Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[N:22]1([C:15]2[CH:14]=[CH:13][C:12]([NH:11][S:8]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:10])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc(N2CCOCC2)c2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(N2CCOCC2)c2cccnc12)c1ccccc1
Yield: 6.9 %

Procedure:
In a similar fashion using route 20 general procedure 36, 2-amino-N-(5-morpholin-4-yl-quinolin-8-yl)-benzenesulfonamide 583 (150 mg, 0.39 mmol), tert-butyl nitrite (79.53 μl, 0.66 mmol), AcOH (1.5 ml) and THF (3 ml) gave the title compound (10 mg, 7%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH2:12][CH2:13][N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:10]#[N:11].[CH:21]([N:24]([CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:26]C(C1C=CC=CC=1)C#N)([CH3:23])[CH3:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([CH2:26][CH2:25][N:24]([CH:36]([CH3:38])[CH3:37])[CH:21]([CH3:23])[CH3:22])([CH2:12][CH2:13][N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[C:10]#[N:11]
Reactant: CC(C)N(CCC(C#N)c1c(Cl)cccc1Cl)C(C)C
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Product: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1c(Cl)cccc1Cl)C(C)C

Procedure:
Substitution of an equivalent quantity of the preceding acetonitrile for α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile called for in Example 2, Method B and substantial repetition of the procedure detailed in that example, affords α-(2,6-dichlorophenyl)-α,α-bis[2-(diisopropylamino)ethyl]acetonitrile, as an oil boiling at about 180°-185° C. at 0.3 mm. pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[CH:10]=2)[CH:7]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:11]1([C:9]2[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([C:22]#[C:21][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:7][N:6]3[N:8]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: Brc1cnc2cc(C3CCC3)nn2c1
Reactant: C#Cc1ccccc1
Product: C(#Cc1cnc2cc(C3CCC3)nn2c1)c1ccccc1

Procedure:
The title compound, light brown solid, MS: m/e=274.3 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-cyclobutyl-pyrazolo[1,5-a]pyrimidine (example 18, step 1) and phenylacetylene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][N:26]4[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 89.1 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (55 mg, 0.20 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (49 mg, 0.20 mmol) and DIPEA (105 μL, 0.60 mmol) in IPA (0.5 mL) was heated for 24 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-5% MeOH in DCM) to afford the title compound as a pale brown oil (84 mg, 89%). LCMS (Method J): RT=3.30 min, [M+H]+=471.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].C1COCC1.[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[C:47](F)[CH:48]=1)[C:44]#[N:45]>CS(C)=O.O>[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([CH3:10])[C:6]=2[F:9])[CH:48]=1)[C:44]#[N:45]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Temperature: 125 °C
Yield: 62.8 %

Procedure:
6-chloro-2-fluoro-3-methylphenol (8.03 g, 50.0 mmol) and 18-crown-6 (7.7 g, 29.1 mmol) were dissolved in dry DMSO (100 mL) and treated with 20% potassium t-butoxide in THF (28.1 g, 50.0 mmol) for 15 minutes at room temperature. 3-bromo-5-fluorobenzonitrile (10 g, 50.0 mmol) was added in one portion and the reaction mixture heated at 125° C. for 20 h at which time LC-MS indicated >90% conversion. The reaction mixture was cooled to ambient temperature and water was added to afford the crude product as a black precipitate which was filtered off, washed with water and air dried. The crude product was dissolved in DCM, dried over MgSO4, and filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized by addition of IPA (100 mL). The precipitate was cooled in an ice bath and filtered to afford 3-bromo-5-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (10.7 g, 31.4 mmol, 62.8% yield) as a tan solid in >90% purity as determined by LCMS. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.28-7.45 (m, 2H), 2.28 (s, 3H).
Reaction SMILES: CC(C)=C1C(C2C=CC(OCC(O)CO)=CC=2)C=CC=C1.C[C@@:23]1(O)[C:38]2C=CC=C(O)[C:37]=2[C:36](O)=[C:35]2[CH:24]1C[CH:26]1[C@:32](O)([C:33]2=O)[C:31](O)=[C:30](C(N)=O)[C:28](=O)[CH:27]1[N:50](C)C.Cl.CC1C=C(C2(C3C=CC(N)=C(C)C=3)C3C=CC=CC=3C3C2=CC=CC=3)C=CC=1N.OS(C(F)(F)F)(=O)=O.C(C1NC=C(C)N=1)C>>[C:27]1([NH2:50])[C:26]2[CH2:36][C:35]3[C:33](=[CH:37][CH:38]=[CH:23][CH:24]=3)[C:32]=2[CH:31]=[CH:30][CH:28]=1
Reactant: CN(C)C1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)cccc4[C@@](C)(O)C3CC12
Agent: CC(C)=C1C=CC=CC1c1ccc(OCC(O)CO)cc1
Agent: CCc1nc(C)c[nH]1
Agent: Cc1cc(C2(c3ccc(N)c(C)c3)c3ccccc3-c3ccccc32)ccc1N
Product: Nc1cccc2c1Cc1ccccc1-2

Procedure:
An adhesive of the present invention was made by mixing together 25 parts of PKHS, a phenoxy resin from the Union Carbide Corporation, 52 parts of Quatrex 1010, a diglycidyl ether of bisphenol A epoxy resin from the Dow Chemical Company, and 23 parts of 9,9-bis(3-methyl-4-aminophenyl)fluorene (hereinafter BAFOT). These three constituents were stirred to a uniform paste, using methyl ether ketone (MEK) as a solvent for the solution of the phenoxy and epoxy resins, followed by blending in the relatively insoluble BAFOT, and dilution of the resultant paste to 50% solids by weight with additional MEK. The fluorene-amine curative was prepared for dispersion in this epoxy resin system by jet milling to a mean particle size of <5 um. To this dispersion an accelerator, the triflic acid half salt of 2-ethyl-4-methylimidazole was added at a rate of 4 parts per hundred of the solids in the dispersion.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[S:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[S:26].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12](/[CH:13]=[C:30]3/[C:28](=[O:29])[NH:27][C:25](=[S:26])[S:24]/3)[CH:15]=[CH:16][CH:17]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CCCc1c(OCc2cccc(C=O)c2)ccc(C(C)=O)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1c(OCc2cccc(/C=C3\SC(=S)NC3=O)c2)ccc(C(C)=O)c1O

Procedure:
Under a nitrogen atmosphere in a three-neck round bottom flask 3-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzaldehyde (0.73 g, 2.34 mmol), rhodanine (0.34 g, 2.55 mmol), sodium acetate (0.23 g, 2.80 mmol) and acetic acid (20 ml) were combined and then heated to reflux. The reaction mixture was allowed to reflux. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([OH:3])=[O:2].[CH3:17][O:18][C:19](=[O:34])[CH:20]([NH:29][C:30](=[O:33])[CH2:31]O)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:17][O:18][C:19](=[O:34])[CH:20]([NH:29][C:30](=[O:33])[CH2:31][O:2][C:1](=[O:3])[CH2:4][O:5][C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: O=C(O)COC(=O)CCc1ccc(O)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)COC(=O)COC(=O)CCc1ccc(O)cc1

Procedure:
A solution of 3-(4-hydroxy-phenyl)-propionic acid carboxymethyl ester 5 (10 grams, 44.64 mmol) and 2-(2-hydroxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester 3 (11.3 grams, 44.66 mmol) in anhydrous dichloro methane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide (23 grams, 111.47 mmol) in dichloro methane (60 mL). The resulting solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 8, which can be purified in an appropriate solvent.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([N:7]=[C:8]=[S:9])[CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:3]3[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=3)=[S:9])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: S=C=Nc1cccnc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=S)Nc1cccnc1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of pyridine-3-isothiocyanate (0.136 g, 1.0 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol and then concentrated under vacuum to provide an off-white solid. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.2 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(3-pyridyl)thiourea as a white solid, m.p. 118-120° C. Mass spec M+1=468.3. Analysis: Calculated for C26H25N7S: % C, 66.79; % H, 5.39; % N, 20.97. Found: % C, 64.29; % H, 5.46; % N, 20.06.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(C3C=C4C(C(C5CCN(C)CC5)=NN4C)=CC=3)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[C:44]([O:48][C@@H:49]([C:55]1[C:80]([CH3:81])=[CH:79][C:58]2[N:59]=[C:60]([C:62]3[CH:63]=[C:64]4[C:68](=[CH:69][CH:70]=3)[N:67]([CH3:71])[N:66]=[C:65]4[C:72]3[CH2:73][CH2:74][N:75]([CH3:78])[CH2:76][CH:77]=3)[S:61][C:57]=2[C:56]=1[C:82]1[CH:87]=[CH:86][C:85]([Cl:88])=[CH:84][CH:83]=1)[C:50]([O:52]CC)=[O:51])([CH3:47])([CH3:46])[CH3:45]>>[C:44]([O:48][C@@H:49]([C:55]1[C:80]([CH3:81])=[CH:79][C:58]2[N:59]=[C:60]([C:62]3[CH:63]=[C:64]4[C:68](=[CH:69][CH:70]=3)[N:67]([CH3:71])[N:66]=[C:65]4[CH:72]3[CH2:77][CH2:76][N:75]([CH3:78])[CH2:74][CH2:73]3)[S:61][C:57]=2[C:56]=1[C:82]1[CH:83]=[CH:84][C:85]([Cl:88])=[CH:86][CH:87]=1)[C:50]([OH:52])=[O:51])([CH3:47])([CH3:45])[CH3:46]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(C3=CCN(C)CC3)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(-c3ccc4c(C5CCN(C)CC5)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3ccc4c(c3)c(C3CCN(C)CC3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(1-methylpiperidin-4-yl)-1H-indazol-6-yl)benzo[d]thiazol-6-yl)acetic acid except using (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetate instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-6-yl)benzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C34H37ClN4O3S: 617.2, 619.2 (M+H+); Found: 617.3, 619.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.47 (s, 1H), 8.13 (dd, J=8.9, 1.5 Hz, 1H), 7.83 (s, 1H), 7.74-7.54 (m, 5H), 5.26 (s, 1H), 4.10 (s, 0.3H, minor diastereomer), 4.06 (s, 2.7H, major diastereomer), 3.76-3.60 (m, 2H), 3.58-3.39 (m, 2H), 3.30-3.19 (m, 2H), 2.97 (s, 2.7H, major diastereomer), 2.94 (s, 0.3H, minor diastereomer), 2.63 (s, 3H), 2.49-2.29 (m, 2H), 2.29-2.09 (m, 1H), 0.99 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:9][C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccncc1C#N
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccncc1C#N

Procedure:
A solution of 3-cyano-4-methylpyridine (25 g, 0.21 mol), and N,N-dimethylformamide dimethyl acetal (29.2 mL, 0.22 mol) in dry DMF was heated at reflux overnight. Most of the DMF was removed under reduced pressure. The crude red oil was partitioned between EtOAc (300 mL) and H2O (300 mL) and the organic phase was washed with H2O, brine and dried (Na2SO4). Removal of the solvent afforded the product (34.3 g, 94%, as a light red solid of suitable purity for use directly in the next step, mp 80°-83° C.). An analytical sample was prepared by recrystallizing a sample of the crude product from benzene/petroleum ether, (mp 88°-89° C., light red solid).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](/[CH:23]=[CH:24]/[S:25]([NH2:28])(=[O:27])=[O:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]>C(Cl)Cl.[Pd]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH2:23][CH2:24][S:25]([NH2:28])(=[O:26])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(/C=C/S(N)(=O)=O)cc1OCC2
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CCS(N)(=O)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a solution of (E)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-ethenesulfonic acid amide (151 mg, 0.38 mmol) in DCM (5 mL) and IMS (2 mL) was added 10% palladium on carbon (150 mg, 10%). The reaction mixture was stirred at RT under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (C18, eluting with 10-90% acetonitrile in H2O, 0.1% formic acid, 25 min gradient) to yield 445 as a white solid (74 mg, 49%). LCMS: RT=3.24 min, [M+H]+=403. 1H NMR 400 MHz δ (DMSO-d6): 8.29 (1H, d, J=8.7 Hz), 7.87 (1H, s), 7.86 (1H, s), 7.02 (1H, dd, J=8.5, 1.8 Hz), 6.93 (1H, d, J=1.8 Hz), 6.83 (2H, br s), 5.84 (1H, sept, J=6.6 Hz), 4.52-4.41 (4H, m), 3.27-3.20 (2H, m), 3.02-2.92 (2H, m), 1.44 (6H, d, J=6.6 Hz)
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>N1C=CC=CC=1>[C:1]1([O:11][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1cccc2c1CCCC2)c1cccnc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
7 g (47 mmol) of 5,6,7,8-tetrahydro-1-naphthol and 9 g (50 mmol) of nicotinic acid chloride hydrochloride was mixed with 130 ml of dry pyridine and stirred for 24 hours at 30° C. After cooling precipitated pyridine hydrochloride was sucked off, and the filtrate mixed with 300 ml of water. The precipitated raw product was washed with two 200 ml portions of water and recrystallized from methanol.
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N+:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)#[N:3].C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26](=[O:29])[C:27]#[CH:28]>O1CCCC1>[C:26]([C:27]1[CH:28]=[C:11]([C:10](=[O:18])[C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=2)[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)(=[O:29])[CH3:25]
Reactant: C#CC(C)=O
Reactant: N#Cc1ccc(C(=O)C[n+]2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(=O)c2ccc(C#N)cc2)n2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A slurry of 1-(2-(4-cyano-phenyl)-2-oxo-ethyl)-pyridinium bromide (11) (4.04 grams, 13.2 mmol) and potassium carbonate (2.21 grams, 16.0 mmol) in tetrahydrofuran (250 mL) was stirred at room temperature for 10 minutes. To it was added 3-butyn-2-one (1.4 mL, 16.0 mmol), and the reaction mixture was kept stirring at room temperature for 6 hours. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was subjected to column chromatographic purification on silica gel using 3:1 hexane and ethyl acetate (Rf 0.2) to afford 1-acetyl-3-(4-cyanobenzoyl)indolizine (12) as a yellow solid (2.55 grams, 72%). 1H NMR (CDCl3) δ 2.56 (s, 3H), 7.23 (m, 1H), 7.62 (m, 2H), 7.90 (m, 4H), 8.72 (d, J=9.0, 1H), 10.02 (d, J=6.6, 1H); ESMS calcd (C18H12N2O2): 288.1. found: 289.1 (M+H)+.
Reaction SMILES: CN1C2C(=CC3CCC(=O)C=3C=2)CC1=O.[C:16]1([N:22]2[C:30]3[C:25](=[CH:26][C:27]4[CH2:33][CH2:32][C:31](=[O:34])[C:28]=4[CH:29]=3)[CH2:24][C:23]2=[O:35])C=CC=C[CH:17]=1.C(N1C2C(=CC3CCC(=O)C=3C=2)CC1=O)CC.C(N1C2C(=CC3CCC(=O)C=3C=2)CC1=O)(C)C>>[CH2:16]([N:22]1[C:30]2[C:25](=[CH:26][C:27]3[CH2:33][CH2:32][C:31](=[O:34])[C:28]=3[CH:29]=2)[CH2:24][C:23]1=[O:35])[CH3:17]
Reactant: O=C1CCc2cc3c(cc21)N(c1ccccc1)C(=O)C3
Agent: CC(C)N1C(=O)Cc2cc3c(cc21)C(=O)CC3
Agent: CCCN1C(=O)Cc2cc3c(cc21)C(=O)CC3
Agent: CN1C(=O)Cc2cc3c(cc21)C(=O)CC3
Product: CCN1C(=O)Cc2cc3c(cc21)C(=O)CC3

Procedure:
Starting with the appropriate 1-substituted-5-hydroxyoxindole and following the procedure of Preparation A, 1-methyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole, 1-phenyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole, 1-n-propyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole and 1-i-propyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole are prepared.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[H-].[Na+].[CH2:19](I)[CH3:20].O>C1COCC1>[CH2:19]([O:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[CH3:20]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (500 mg) was dissolved in THF (5 ml), and NaH (174 mg) was added thereto under ice-cooling, and subsequently, ethyl iodide (680 mg) was added thereto, followed by elevating the temperature to room temperature and stirring overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5% to 20% EtOAc/hexane) to obtain tert-butyl 4-(2-ethoxyethyl)piperidine-1-carboxylate (496 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CC(C)=O.O>[CH2:13]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:10])([F:11])[F:12])=[CH:3][C:2]=1[Br:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(Br)c1
Yield: 84.6 %

Procedure:
A solution of 3-bromo-4-hydroxybenzotrifluoride (6.03 g, 25 mmol) in acetone (1000 ml) was treated with benzyl bromide (4.67 g, 3.25 ml, 27.5 mmol) and potassium carbonate (5.18 g, 37.5 mmol). The mixture was stirred and heated to reflux under nitrogen for 2 h. After cooling, diethyl ether (300 ml) and water (300 ml) were added and the aqueous phase re-extracted with diethyl ether (100 ml). The combined organic layers were washed with water, dried (MgSO4) and the solvent removed in vacuo. The orange oil was flash chromatographed (silica gel, 2-5% dichloromethane-isohexane) to give the title compound as a clear oil (7.0 g, 85%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([CH2:35][O:36]C(=O)C)=[O:34]>>[OH:36][CH2:35][C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(CO)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A160) acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].Cl>CCCCCC.C1COCC1.CCOC(C)=O>[O:24]=[C:23]([CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:22][CH2:21][C:20]([OH:25])=[O:19]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)CCC(=O)C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 46.2 %

Procedure:
1.59M n-Butyllithium solution in n-hexane (25 mL) was added dropwise to a stirred solution of 1,1′-methylenedibenzene (6.73 g) in THF (75 mL) below 35° C. under N2 gas atmosphere. The reaction mixture was added dropwise to a solution of dihydrofuran-2,5-dione(2 g) in THF (50 mL) below 25° C. After stirring for 4 hours. 1M HCl aqueous solution (45 mL) and EtOAc were poured into the reaction mixture. The organic layer was separated and was washed with water and brine, and dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH). The desired fractions were collected and evaporated in vacuo to give 4-oxo-5,5-diphenylpentanoic acid (2.48 g) as a yellow solid.