepared similarly to Example 48 from 2-fluoro-6-(trifluoromethyl)benzoyl chloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [OH2:1].[C:2]([OH:5])(=O)[CH3:3].[C:6](#N)[CH3:7]>C(OCC)(=O)C>[O:1]=[CH:7][CH2:6][C@:7]([C@H:6]([C@H:2]([CH3:3])[OH:5])[OH:1])([O:5][CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC#N
Reactant: O
Solvent: CCOC(C)=O
Product: CO[C@](C)(CC=O)[C@@H](O)[C@H](C)O

Procedure:
A sample of the compound from Step 2b (330 mg) was stirred in a solution of water (0.5 mL) and acetic acid (0.25 mL) in acetonitrile (2 mL) for 2 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was re-treated with the same procedure (4 hours) to hydrolyse remaining protecting groups. The product was re-isolated as described, then purified by chromatography on silica gel, eluting with 1:98:1 methanol/dichlomethane/ammonium hydroxide to give the title compound (78 mg). 13C NMR (CDCl3) δ 82.6(C-9), 175.4(C-1), 153.4(carbonate carbonyl carbon), 102.9, 96.2, 88.6, 85.8, 84.0, 82.8, 80.3, 79.7, 77.9, 76.8, 72.6, 70.9, 68.9, 65.6, 65.4, 49.4, 44.9, 40.2, 39.6, 39.2, 34.9, 34.4, 28.6, 28.5, 21.8, 21.5,21.4, 19.8, 18.6, 17.8, 16.5, 15.9, 15.5, 9.9, 9.2. MS FAB High Resolution (M+H)+ : calcd: 787.4592; observed: 787.4606.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH3:12])[C:5]#[N:6].[CH2:13]([N:20]=[C:21]=[S:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH3:12])=[S:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCNc1ccc(C#N)cc1N
Reactant: S=C=NCc1ccccc1
Solvent: C1CCOC1
Product: CCNc1ccc(C#N)cc1NC(=S)NCc1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 92.5 %

Procedure:
To a solution of 3-amino-4-ethylamino-benzonitrile (1.0 g, 6.2 mmol) in THF (50 mL, anhyd) was added benzylisothiocyanate (0.92 g, 6.2 mmol). The reaction mixture was heated at 50° C. with stirring. After 6 h, the reaction mixture was cooled, concentrated under reduced pressure, and chromatographed (silica gel, 1:1 EtOAc/Hex) to yield 1-benzyl-3-(5-cyano-2-ethylaminophenyl)thiourea (1.78 g, 93%). 1H-NMR (CDCl3): δ 7.48 (1H, dd), 7.37 (1H, d), 7.31 (3H, m), 7.24 (1H, s), 7.18 (1H, br), 6.67 (1H, d), 5.95 (1H, br), 4.81 (2H, d), 4.68 (1H, br), 3.19 (2H, m), 1.23 (3H, t).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[F:6][C:7]([F:25])([F:24])[C:8]1[CH:9]=[C:10]([N:14]2[C:19](=[O:20])[NH:18][CH:17](SC)[NH:16][C:15]2=[O:23])[CH:11]=[CH:12][CH:13]=1>C(O)(=O)C>[F:6][C:7]([F:25])([F:24])[C:8]1[CH:9]=[C:10]([N:14]2[C:19](=[O:20])[NH:18][CH:17]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[NH:16][C:15]2=[O:23])[CH:11]=[CH:12][CH:13]=1
Reactant: CCCCN
Reactant: CSC1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Solvent: CC(=O)O
Product: CCCCNC1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
n-Butylamine (3.92 ml.) was added during 15 minutes to stirred acetic acid (2.4 ml.). After 30 minutes at room temperature, 3-(3-trifluoromethylphenyl)-6-methylthio-tetrahydro-1,3,5-triazine-2,4-dione (6.1 g.) was added to the acetic acid solution. The mixture obtained was then heated at 145° C., for 4 hours. (The liberated methylmercaptan was absorbed into a trap containing an excess of aqueous sodium hydroxide and sodium hypochlorite.) The reaction mixture was cooled to room temperature and then water (75 ml.) was added. The mixture was then stirred for 15 minutes and the white solid which formed was separated by filtration, washed with water (3×150 ml.), and dried (over phosphorus pentoxide) to give 3-(3-trifluoromethylphenyl)-6-n-butylamino-tetrahydro-1,3,5-triazine-2,4-dione (6.0 g., 95%), m.p. 245°-247° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([O:55][C:56]2[CH:63]=[CH:62][C:59]([C:60]#[N:61])=[CH:58][C:57]=2[CH:64]2[CH2:66][CH2:65]2)=[N:53][CH:54]=1>CN(C)C=O>[C:60]([C:59]1[CH:62]=[CH:63][C:56]([O:55][C:52]2[N:53]=[CH:54][C:49]([NH:48][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:50][CH:51]=2)=[C:57]([CH:64]2[CH2:65][CH2:66]2)[CH:58]=1)#[N:61]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1ccc(Oc2ccc(N)cn2)c(C2CC2)c1
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
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C#N)cc2C2CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (121.4 mg, 0.60 mmol) was dissolved in N,N-Dimethylformamide (1 mL). N,N-Diisopropylethylamine (0.126 mL, 0.72 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (227.2 mg, 0.60 mmol) were added. The reaction mixture was stirred at r.t. for 30 min. 4-[(5-amino-2-pyridinyl)oxy]-3-cyclopropylbenzonitrile (Reference Intermediate R24, 100 mg) was dissolved in 1.0 mL of DMF and the obtained solution was added to the reaction mixture. The reaction mixture was stirred and heated at 60° C. for 2 h. After cooling down to r.t., the reaction mixture was evaporated under vacuum and the crude obtained was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 100:0 to 50:50 Cyclohexane/EtOAc, then plateau at 50:50) affording 133 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([NH2:39])=[O:38].C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:39][C:37]([C:36]1[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=1[NH:34][C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1)=[O:9])=[O:38]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(O)c1csc(Br)n1
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
Product: NC(=O)c1ccccc1NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 144 h
Yield: 89.9 %

Procedure:
2-Bromo-4-thiazolecarboxylic acid (1 g), HATU (2.01 g) and 2-aminobenzamide (0.65 g) are introduced into N,N-dimethylformamide (DMF) (20 ml). The mixture is cooled with an ice bath, and N,N-diisopropylethylamine (0.90 ml) is added. The reaction mixture is stirred at room temperature for 6 days, poured into ice-water and allowed to thaw with stirring, and the precipitated solid is filtered off with suction, washed twice with water, twice with diethyl ether and dried in vacuo. Intermediate III.2 is obtained as a solid (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:20]([CH:16]3[CH2:19][CH2:18][CH2:17]3)=[O:21])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: O=C(Cl)C1CCC1
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: Cn1c(C#N)ccc1-c1ccc(NC(=O)C2CCC2)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using cyclobutane carbonyl chloride (60 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]cyclobutane carboxamide (0.048 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[I:22]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[C:20]([I:22])=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N)n3)ccc21
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3nc(N)ncc3I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
N1-Methyl-5-(2-amino-4-pyrimidyl)oxy-1H-1-indolecarboxamide (302 mg, 1.07 mmol) and N-iodosuccinimide (301 mg, 1.34 mmol) were dissolved in N,N-dimethylformamide (3.0 ml); and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. The solvent was distilled off; and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=2:1) to yield the title compound as yellow crystals (224 mg, 0.547 mmol, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH2:5][C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH:5]=[CH:6]2
Reactant: CC1CC(=O)c2cccc(Br)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1C=Cc2cccc(Br)c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 116 g (0.52 mol) of 4-bromo-3-methylindan-1-one in 950 ml of a mixture of THF-methanol (2:1, vol.) 38.3 g (1.02 mol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 1000 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 1500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 2 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The product was isolated by vacuum distillation (bp 104-108° C./5 mm Hg). Yield 100 g (93%).
Reaction SMILES: [Si]([N:8]1[CH:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[CH2:10][C:9]1=[O:29])(C(C)(C)C)(C)C.Cl.P([O-])([O-])(O)=O.[K+].[K+]>CO>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:15]([CH2:14][C:13](=[O:28])[CH2:12][CH:11]2[NH:8][C:9](=[O:29])[CH2:10]2)=[O:16])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CO
Product: O=C(CC(=O)OCc1ccc([N+](=O)[O-])cc1)CC1CC(=O)N1
Reaction time: 3.33 h
Yield: 90.8 %

Procedure:
A solution of N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one (5.17 g, 12.3 mMol) in methanol (55 ml) is treated with 1N hydrochloric acid (6.2 ml) and then kept at room temperature for 200 mins. The solution is treated with 1M dipotassium hydrogenphosphate (6.2 ml) and concentrated under vacuum. The residue is taken up in ethyl acetate (100 ml), washed with brine, dried over magnesium sulfate, filtered, and evaporated under vacuum. Triturating the resulting oil with diethyl ether yields 4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one (3.42 g, 91%) as an off-white powder: mp 50°-52°; IR (CH2Cl2) 3416, 1767, 1723, 1528, and 1352 cm-1 ; NMR (CDCl3) δ 2.60 (ddd, 1, J=1, 2.7, and 15.1, H3β), 2.77 (dd, 1, J=8.4 and 18.2, CHCH2CO), 3.13 (dd, 1, J=5.1 and 18.2, CHCH2CO), 3.20 (ddd, 1, J=2.4, 5.0, and 15.1, H3α), 3.57 (s, 2, COCH2CO2), 3.98 (m, 1, H4); 5.27 (s, 2, CH2Ar), 6.28 (or s, 1, NH), 7.53 and 8.23 (two d's, 4, J=8.5, ArH); mass spectrum m/e 306(M+), 264(M+-42), 237, 153, 125, 111, and 136.