Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15]1.CN(C)[CH:25]=[O:26]>CCCCCC.O>[CH:25]([C:19]1[C:18]2[O:14][CH2:15][CH2:16][C:17]=2[CH:22]=[CH:21][CH:20]=1)=[O:26]
Reactant: c1ccc2c(c1)CCO2
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: O=Cc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
108 ml of an n-butyllithium solution (2.1M) in hexane and 26.7 g (230 mmol) of tetramethylethylenediamine (TMEDA) are introduced into a 1 liter round-bottomed flask. The mixture is stirred at room temperature for 15 minutes and 23 g (190 mmol) of 2,3-dihydrobenzofuran are added. The mixture is stirred for 4 hours at 35° C., cooled to -78° C. and 13.9 g (190 mmol) of dimethylformamide are added. The temperature is allowed to return to 20° C., 500 ml of water are added and extraction is carried out with ethyl acetate (3×200 ml). The organic phases are combined, dried and concentrated under vacuum. The residue is purified by silica flash chromatography (elution: 5% ethyl acetate in petroleum ether). 9.85 g (Yield: 35%) of 7-formyl-2,3-dihydrobenzofuran are obtained--M.p.: 55° C.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH3:2].[C:12]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:39])=[C:25]([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[NH2:37])[CH:26]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:39])=[C:25]([N:27]2[C:28](=[O:38])[C:29]3[C:30](=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[N:37]=[C:1]2[CH3:2])[CH:26]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c(N)c1
Product: COc1ccc2c(=O)n(-c3cc(NC(=O)c4ccccc4)ccc3Cl)c(C)nc2c1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 1, triethyl orthoacetate was reacted with N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide. The material so obtained was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound in 27% yield; NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 3.91 (s, 3H), 7.09–7.14 (m, 2H), 7.46–7.6 (m, 3H), 7.71 (d, 1H), 7.87–8.06 (m, 5H), 10.57 (s, 1H); Mass Spectrum: M+H+420 and 422.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH2:7]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH2:7]1)(=[S:30])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Solvent: C1COCCO1
Product: CNc1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(S)-acetamidomethyl-3-[4′-methylamino-3′-fluoro-phenyl]oxazolidine-2-one (0.100 g, 0.356 mmol) and Lawesson reagent (0.144 g, 0.356 mmol) in dioxane (3 mL) was stirred at 65° C. for 2 h. Solvent was removed under vacuum and the residue purified by PTLC (10% methanol/dichloromethane) to give a product as foam. Yield 0.097 g (92%). MS (m/z): [M+H]+=298.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]1[C@@H:9]([CH3:12])[CH2:10][OH:11].CO[C:15](OC)([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>ClCCl>[CH3:16][C:15]1([CH3:17])[O:11][CH2:10][C@H:9]([CH3:12])[C@H:4]2[C@@H:3]([C@@H:7]([CH3:8])[CH2:6][CH2:5]2)[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: C[C@@H](CO)[C@H]1CC[C@H](C)[C@H]1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H]1COC(C)(C)OC[C@H]2[C@H]1CC[C@@H]2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.9 %

Procedure:
(2R)-2-[(1R, 2R, 3S)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]propan-1-ol (100 mg, 0.00058 mol) (obtained in Definite Example 45) was dissolved in 5 ml of dichloromethane, and 2 ml of 2,2-dimethoxypropan and 5 mg of p-toluenesulfonic acid were added. After being stirred at room temperature for 12 hours, the reaction mixture was poured into 50 ml of ethyl acetate. After the organic layer was washed with an aqueous mixed solution of aqueous sodium bicarbonate (10 ml) and saturated sodium chloride solution (20 ml), it was dried by magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual substance was purified by a chromatography using silica gel. When the solvent of the fraction obtained from hexane:ether=8:2 eluent was distilled off, a colorless oily substance, i.e., (1R, 7R, 8S, 11S)-4,4,7,11-tetramethyl-3,5-dioxabicyclo[6.3.0]undecane (10 mg, yield=7.9%). This (1R, 7R, 8S, 11S)-4,4,7,11-tetramethyl-3,5dioxabicyclo[6.3.0]undecane had the following physicochemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2Cl.[CH3:19][N:20]([CH3:28])[C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([N:20]([CH3:28])[CH3:19])[CH2:22][CH2:23]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2cc(F)c(Br)cc2c1Cl)C1CC1
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(Br)cc23)CC1

Procedure:
Following general procedure C, (6-bromo-4-chloro-7-fluoroquinolin-3-yl)(cyclopropyl)methanone (297 mg, 0.900 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine (290 mg, 1.35 mmol) to afford the desired product (212 mg, 54%) as an off-white solid: ESI MS m/z 435 [C21H25BrFN3O+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[CH:16][C:11]([CH:12]=CCN)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.NC1C=CC(C=[O:24])=CC=1.C(CC(=O)C)C(C)=O>>[CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[CH:16][C:11]([CH:12]=[O:24])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Nc1ccc(C=O)cc1
Reactant: Cc1ccc(C)n1-c1ccc(C=CCN)cc1
Agent: CC(=O)CCC(C)=O
Product: Cc1ccc(C)n1-c1ccc(C=O)cc1

Procedure:
Similarly prepared is N-acetyl-N-acetyloxy-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-cinnamylamine. The starting material is prepared by first condensing p-amino-benzaldehyde with acetonylacetone to obtain 4-(2,5-di-methyl-1H-pyrrol-1-yl)-benzaldehyde which is in turn condensed with diethyl phosphonoacetaldehyde diethylacetal to obtain 4-(2,5-dimethyl-1H-pyrrol-1-yl)-cinnamaldehyde. The aldehyde is then converted to the oxime and reduced to the hydroxylamine according to previously described procedures.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][CH:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 3-hydroxy-6-methylpyridine (5.00 g, 45.8 mmol) was added sodium hydride (2.02 g, 50.4 mmol, 60% in oil), which was stirred for 15 minutes at 0° C. Next, benzyl bromide (5.99 mL, 50.4 mmol) was added to this reaction mixture at 0° C., which was stirred for 3.5 hours at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the tile compound (5.99 g, 66%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)/C=C\C(O)=O.[Cl:33][C:34]1[CH:53]=[CH:52][C:37]2[O:38][C:39]3[CH:51]=[CH:50][CH:49]=[CH:48][C:40]=3[C@@H:41]3[C@H:46]([NH2:47])[CH2:45][CH2:44][CH2:43][N:42]3[C:36]=2[CH:35]=1>C(Cl)Cl>[Cl:33][C:34]1[CH:53]=[CH:52][C:37]2[O:38][C:39]3[CH:51]=[CH:50][CH:49]=[CH:48][C:40]=3[C@@H:41]3[C@H:46]([NH:47][C:20](=[O:21])[C:19]4[CH:23]=[CH:24][C:16]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:17][CH:18]=4)[CH2:45][CH2:44][CH2:43][N:42]3[C:36]=2[CH:35]=1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
DIPEA (18.6 μL, 0.14 mmol) and 4-phenylbenzoyl chloride (15.2 mg, 0.07 mmol) were added to a solution of trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine maleate (9.6 mg, 0.02 mmol) in 1 mL of CH2Cl2. The resulting mixture was stirred for 18 h at room temperature. The organic layer was washed with 5% aqueous sodium bicarbonate and H2O, dried (Na2SO4) and evaporated. Additional chromatography on silica (elution with toluene/ethyl acetate 9:1→toluene/ethyl acetate 1:1) gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-4-phenylbenzamide (4.6 mg, 44%). Data: (m/z)=350 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]=1.C(N(C(C)C)CC)(C)C>C(O)C>[CH2:21]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=2)[C:16]([C:17]#[N:18])=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[C:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:25]=2)=[CH:7][CH:6]=1)[CH3:22]
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(-c2ccc(Nc3nc(-c4ccccc4)nc4ccccc34)cc2)c(C#N)c2ccc(OC)cc21
Yield: 82.4 %

Procedure:
A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.343 mmol), 4-chloro-2-phenyl-quinazoline (83 mg, 0.34 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in absolute ethanol (3 mL) is heated to reflux overnight. The solution is cooled and evaporated, and the residue taken up in ethyl acetate (50 mL). This is washed with water and saturated brine (50 mL each), then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting solid is triturated with ether, collected by filtration and dried under vacuum to afford 1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile (139 mg, 0.280 mmol, 82%).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH2:23][CH2:24][CH3:25]>C(C1C=CC=CC=1)(=O)C.CCOCC>[CH2:22]([O:8][C:7]1[C:4]([O:5][CH3:6])=[CH:3][C:2]([C:1]([OH:14])=[O:13])=[CH:12][C:9]=1[O:10][CH3:11])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCBr
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)c1ccccc1
Solvent: CCOCC
Product: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Temperature: 135 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
Methyl syringate (10 g, 0.047 mol) and potassium carbonate (8.5 g, 0.061 mol) were stirred in acetophenone (100 mL) at 135° C. Butyl bromide (6.6 mL, 0.061 mol) was added dropwise over 1.5 h and the reaction was stirred over 18 h at 135° C. The reaction was cooled, filtered and the inorganic solids washed with acetone (20 mL). The combined filtrate was concentrated under high vacuum to give a red oil which was redissolved in ether (50 mL) and washed with 2N aqueous NaOH (2×10 mL) and water (3×10 mL). The organic layer was dried using anhydrous NaSO4 and the solvent removed under reduced pressure. The crude product was redissolved in methanol (250 mL) followed by addition of aqueous potassium hydroxide (44%, 20 mL). After heating at reflux for 2 h the reaction mixture was allowed to cool down to room temperature and left to rest over 18 h. The solvent was then concentrated under reduced pressure, the residue reconstituted in water (100 mL) and the resulting aqueous solution washed with ether (3×30 mL). The aqueous layer was acidified to pH=1 with 5N HCl and the precipitated product collected by filtration. The crude product was recrystallised from methanol to give 6.1 g, 51% yield of 4-butyloxy-3,5-dimethoxybenzoic acid as a colourless solid. 1H NMR (CDCl3) δ: 0.98 (t, J=5.1 Hz, 3H), 1.49 (m, 2H), 1.74 (m, 2H), 3.91 (s, 6H), 4.06 (t, J=5 Hz, 2H), 7.37 (s, 2H). MS m/z 255.4 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.O.[SH-:19].[Na+]>C(O)C>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[N:7]=[C:2]([SH:19])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: [SH-]
Reactant: Fc1ccccc1-c1nnc2ccc(Cl)nn12
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccccc1-c1nnc2ccc(S)nn12

Procedure:
A solution of 6-chloro-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 mmol) and sodium hydrosulfide hydrate (1.5 equiv.) in ethanol was refluxed for 2-6 hours. The solvent was removed under reduced pressure, water (2 ml) was added, and the pH adjusted to 9 with sodium hydroxide solution. After removing the resulting precipitate, the filtrate was acidified with 6M HCl to a pH of 3, and the formed precipitate was collected, washed with cold water, and dried to give 3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-thiol. This compound is taken on to the next step without purification
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH:6]1[C:19]2[C:10](=[S+:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[C-:20]#[N:21].[K+]>O.C(Cl)Cl>[C:20]([CH:18]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:19]1=[CH:6][CH:7]=[CH:8][CH:9]=2)#[N:21]
Reactant: c1ccc2[s+]c3ccccc3cc2c1
Reactant: [C-]#N
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: N#CC1c2ccccc2Sc2ccccc21
Reaction time: 1 h
Yield: 91.2 %

Procedure:
8.0 g (27.0 mmol) of thioxanthylium perchlorate [C. C. Price et al, J. Amer. Chem. Soc. 85, 2278 (1963)] are added-toi well-stirred mixture of 3.5 g (53.8 mmol) of potassium cyanide in 4 ml of water and 30 ml of methylene chloride under a nitrogen atmosphere. After one hour, the mixture is dried over potassium carbonate and filtered and the filtrate is concentrated on a vacuum rotary evaporator. Crystallization of the residue from isopropanol gives 5.5 g (91%) of 9-cyano-thioxanthene, melting point 103°-105° C., colourless needles (compound (103), Table 1).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:15]1[CH:19]=[C:18]([CH2:20][C:21]([NH2:23])=[S:22])[N:17]=[CH:16]1>>[NH:15]1[CH:19]=[C:18]([CH2:20][C:21]2[S:22][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][C:6]([O:11][CH3:12])=[CH:5][C:4]=4[C:3]=3[N:23]=2)[N:17]=[CH:16]1
Reactant: COc1ccc2c(c1)C(=O)C(Br)C2
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Product: COc1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1C2

Procedure:
Starting compounds: 2-bromo-6-methoxy-1-indanone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: [C:1]([C:3]1[C:4]2[CH2:24][CH2:23][CH2:22][C:5]=2[S:6][C:7]=1[NH:8][C:9](=[O:21])[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:11]([CH3:14])[CH2:12][CH3:13])#[N:2].N[C:26]1SC2CCCC=2C=1C#N>>[C:1]([C:3]1[C:4]2[CH2:24][CH2:23][CH2:22][C:5]=2[S:6][C:7]=1[NH:8][C:9](=[O:21])[CH:10]([CH:11]1[CH2:14][CH2:26][CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: N#Cc1c(N)sc2c1CCC2
Reactant: CCC(C)C(C(=O)Nc1sc2c(c1C#N)CCC2)c1ccccc1
Product: N#Cc1c(NC(=O)C(c2ccccc2)C2CCCC2)sc2c1CCC2
Reaction time: 20 h

Procedure:
Reaction of α-phenylcyclopentaneacetyl chloride (Prepared in Example 12, Step1) and 2-Amino-3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophene (164 mg; 1.0 mmol) according to the procedure outlined in Example 5 for 20 h at room temperature provided after workup, crude product which triturated with diethylether to give 111 mg of which was further purified by recrystallization from ethylacetate/hexanes to provide 44 mg (%) of N-(3-Cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-2-cyclopentyl-2-phenyl-acetamide as a light brown solid. EI-HRMS m/e calcd for C21H32N2OS (M+) 350.1453, found 350.1456.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].CS(O[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:13]([O:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O=C1OCCC1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC1CCOC1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of α-hydroxybutyrolactone (2.0 g, 19.6 mmol) and linoleyl methane sulfonate (5.4 g, 15.7 mmol) in anhydrous DMF (60 mL), was added cesium carbonate (8.0 g, 24.5 mmol). The solution was stirred overnight under nitrogen at 80° C. Upon completion, the reaction was poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (3×50 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel 60 (eluted with 10% ethyl acetate in hexanes) to afford 3-((9Z,12Z)-octadeca-9,12-dienyloxy)dihydrofuran-2(3H)-one as a pale yellow oil (3.5 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cccc(F)c1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cccc(F)c2)cc1

Procedure:
63 mg of pale yellow solid 3-{4-[3-(3-fluorophenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3-fluorophenyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([O:34]C)=[O:33])=[N:30][CH:31]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)nc4)C3)nc3scnc23)cc1OC
Temperature: 35 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of methyl 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)picolinate (80 mg, 0.15 mmol) in dioxane/H2O (60 mL/6 mL) was added NaOH (60 mg, 1.5 mol), the reaction mixture was heated to 35° C. with stirring for 1 hour, then dioxane was removed in vacuo, and the aqueous layer was adjusted to pH˜4-5 with conc. HCl, the precipitate was collected by filtration and washed with water (5 mL) and dried to afford 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)picolinic acid as brown solid (67 mg, 84.8%). 1H NMR (300 MHz, DMSO): δ 9.56 (s, 1H), 9.06 (s, 1H), 8.96 (d, 1H, J=6.3 Hz), 8.79 (s, 1H), 8.33 (dd, 1H, J1=8.1 Hz, J2=1.8 Hz), 8.07 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 7.50 (brs, 1H), 6.90 (d, 1H, J=8.7 Hz), 4.60-4.58 (brs, 1H), 3.76-3.52 (m, 10H), 2.30-2.24 (m, 1H), 2.11-2.07 (m, 1H). LC-MS: 522 [M+H]+, tR=1.31 min. HPLC: 98.03% at 214 nm, 97.82% at 254 nm, tR=3.20 min.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]>O.CO>[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:15])=[O:16]
Reactant: COC(=O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Reaction time: 4 h
Yield: 87.7 %

Procedure:
A solution of lithium hydroxide (1.56 g, 37.3 mmol) in water (5 mL) was added to a stirred solution of 4-fluoro-3-(morpholine-4-sulfonyl)-benzoic acid, methyl ester (Example 5, 2.26 g, 7.45 mmol) in methanol (50 mL) / water (10 mL) at 0° C. After 4 hours, the clear solution was quenched with aqueous hydrochloric acid (2M, 10 mL). Concentration in vacuo to remove the methanol afforded a white precipitate. Filtration and drying afforded the title compound as a white powder (1.89 g, 88% yield): 1HNMR (CDCl3) δ3.21 (td, J=7, 1.5 Hz, 4H), 3.75 (td, , J=7, 1.5 Hz , 4H), 3.98 (s, 3H), 7.28 (dd, J=18, 15 Hz, 1H), 8.28 (ddd, J=7, 5, 2 Hz, 1H), 8.51 (dd, J=7, 2 Hz, 1H): MS (ESI) [M−H]− at m/z 303.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH3:5].[C:7]([O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])(=[O:13])/[CH:14]=[CH:1]/[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC=O
Solvent: C1CCOC1
Product: CCCC/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a solution of valeraldehyde (5.81 g) in THF (100 mL) was added tert-butoxycarbonylmethylenetriphenylphosphorane (25.4 g) and the reaction mixture stirred for 16 h at rt. The solvents were evaporated, the residue slurried in diethyl ether and filtered. The filtrate was evaporated and the residue purified by chromatography eluting with 3% EtOAc in isohexane to give the subtitle compound 8.5 g.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][O:19][C:20]([C:22]1[C:30]2[O:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH:25]=[C:24]([OH:32])[CH:23]=1)=[O:21]>CN(C=O)C>[CH3:18][O:19][C:20]([C:22]1[C:30]2[O:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH:25]=[C:24]([O:32][C:14]2[CH:15]=[CH:16][C:11]([S:8]([CH3:7])(=[O:10])=[O:9])=[CH:12][CH:13]=2)[CH:23]=1)=[O:21]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc2cc(C)oc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C)oc12
Temperature: 120 °C
Yield: 92 %

Procedure:
Cs2CO3 (2.36 g, 7.24 mmol) and 4-fluorophenyl methyl sulfone (631 mg, 3.62 mmol) were added to a solution of 5-hydroxy-2-methyl-benzofuran-7-carboxylic acid methyl ester (4d) (746 mg, 3.62 mmol) in DMF (5 mL). The mixture was heated to 120° C. overnight and then cooled to RT. The mixture was then quenched with H2O (80 mL) and extracted with EtOAc 92×100 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 4% CH3OH/CH2Cl2 to afford brown color oil (1.2 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 2 H) 7.86-7.90 (m, 1 H) 7.58 (d, J=2.53 Hz, 1 H) 7.38 (d, J=2.53 Hz, 1 H) 7.05 (d, J=8.84 Hz, 1 H) 6.44 (s, 1H) 3.99 (s, 3 H) 3.05 (s, 3 H) 2.56 (s, 3 H); LCMS for C18H16O6S m/z 361.00 (M+H)+.