Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH3:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]1)=[O:13])([OH:3])=O.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O=S(Cl)Cl>[CH3:25][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][C:12](=[O:13])[N:14]([CH2:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([N:35]3[CH2:36][CH2:37][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)[CH2:33][CH2:34]3)=[O:24])[CH2:20][CH2:21]2)[C:1]1=[O:3]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CN(C(=O)O)c1ccccc1CC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O=S(Cl)Cl
Product: CN1C(=O)N(C[C@H]2CC[C@H](C(=O)N3CCN(c4ccccn4)CC3)CC2)C(=O)Cc2ccccc21
Temperature: 25 °C

Procedure:
A solution of trans-4-({2-[2-(Carboxy-methyl-amino)-phenyl]-acetylamino}-methyl)-cyclohexanecarboxylic acid (0.14 mmol, 0.05 g) in SOCl2 (0.8 mL) was heated under reflux for 1.5 hours. The solvent was removed under reduced pressure and the residue was put under vacuum overnight. Then crude product was diluted with 5 ml of dry DCM. 1 ml of this stock solution was transferred in a glass vial. 39 μL (0.27 mmol) of 1-Pyridin-2-yl-piperazine were added and the reaction mixture was left stirring at room temperature under argon over night. The solvent was removed under vacuum and the crude purified by preparative HPLC (Method d) to give 26 mg of the titled compound (yield 39%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=3[C:9](=O)[CH2:8]2)=[CH:4][CH:3]=1.C(NN)(N)=N.Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=3[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccc(Cl)s1)C2
Agent: Cl
Agent: N=C(N)NN
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1CCC(c1ccc(Cl)s1)C2
Yield: 60.9 %

Procedure:
A mixture of 7-(5-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.79 g), aminoguanidine hydrochloride (0.33 g), concentrated hydrochloric acid (0.7 ml), water (0.7 ml) and ethanol (40 ml) was refluxed for 8.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethanol and recrystallized from ethanol-water. The resulting crystals were washed with ethanol to give 7-(5-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 72) (0.26 g) as crystals.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.[NH2:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23]([NH2:30])=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=1.C(O)(C(F)(F)F)=O>C(O)(C)C>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[N:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23]([NH2:30])=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=1
Reactant: Nc1ccc2c(c1)Cc1cc(N)ccc1-2
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Nc1ccc2c(c1)Cc1cc(N=Cc3ccc4c(c3)Cc3ccccc3-4)ccc1-2
Reaction time: 12 h

Procedure:
2-Fluorenecarboxaldehyde (49.5 mg, 0.25 mmol) was added to 2,7-diaminofluorene (50 mg, 0.25 mmol) in anhydrous isopropanol, under an N2 atmosphere and a catalytic amount of TFA. No heating was required. The reaction was run for 12 hours until a green precipitate was filtered, yielding 94.9 mg. of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13].[Na+].[I-].[CH3:18][CH2:19][SH:20].O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][S:20][CH2:19][CH3:18])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: CCS
Reactant: FC(F)(F)COc1ccc(CCl)cc1Br
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCSCc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 30 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
To a solution of the title compound from Step 3 (2.00 g, 6.59 mmol) in DCM (200 mL) was added TEA (1 g, 9.89 mmol), NaI (898 mg, 5.99 mmol) and EtSH (613 mg, 9.89 mmol). The mixture was stirred at 30° C. for 4 hrs. The reaction was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (PE:EA=1:03:1) to give the title compound (2.1 g, 96.8%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, J=2.0 Hz, 1 H), 7.24 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.42 (q, J=8.0 Hz, 2H), 3.66 (s, 2H), 2.47-2.41 (m, 2H), 1.26-1.22 (m, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@H:8]1[CH2:13][O:12][CH2:11][CH2:10][N:9]1[C:14]1[N:15]=[C:16]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]2[CH3:42])[C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([CH:33]=3)[C:29](OC)=[O:30])=[N:20][C:18]=2[N:19]=1>C1COCC1>[CH3:7][C@H:8]1[CH2:13][O:12][CH2:11][CH2:10][N:9]1[C:14]1[N:15]=[C:16]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]2[CH3:42])[C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([CH2:29][OH:30])[CH:33]=3)=[N:20][C:18]=2[N:19]=1
Reactant: COC(=O)c1cc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of lithium aluminium hydride (2M solution in THF, 1.01 mL, 2.01 mmol) was added to a solution of methyl 5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxybenzoate (1.47 g, 2.68 mmol) in THF (19.8 mL) at 0° C. under an atmosphere of nitrogen. After 60 minutes, further lithium aluminium hydride (2M solution in THF, 0.67 mL, 1.34 mmol) was added and the solution allowed to stir at RT for 900 minutes. The resulting solution was quenched by the addition of water (11.76 mL) and extracted with ethyl acetate (22 mL). On evaporation of the ethyl acetate, 1.2 g of (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (6) is obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=O)=[CH:21][CH:22]=1.[OH-].[K+].O>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH:13]=[CH:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
To a stirred solution containing 196 mg of 2'-hydroxy-4',6'-dimethoxyacetophenone and 150 mg of anisaldehyde in 3 ml of ethanol was added 50% aqueous potassium hydroxide (3 ml). After being stirred at room temperature for 3 days, the mixture was poured into 30 ml of cold water. The mixture was then extracted with three 30 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with water, dried over anhydrous sodium sulfate and then evaporated under reduced pressure to give a crystalline residue. Recrystallization of the residue from methanol gave 182 mg (50% yield) of 2'-hydroxy-4,4',6'-trimethoxychalcone as yellow needles: m.p. 110.7° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[C:36]([C:41]([OH:43])=O)[CH:35]=[CH:34]3)=[O:29])[CH:5]=[CH:6][CH:7]=1.C[N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>C(Cl)Cl.CO>[C:41]([C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([NH:30][C:28]([C@H:9]1[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:44])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]1)=[O:29])[CH:40]=[CH:39]2)(=[O:43])[NH2:46]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3cc(C(=O)O)ccc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3cc(C(N)=O)ccc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-naphthoic acid (58 mg, 0.091 mmol) in methylene chloride (8 ml), HATU (35 mg, 0.091 mmol) was added followed by DIPEA (0.15 ml). The solution was stirred for 5 minutes and then ammonia in methanol (2M in methanol, 1.0 ml) was added and the mixture was stirred at rt for 3 hrs. The solvent was reduced to 4 ml and loaded onto a silica gel column and eluted with 5% Methanol/methylene chloride on a combifalsh machine to give a white solid. 49 mg, 84.5%. (ES+) m/z Calcd: [(M+H)+]: 635. found: 635.
Reaction SMILES: Br[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.[OH-].[Na+]>C1C=CC=CC=1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:13]1([CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: c1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2-bromomalonate (0.15 m) and indole (0.1 m) in 100 ml of benzene is added a solution of sodium hydroxide (0.l m) in water. To this mixture is added tetra-n-butylammonium bromide (0.5 mmole). This mixture is stirred at about 25° C. for 16 hours. The phases are separated, the organic phase is dried and evaporated to give diethyl (1H-indol-1-yl)malonate.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]1[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>C(#N)C>[CH2:1]([C:4]1[N:5]([CH2:26][C:27]2[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(C(F)(F)F)o1
Yield: 119.2 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.100 g, 0.396 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (1.30 g, 4.00 mmol) and 2-(bromomethyl)-5-(trifluoromethyl)furan (0.1.36 g, 0.594 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.189 g, 89% yield): MS (ES) m/z 400 (M+).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][C:9]2[C:10]([N:18]=1)=[CH:11]N=[N:13][C:14]=2OCC)[CH2:2][CH2:3][CH3:4].[F:24][C:25]([F:34])([F:33])[C:26]1C=C(C=C[CH:32]=1)N>C(N(CC)CC)C>[C:14]([C:9]1[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]([NH:5][C:1]2[CH:2]=[CH:3][CH:4]=[C:26]([C:25]([F:34])([F:33])[F:24])[CH:32]=2)=[N:18][C:10]=1[CH3:11])#[N:13]
Reactant: CCCCNc1nc2cnnc(OCC)c2cc1C(=O)OCC
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#N)c(C)nc1Nc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
56 g of 2-chloro-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester (0.25 mol) of Example 2 (b) are dissolved in 200 ml of alcohol. 30 g of triethylamine are added and the solution is heated at 80° C. with stirring. Now 34 g of 3-trifluormethylaniline are added and heating is continued for 5 hours. The solution is poured onto ice and the precipitated title compound filtered off. Yield 70 g (80%); m.p. 149°-151° C. (methanol).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][NH:19][CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[CH:15]=2)[C:10]1=[O:26])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[CH2:36][C:32]3[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=3)[CH:15]=2)[C:10]1=[O:26])[CH2:28][CH3:29]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN1Cc2cc(CNCc3ncc[nH]3)ccc2C1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN1Cc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
The compound (20.3 mg) obtained in Example 7-7 was dissolved in methanol (2.0 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (6.8 mg) and sodium cyanoborohydride (6.4 mg). The solution was adjusted to pH 4 by addition of acetic acid, followed by stirring at room temperature for 6 hours. Then, the solution was added with a saturated aqueous sodium hydrogen carbonate solution to stop the reaction and then subjected to extraction with chloroform. After that, the organic layer was washed with water and a saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (24.0 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: CC(C)(C(=O)[N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][N:9]([C:14]1[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2)C#N.C(N(CC)CC)C.[CH3:32][C:33]([S:36](Cl)=[O:37])([CH3:35])[CH3:34]>C1COCC1>[CH3:32][C:33]([S:36]([N:6]1[CH2:7][CH2:8][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][C:11]21[CH2:12][CH2:13]2)=[O:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)S(=O)Cl
Reactant: CC(C)(C#N)C(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reaction time: 16 h

Procedure:
Intermediate 2 (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and 2-methylpropane-2-sulfinyl chloride (0.06 mmol) was added. The reaction mixture was left at rt for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.8 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (60 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH3:17][NH2:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:18][CH3:17])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN
Product: CNS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 61 %

Procedure:
According to general procedure A, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and methylamine (10 mL, 33% in ethanol) were stirred in sealed tube for 16 hours. 4-bromo-N-methyl-2-(trifluoromethoxy)benzenesulfonamide (0.21 g, 61%) was provided after purification. MS (ESI) m/z 334. HPLC purity 98.0% at 210-370 nm, 8.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:6]([CH3:21])[CH:5]=[CH:4][N:3]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CO.O>C1COCC1>[CH3:21][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:9](=[O:10])[NH:8][C:7]=12
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 64.5 °C

Procedure:
A reaction flask equipped with a magnetic stirrer, temperature controller thermodouple, addition funnel and condenser with an oil bubbler for exclusion of ambient air was inerted with nitrogen and charged with 3.02 g (0.010 mol) of N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide from Example 4 and 30 ml of anhydrous THF. A 40% solution of sodium hexamethyldisilazane in THF (12.7 ml, 0.025 mol) was added dropwise maintaining the temperature of the reaction mixture at no more than 30° C. When the addition of the NaHMDS solution was completed, the reaction mixture was heated to reflux temperature (about 63-66° C.). When the reaction was completed (HPLC analysis), the mixture was cooled to ambient temperature. The reaction mixture was treated with 1.55 g (0.050 mol) of methanol and 0.45 g of water (0.025 mol). The mixture was concentrated on a rotary evaporator at 25-30 in. Hg with a 50-60° water bath temperature. The residual product weighing 4.44 g was triturated with 50 ml of water and the pH 10-12 solution was acidified to pH 3 by adding 10% HCl solution. The solid product was collected by filtration and the filter cake rinsed three times with 10 ml portions of water. The filter cake was dried in a vacuum oven at 50-60° C. to obtain nevirapine.
Reaction SMILES: [CH2:1]([CH:3]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH2:1]([CH:3]([CH:6]1[CH2:7][C:8](=[O:13])[CH:9]([C:24](=[O:25])[NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:26])=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C:10](=[O:12])[CH2:11]1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCC(CC)C1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CCC(CC)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-(1-ethylpropyl)-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-(1-ETHYLPROPYL)-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 111.5°-112.5° C. (corr.).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:45]1[CH2:50][CH2:49][CH:48]([CH2:51][NH2:52])[CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:52][CH2:51][CH:48]3[CH2:49][CH2:50][O:45][CH2:46][CH2:47]3)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: NCC1CCOCC1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Yield: 81.7 %

Procedure:
Combined 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid (30 mg, 0.096 mmol), EDCI (27.6 mg, 0.144 mmol), HOBT (19.47 mg, 0.144 mmol), and DMF (961 μl), then added (tetrahydro-2H-pyran-4-yl)methanamine (17.66 μl, 0.144 mmol) and Hunig's base (68.3 μl, 0.384 mmol) and stirred at room temperature overnight. The reaction mixture was purified via preparative HPLC to give the title compound (32.1 mg, 82%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.35 (qd, J=12.38, 4.55 Hz, 2H) 1.71 (d, J=12.88 Hz, 2H) 1.84-1.99 (m, 1H) 3.42 (td, J=11.68, 1.64 Hz, 2H) 3.95 (d, J=3.28 Hz, 1H) 3.98 (s, 3H) 4.19 (s, 3H) 7.76 (d, J=6.57 Hz, 1H) 7.84 (s, 1H) 8.03 (d, J=6.57 Hz, 1H) 8.28-8.47 (m, 2H) 8.55 (br. s., 1H) 8.85 (br. s., 1H). MS m/z [M+H]+410.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.O=S(Cl)Cl.[CH2:41]1COCC1>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][O:12][CH3:41])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C1CCOC1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1COC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of Example 23 (N-{4-[4-amino-7-(hydroxymethyl)-6-(methoxy-methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)-phenyl]urea (22 mg, 0.04 mmol)) in anhydrous THF (1 mL) and CH2Cl2 (1 mL) was added SOCl2 (0.006 ml, 0.08 mmol). After 20 min, analytical HPLC shoved half of the starting material remained. Additional SOCl2 (0.01 ml) was added and the reaction was stirred at rt for 2.5 h until completion. The mixture was evaporated to dryness and CH2Cl2 (3 ml) was added. The solvent was evaporated to dryness and the crude concentrate was re-suspended in CH2Cl2 and evaporated to remove the excess SOCl2 completely. To the resulting solid was added anhydrous MeOH (1 ml) and Hunig's base (0.008 ml), the reaction was stirred at 70° C. overnight. After 16 h, the reaction was cooled to rt and solvent was evaporated. The crude material was taken up in ethyl acetate, washed with aq. saturated sodium bicarbonate three times and dried over Na2SO4. After concentration, the resulting crude was purified via column chromatography (5:95 v/v MeOH—CH2Cl2) to afford 12 mg of the title compound (yield 53%). 1H-NMR (DMSO-d6) δ 9.32 (s, 1H), 8.96 (d, J=3 Hz, 1H), 8.63 (dd, J=7, 3 Hz, 1H), 7.92 (s, 1H), 7.59 (t, J=3 Hz, 2H), 7.57 to 7.32 (m, 4H), 4.73 (s, 2H), 4.28 (s, 2H), 3.26 (s, 3H), 3.24 (s, 3H) ppm; MS [M+H]+=519.1; LCMS RT=2.84 min