Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:27]([CH:28]=[O:29])=[CH:26][C:8]2[C:9]3[N:13]([CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)[CH:12]=[C:11]([C:17]1[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=1)[N:10]=3>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[F:4][C:5]1[C:27]([CH:28]([OH:29])[CH3:1])=[CH:26][C:8]2[C:9]3[N:13]([CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)[CH:12]=[C:11]([C:17]1[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=1)[N:10]=3
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C=O)c(F)cc2OCC3)n(C(C)C)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)O)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Methylmagnesium bromide (10.1 mL of a 1.4 M solution in THF/PhMe) was added to a solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-carbaldehyde (968 mg, 2.83 mmol) in THF (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched by addition of sat. NH4Cl (10 mL). The mixture was extracted with EtOAc (3×25 mL) and the combined organics were washed (brine), dried (Na2SO4) and concentrated in vacuo. Compound purified by column chromatography (Si-PPC, gradient 0-5% MeOH in DCM) to give the title compound (361 mg, 0.97 mmol, 34%) as a pale brown solid. LCMS (Method J): RT=2.53 min, [M+H]+=372
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.C(OCC)C>[C:1]1([CH2:7][CH2:8][CH:9]=[CH:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(=O)C=CCCc1ccccc1

Procedure:
A mixture of 3-phenylpropanol (2.68 g., 20 mmole), triphenyl-(2-keto-n-heptyl)phosphonium chloride (8.22 g., 20 mmole), sodium carbonate (2.36 g., 22.3 mmole) and water (20 ml.) in tetrahydrofuran (70 ml.) is refluxed for 6 hours under an atmosphere of argon. The cooled mixture is diluted with ethyl ether and the layer separate. The organic phase is washed with saturated sodium chloride solution, dried over Na2SO4 and evaporated. The residue is taken up in hexane and insoluble triphenyl phosphine oxide is filtered off. The residue obtained on evaporation of the hexane is purified by flash chromatography on silica gel (120 g.) eluting with ethyl ether/hexane (1:30) to give two isomers of 1-phenyl-3-decen-5-one; 2.93 g. Rf (ethyl ether/hexane 1:4) 0.73 and 0.42 g. Rf (ethyl ether/hexane 1:4) 0.85.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:16])([F:15])[CH2:12][O:13][CH3:14])=[N:9][N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)#[CH:18]>C1COCC1.[Cu]I>[F:15][C:11]([C:8]1[N:6]2[CH:7]=[C:2]([C:18]#[C:17][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([F:16])[CH2:12][O:13][CH3:14]
Reactant: COCC(F)(F)c1nnc2ccc(Br)cn12
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COCC(F)(F)c1nnc2ccc(C#Cc3ccc(C(F)(F)F)cc3)cn12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-bromo-3-(1,1-difluoro-2-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyridine (46 mg, 0.16 mmol) in THF (5 mL) was added catalytic amount of dichlorobis(triphenylphosphine) palladium(II) (11 mg) and copper(I) iodide (3 mg), followed by 1-ethynyl-4-(trifluoromethyl)benzene (41 mg, 0.24 mmol). The resulting mixture was flushed with N2 and Et3N (2 mL) was added. The reaction mixture was stirred at 70° C. overnight and purified by prep-TLC (EtOAc: hexanes=2:3) followed by HPLC to give 3-(1,1-difluoro-2-methoxyethyl)-6-((4-(trifluoromethyl)phenyl)ethynyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[N:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]([CH3:26])([C:22](OC)=[O:23])[CH3:21])=[O:18])=[CH:12][CH:11]=2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1)#[N:2].C[O-].[Na+]>CO>[CH3:21][C:20]1([CH3:26])[C:22](=[O:23])[N:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:27]([F:28])([F:29])[F:30])=[N:15][CH:14]=2)[C:17](=[O:18])[NH:19]1
Reactant: COC(=O)C(C)(C)NC(=O)Nc1ccc(Oc2ccc(C#N)cc2C(F)(F)F)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)NC(=O)N(c2ccc(Oc3ccc(C#N)cc3C(F)(F)F)nc2)C1=O
Yield: 18.1 %

Procedure:
A solution of methyl N-{[(6-{[4-cyano-2-(trifluoromethyl)phenyl]oxy}-3-pyridinyl)amino]carbonyl}-2-methylalaninate (Intermediate 165, 49 mg) in MeOH (10 mL) was heated at reflux for 10 min. Sodium methoxide (4 mg) was added to the hot reaction mixture and it was left refluxing for 2.5 hours. The solvent was evaporated to dryness and the residue obtained was purified by flash-chromatography (companion system, 12 g Si cartridge), with Cyclohexane/EtOAc as eluents from 70/30 to 50/50, to give two batches. The second batch was purified again by mass directed purification (METHOD K), leading to the desired compound which was gathered to the first batch, to afford the title compound as a white solid (8.2 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(F)c(F)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-difluoro-1,2-phenylendiamine (144 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (297 mg, 1.0 mmol) in xylene (6 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as an off-white solid (224 mg, 64%).
Reaction SMILES: C[N:2]([C@@H:19]1[CH2:34][C:33]2=[CH:35][CH:36]=[C:30]([CH:31]=[CH:32]2)[O:29][CH2:28][CH:27]=[CH:26][CH2:25][O:24][CH2:23][C@H:22]([CH:37]([CH3:39])[CH3:38])[NH:21][C:20]1=[O:40])C(=O)OC1C2C=CC=CC=2C2C1=CC=CC=2.C(NCC)C>ClCCl>[NH2:2][C@@H:19]1[CH2:34][C:33]2=[CH:32][CH:31]=[C:30]([CH:36]=[CH:35]2)[O:29][CH2:28][CH:27]=[CH:26][CH2:25][O:24][CH2:23][C@H:22]([CH:37]([CH3:38])[CH3:39])[NH:21][C:20]1=[O:40]
Reactant: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](N(C)C(=O)OC2c3ccccc3-c3ccccc32)C(=O)N1
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3.66 g (6.78 mmol) of 9H-fluoren-9-yl methyl((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-12-yl)carbamate (1-1D) in 300 ml of dichloromethane was mixed with 75 ml of diethylamine and stirred at RT for 5 h. The mixture was concentrated and purified by preparative HPLC. Acetonitrile was removed from the combined product fractions in a rotary evaporator, saturated NaHCO3 solution was added, and the mixture was extracted twice with ethyl acetate, saturated with sodium chloride and again extracted with ethyl acetate. The combined ethyl acetate phases were dried over Na2SO4, filtered and concentrated. The resulting substance was pure enough for further reactions.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)C>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:14])=[O:6]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reaction time: 144 h

Procedure:
3-Hydroxy-4-nitrobenzoic acid (I) (100.3 g, 95% pure, 0.53 mole) was added to methanol (1250 ml) to which had been added acetyl chloride (25 ml). The solid dissolved over a period of two days. After six days, the solution was filtered to remove undissolved impurities. The crude ester was obtained by evaporation of the solution. Several crops of crystals were taken, the last from a 50 ml volume. The combined crops were recrystalized from methanol (150 ml). Two crops of the ester (II) as yellow-brown crystals, m.p. 89°-91°, (98.7 g, 0.50 mole) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([NH:21]/[C:22](=[N:35]/[C@H:36]4[CH2:41][C@H:40]5[CH2:42][C@H:38]([C:39]5([CH3:44])[CH3:43])[C@@H:37]4[CH3:45])/[N:23]4[CH2:26][CH:25]([NH:27]C(=O)OC(C)(C)C)[CH2:24]4)=[CH:16][CH:17]=3)[N:12]=[CH:11]2)=[CH:4][CH:3]=1.N1CC(NC(=O)OC(C)(C)C)C1.Cl.O1CCOCC1>>[NH2:27][CH:25]1[CH2:24][N:23]([C:22](=[N:35][C@H:36]2[CH2:41][C@H:40]3[CH2:42][C@H:38]([C:39]3([CH3:44])[CH3:43])[C@@H:37]2[CH3:45])[NH:21][C:15]2[CH:14]=[C:13]3[C:18]([C:19](=[O:20])[N:10]([CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:26]1
Reactant: C[C@@H]1[C@@H](/N=C(/Nc2ccc3c(=O)n(CCc4ccc(F)cc4)cnc3c2)N2CC(NC(=O)OC(C)(C)C)C2)C[C@H]2C[C@@H]1C2(C)C
Agent: CC(C)(C)OC(=O)NC1CNC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1[C@@H](N=C(Nc2ccc3c(=O)n(CCc4ccc(F)cc4)cnc3c2)N2CC(N)C2)C[C@H]2C[C@@H]1C2(C)C
Reaction time: 8 h

Procedure:
1,1-dimethylethyl [1-((Z)-({3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}amino){[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1 ]hept-3-yl]imino}methyl)-3-azetidinyl]carbamate (synthesized using 1,1-dimethylethyl 3-azetidinylcarbamate by the methods described previously) was treated with 4.0 N HCl/dioxane (4 mL) and stirred overnight. The reaction was then purified by preparatory HPLC to provide 3-amino-N-{3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1 ]hept-3-yl]-1-azetidinecarboximidamide as a white solid. LC/MS: M+H 517.20 at 2.19 minutes, Method D.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C(O)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[C:18]1[S:12][C:13](=[S:14])[NH:15][C:16]1=[O:17]
Reactant: O=C1CSC(=S)N1
Reactant: COc1ccc(F)c(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(C=C2SC(=S)NC2=O)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 91.5 %

Procedure:
To a suspension of 2-fluoro-5-methoxybenzaldehyde (5.00 g, 32.46 mmol) and rhodanine (4.31 g, 32.46 mmol) in dry toluene (1000 mL) was added ammonium acetate (50 mg) and acetic acid (2 mL). The resulting suspension was allowed to stir at 120° C. for 12 h under Dean-Stark apparatus before being allowed to cool and filtered. Resultant solid was washed with hexane and allowed to dry in vacuo to give an orange crystalline solid (8.00 g, 91%); δH (300 MHz, CDCl3) 7.50 (1H, s, CH═C); 7.31 (1H, t, Ar), 7.20–7.11 (1H, m, Ar), 6.95–6.89 (1H, m, Ar), 3.80 (3H, s, OCH3).
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[C:18]1([C@@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: C[C@H](N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@@H](c1ccccc1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 74.4 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 121 mg of (S)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 2 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 240 mg of the desired product as colorless needles. Yield: 74%. m.p. 95-96° C.; [α]20D−=242.2° (C=0.386 AcOEt); MS(EI+) 323(M)+
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C(COC)OC>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: COCCOC
Product: CCCC[Sn](CCCC)(CCCC)C1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 15.85 g (0.0837 mole) of 1-benzyl-4-piperidone in 140 ml of anhydrous dimethoxyethane and g (0.0837 mole) of trisilidrazine in 140 ml of anhydrous dimethoxyethane is stirred at room temperature for 3 hours. The solvent is evaporated off under reduced pressure. The residue is taken up into 420 ml of anhydrous hexane and 420 ml of anhydrous tetramethylethylenediamine are added thereto. The mixture is cooled to −78° C. and 156 ml of n-butyllithium (0.25 mole)(1.6 M solution in hexane) are added dropwise thereto. After about 30 minutes the temperature is allowed to attain 0° C. and stirring is effected for 15 minutes. 45 ml (0.167 mole) of tributylstannyl chloride are then added to the reaction mixture. After 1 hour, a water/ice mixture is added with extreme caution. Extraction is carried out with ethyl ether, the organic phase is washed with water, drying is effected over sodium sulphate and the solvent is evaporated off under reduced pressure. 70 g of crude product are obtained which are purified by silica gel column chromatography in eluting with a cyclohexane/ethyl acetate mixture=95/5. The title compound is obtained as an oil.
Reaction SMILES: [CH2:1](I)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:10]1([CH2:13][O:14][C:15]2[C:16]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:36])[N:28]([CH3:37])[CH:27]=3)=[N:17][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:19][CH:20]=2)[CH2:12][CH2:11]1>CC#N>[CH:10]1([CH2:13][O:14][C:15]2[C:16]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:36])[N:28]([CH3:37])[CH:27]=3)=[N:17][C:18]([N:21]([CH2:1][CH3:2])[S:22]([CH3:25])(=[O:24])=[O:23])=[N:19][CH:20]=2)[CH2:12][CH2:11]1
Reactant: CCI
Reactant: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(c1ncc(OCC2CC2)c(-c2cn(C)c(=O)c3ccccc23)n1)S(C)(=O)=O
Yield: 15.7 %

Procedure:
Ethyl iodide (95 mg, 0.6 mmol) and K2CO3 (55 mg, 0.4 mmol) were added to a solution of the title compound of Example 152 (80 mg, 0.2 mmol) in MeCN (5 mL). After refluxing 1 h, the mixture was cooled, concentrated under vacuum and subjected to CH2Cl2 extractive work up. HPLC purification gave the title compound (13.42 mg, yield: 15.2%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 4.02 (q, J=6.8 Hz, 2H), 3.97 (d, J=7.2 Hz, 1H), 3.60 (s, 3H), 3.43 (s, 3H), 1.25 (t, J=6.8 Hz, 1H), 1.10-1.07 (m, 1H), 0.46-0.42 (m, 2H), 0.24-0.20 (m, 2H). LCMS: 429.1 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[CH2:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].C1(C)C=CC=CC=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[O:18]=[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(CCl)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (4 g, 19.87 mmol), tetrabutylammonium hydrogensulfate (0.337 g, 0.99 mmol) and 2-chloro-1-pyrrolidin-1-yl-ethanone (3.87 g, 25.84 mmol) were added to toluene (50 mL) to this was added NaOH (19.87 g, 198.75 mmol) in water (20 ml) and the reaction was stirred at 25° C. overnight. The reaction mixture was quenched with water (100 mL), extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as an orange liquid (7.20 g, >100% yield); 1H NMR (400.13 MHz, DMSO-d6) δ 1.40 (9H, s), 1.86 (8H, m), 3.02 (4H, s), 3.38 (2H, t), 3.54 (1H, m), 3.60 (2H, m), 4.07 (2H, s).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:12]=[C:13]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:14]=1
Reactant: CC(=O)NCCN
Reactant: Clc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)NCCNc1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Temperature: 85 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
N-Acetylethylenediamine (1.02 g) was dissolved in ethanol (250 ml) and 4,6-dichloro-2-(4-chlorophenyl)pyrimidine (2.5 g) then triethylamine (1.35 ml) added. The mixture was heated to 85° C. with stirring for 48 hrs. The solvent was then removed in vacuo and purified by column chromatography on silica gel eluting first with ethyl acetate then a mixture of ethyl acetate and methanol (9:1 v/v) to furnish the title compound (1.29 g).
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[C:7]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:8]2[CH:9]=[CH:10][N:11]([CH:14]([CH3:16])[CH3:15])[C:12]=2[CH:13]=1>[Pd].O1CCCC1>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:17]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]([CH:14]([CH3:16])[CH3:15])[C:12]=2[CH:13]=[CH:5][CH:6]=1)=[O:18]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2ccn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C)c(CNC(=O)c2cccc3c2ccn3C(C)C)c(=O)[nH]1
Yield: 60.2 %

Procedure:
To a flask under N2 atmosphere was added 10% palladium on carbon (0.028 g, 0.026 mmol) and ethanol (1 mL) (to wet catalyst). The flask was then charged with 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (0.11 g, 0.264 mmol), ethanol (4 mL) and tetrahydrofuran (1 mL). The suspension was stirred under N2, then evacuated and refilled with H2 (balloon) and stirred overnight. The reaction was then placed back under N2 and diluted with 10% methanol/dichloromethane. Celite was added and the mixture was stirred for 15 min, filtered through a pad of Celite, washed with 10% methanol/dichloromethane, and concentrated. The residue was dissolved in dimethylsulfoxide and acetonitrile (with 0.1% trifluoroacetic acid and purified by Gilson prep HPLC (Sunfire 30×75 mm; Gradient B: 15-75%; A: water+0.1% TFA; B: acetonitrile+0.1% TFA). The resulting residue was dissolved in 10% methanol/dichloromethane and treated with Silicycle carbonate resin (1.5 g). The mixture was stirred for 30 min, filtered through Celite, washed with 10% methanol/dichloromethane, and concentrated. The residue was dissolved in dichloromethane and treated with methyl-t-butylether. The solvents were removed by via N2 stream and the solids dried in a vacuum oven at 45° C. for 18 h to give N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (56 mg, 0.159 mmol, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.48 (m, 6H) 2.09-2.15 (m, 3H) 2.24 (s, 3H) 4.35 (d, J=5.31 Hz, 2H) 4.79 (quin, J=6.63 Hz, 1H) 5.88 (s, 1H) 6.84 (d, J=3.03 Hz, 1H) 7.11-7.18 (m, 1H) 7.39 (d, J=6.57 Hz, 1H) 7.58 (d, J=3.28 Hz, 1H) 7.65 (d, J=8.34 Hz, 1H) 8.08 (t, J=5.31 Hz, 1H) 11.54 (br. s., 1H). MS(ES) [M+H]+ 338.6.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:16]1(Br)[CH2:19][CH2:18][CH2:17]1.[OH-].[Na+]>CN(C)C=O>[CH:16]1([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: BrC1CCC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CCC2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a suspension of 4-hydroxybenzaldehyde (0.12 g) and cesium carbonate (0.49 g) in N,N-dimethylformamide (2 mL) was added cyclobutyl bromide (0.15 g), and the mixture was stirred at 65° C. overnight. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution, and the mixture was extracted with diethyl ether. The organic layer was washed with 0.5 mol/L aqueous sodium hydroxide solution, water and brine, and dried over an hydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-cyclobutyloxybenzaldehyde (0.13 g). To a solution of the obtained 4-cyclobutyloxybenzaldehyde (0.13 g) in methanol (10 mL) was added sodium borohydride (0.056 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-cyclobutyloxybenzyl alcohol (0.12 g).
Reaction SMILES: [C:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[CH2:2]1.[C:8]([O-])([O-])([O:12][CH2:13]C)[CH2:9][CH2:10]C>C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH3:13][O:12][C:8](=[C:2]1[C:3](=[O:6])[CH:4]=[CH:5][C:1]1=[O:7])[CH2:9][CH3:10]
Reactant: O=C1C=CC(=O)C1
Reactant: CCCC([O-])([O-])OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: CCC(OC)=C1C(=O)C=CC1=O

Procedure:
To a suspension of cyclopent-4-ene-1,3-dione (1.22 g, 12.6 mmol) in acetic anhydride (4 ml) were added ethyl orthobutyrate (3.74 g, 25.3 mmol) and anhydrous ZnCl2. The reaction was heated at 80° for 24 h, solid removed by filtration, the filtrate concentrated in vacuo and the residues purified by chromatography (SiO2; 70:30 hexane/EtOAc) to give 2-(α-methoxypropyl idene)cyclopent4-ene-1,3-dione as a brown oil. δH (CDCl3) 6.88 (2H, s), 4.07 (3H, s), 3.00 (2H, t), 1.63 (2H, m), 1.08 (3H, t). m/z (ESI, 70V) 181 (MH+).
Reaction SMILES: [CH:1]1([S:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CC(C)=O>[CH:1]1([S:7][CH2:8][S:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(SCSC2CCCCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Oc1ccc(SCSC2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
In 300 g of acetone was dissolved 26 g of the cyclohexylthio(4-hydroxyphenylthio)methane crude product in Synthesis Example 10. To this were added 21 g (0.15 mol) of potassium carbonate and 13 g (0.11 mol) of methanesulfonylchloride. While heating in an oil bath at 70° C., the solution was ripened for 4 hours. At the end of ripening, the inorganic salt was filtered and washed with 50 g of acetone. The filtrate and wash liquid combined was concentrated, and the residue was dissolved in 300 g of dichloromethane and washed with 50 g of water. The organic layer was concentrated in vacuum again, obtaining 30 g of an oily product, which was used in the subsequent reaction without further purification.