Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]([NH2:45])[CH:36]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:45][C:37]2[CH:36]=[N:35][C:44]3[C:39]([CH:38]=2)=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Nc1cnc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(Cl)nc1

Procedure:
A solution of 6-chloro-nicotinic acid (2.95 g, 18.7 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (7.09 g, 18.7 mmol), quinolin-3-ylamine (2.7 g, 18.7 mmol), and N,N-diisopropylethylamine (8.2 mL, 46.7 mmol) in acetonitrile was heated at reflux. The resultant mixture was cooled, and the crystalline product was collected by filtration, to give a colorless solid, 3.1 g (58%). MS: m/z 284 (MH+). 1H NMR (DMSO-d6): 7.61 (t, 1 H), 7.70 (d of t, 1 H), 7.77, (d, 1 H), 8.00 (d, 2 H), 8.43 (d of d, 1 H), 8.85 (d, 1 H), 9.05 (d, 1 H), 9.14 (d, 1 H) and 10.95 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH2:24]=[O:25]>C1(C)C(C)=CC=CC=1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:24][OH:25])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: C=O
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-n1ccnc1
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 5-(trifluoromethyl)-2-(imidazol-1-yl)benzophenone is heated in a bomb with paraformaldehyde in xylene to 140° C. to give 5-(trifluoromethyl)-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([C@@H:26]([NH2:28])[CH3:27])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])[C:5]([NH:28][C@H:26]([C:24]1[NH:23][C:22]2[CH:29]=[CH:30][C:19]([Cl:18])=[CH:20][C:21]=2[N:25]=1)[CH3:27])=[O:7]
Reactant: O=C(O)c1ccc(N2CCCNC2=O)c(Cl)c1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CCCNC2=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 0 °C

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then pouring into ice water, adding conc. ammonia solution, filtering, washing with water and purifying by chromatography on silica gel (eluting gradient ethyl acetate/(methanol/conc. ammonia solution 19:1)=98:2→90:10) with subsequent filtration through activated charcoal, trituration with ether and drying in the drying pistol at 70° C.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.[C:26]([NH:34][NH2:35])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:11][C:10]1[C:9]([N:8]=[N:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([NH2:13])[N:34]([C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[N:35]=1
Reactant: NNC(=O)c1ccccc1
Reactant: N#CC(C#N)=NNc1ccccc1
Solvent: Nc1ccccc1
Solvent: N#CCC#N
Product: Nc1nn(C(=O)c2ccccc2)c(N)c1N=Nc1ccccc1
Temperature: 25 °C

Procedure:
(3,5-diamino-4-phenylazopyrazol-1-yl)phenylmethanone was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and benzoic hydrazide (68 mg, 0.5 mmol). Solids had not formed after heating the reaction at 75° C. for 3 hrs, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in methanol and then precipitated by the addition of water. The resulting solid was isolated by filtration and dried to yield 20 mg (13%) of the compound as an orange coloured solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Fc1ccccc1CBr
Product: O=Cc1cccc2c1ccn2Cc1ccccc1F

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 2-fluorobenzyl bromide instead of the benzyl bromide used in Example 1 to give 1.22 g of 1-(2-fluorobenzyl)indole-4-carbaldehyde as yellow crystals. The yield thereof was found to be 96%.
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=2)=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: COc1cccc(C(=O)Cl)c1
Agent: COc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
3-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 82%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](N)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])(=[O:3])[CH3:2].[BrH:14].O.N([O-])=O.[Na+]>>[C:1]([C:4]1[CH:5]=[C:6]([Br:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])(=[O:3])[CH3:2]
Reactant: Br
Reactant: CC(=O)c1cc(N)ccc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In the ice bath, the starting material, about 10 mmol of 3-acetyl-4-nitro-aminobenzene was added into HBr/H2O (about 100 mL, 1/2, v/v), and sodium nitrite solution was gradually added. The solution was stirred at about 60° C. for about 2 hours. After the reaction was completed, the precipitate was filtered. The filtered solution was neutralized with about 1N NaOH, and extracted with EtOAc. Then the extracted material was dried with sodium sulfate anhydride. Next, the dried material was distilled under reduced pressure. Then, 3-acetyl-4-nitro-bromobenzene was obtained in a form of about 75% yellow oil using silica gel column chromatography (Hexane/EtOAc=2/1).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:16]=[C:17]([N+:21]([O-])=O)[CH:18]=[CH:19][CH:20]=1.O>CN1C(=O)CCC1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[NH2:21])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 1-piperazinecarboxylate (4 g, 21.5 mmol) and 3-fluoronitrobenzene (2.3 ml, 21.5 mmol) in anhydrous NMP (5 ml) was heated to 120° C. for 3 days. After cooling water (25 ml) was added and the mixture was extracted with ethyl acetate (2×10 ml). The organic extract was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column-chromatography using successively petroleum ether and a mixture of ethyl acetate and petroleum ether (1:1 v/v) as the eluents. Yield of t-butyl 4-(3-nitrophenyl)-1-piperazinecarboxylate: 1.34 g (20%). This intermediate was quantitatively hydrogenated to 2g in ethanol at ambient pressure using Pd (5% on activated carbon) as the catalyst.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=O)[CH:3]=1.[CH3:12][NH2:13]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:13][CH3:12])=[O:10])[CH:3]=1
Reactant: CN
Reactant: COC(=O)c1cc(Cl)ccn1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of methyl 4-chloropyridine-2-carboxylate (29.9 g, 174.9 mmol) in MeOH (15 mL) at 0° C. was added 2M methylamine in THF (437 mL, 874 nunol) dropwise. The reaction was allowed to stir at 0° C. for 3 h. The mixture was then concentrated and extracted with EtOAc (2×). The organic solutions were combined, washed with brine, dried over Na2SO4 and concentrated to give 4-chloro-N-methylpyridine-2-carboxamide (25 g, 84%). 1H NMR (300 MHz, d6-DMSO) δ: 8.85 (br s, 1H), 8.61 (d, 1H), 8.00 (d, 1H), 7.74 (dd, 1H), 2.81 (d, 3H).
Reaction SMILES: [H][H].BrC1C=C2C(C(C)(C)CCC2=O)=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25](OCC)=[O:26])[CH:21]=[CH:22][CH:23]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Br:17][C:18]1[CH:19]=[C:20]([CH2:24][CH:25]=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: [H-]
Product: O=CCc1cccc(Br)c1

Procedure:
In the preferred compounds of the invention the two R1 substituents are methyl, and the R2 and R3 substituents are hydrogen. Reaction Scheme 2 illustrates a synthetic process for preparing 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G) which serves as a starting material for the synthesis of several preferred compounds of the invention. Thus, referring now specifically to Reaction Scheme 2, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL-H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Compound G is covered by Formula 10 and in accordance with Reaction Scheme I serves as a starting material in the synthesis of several preferred compounds of the invention.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:5]=[CH:4][CH:3]=1.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=2)[N:7]=1
Reactant: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc(Oc2cccc(C=C3CCNCC3)c2)n1

Procedure:
tert-Butyl 4-(3-(6-methylpyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (4.3 g, 11 mmol) from Step 4 was dissolved in CH2Cl2 (50 mL) and treated with HCl in dioxane (20 mL, 4.0 M, 80 mmol). After 16 h the reaction was concentrated in vacuo to provide the title compound as a white solid (4.0 g).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][C:11]3=[O:23])[CH:5]=[N:4]1.[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[C:29]([O:36][CH2:37][CH3:38])[C:28]=1[C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:40]=1)[CH3:25]>>[CH2:37]([O:36][C:29]1[CH:30]=[C:31]([C:33]([N:16]2[CH2:15][CH2:14][C:13]3([CH2:12][C:11](=[O:23])[C:10]4[C:20](=[CH:21][CH:22]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=5)[CH:9]=4)[O:19]3)[CH2:18][CH2:17]2)=[O:34])[CH:32]=[C:27]([O:26][CH2:24][CH3:25])[C:28]=1[C:39]1[CH:40]=[CH:41][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:44]=1)[CH3:38]
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Agent: Cl
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)OC)cc1

Procedure:
In the same manner as in Example 25, the intended compound was obtained as a colorless solid using 6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride and 2,6-diethoxy-4′-(methoxycarbonyl)biphenyl-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:18][CH2:19][OH:20])[C:7]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:20][CH2:19][CH2:18][N:6]1[C:5]2[CH:21]=[CH:22][C:2]([Br:1])=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][NH:10][C:11]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:17])(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(Br)ccc2n1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1nc2cc(Br)ccc2n1CCOS(C)(=O)=O
Reaction time: 2 h
Yield: 106.2 %

Procedure:
tert-Butyl ((5-bromo-1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (648 mg, 1.75 mmol) was stirred in methylene chloride (25 mL), and triethylamine (530 mg, 0.74 mL, 5.3 mmol) and methanesulfonyl chloride (400 mg, 0.27 mL, 3.5 mmol) were added. The mixture was stirred for 2 h and then washed with water, dried over sodium sulfate and concentrated to provide the title compound (833 mg, quant) as a yellow solid: ESI MS m/z 448 [M+H]+.
Reaction SMILES: Br[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][SH:23]>C1(C)C=CC=CC=1>[C:15]1([C:2]2([S:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: COC(=O)CS
Solvent: Cc1ccccc1
Product: COC(=O)CSC1(c2ccccc2)c2ccccc2-c2ccccc21
Yield: 78.3 %

Procedure:
A solution of 9-bromo-9-phenylfluorene (Aldrich) (1.9 g, 5.9 mmol) and methyl thioglycolate (0.70 mL, 7.8 mmol) in 50 mL of toluene is heated at reflux for 4 hours. The reaction is cooled and concentrated in vacuo. The resulting oil is chromatographed on silica gel eluting with a gradient of ethyl acetate/toluene/hexane (3:20:77 to 5:40:55). The purified product is co-evaporated with hexane 2 times and dried under vacuum for 3 days to give 1.6 g (77%) of methyl (9-phenylfluoren-9-yl-thio)acetate as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH2:29]>C(#N)C>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH:29][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: NCc1c(F)cccc1F
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(F)c1CNCCOc1cccc(-c2noc3ccsc23)c1
Reaction time: 8 h

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2,6-difluorobenzylamine and acetonitrile essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column chromatography using a solvent gradient of 5% ethyl acetate in dichloromethane to 10% methanol in ethyl acetate. Purity by LC/MS (APCI)=99%, [M+H]+=387.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@@H:19]3[CH2:27][C@:22]4([O:26][CH2:25][CH2:24][CH2:23]4)[CH2:21][C@@H:20]3[C:28](OC)=[O:29])=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].Cl.[NH2:43][OH:44]>CO.C[O-].[Na+]>[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[O:34]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@@H:19]3[CH2:27][C@:22]4([O:26][CH2:25][CH2:24][CH2:23]4)[CH2:21][C@@H:20]3[C:28]([NH:43][OH:44])=[O:29])=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H]1C[C@]2(CCCO2)C[C@H]1NC(=O)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Reaction time: 1 h
Yield: 37 %

Procedure:
Methyl (5R,7S,8R)-8-{[4-(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction 33f (0.165 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.03 g, 37%) as a white solid. MS found: (M+H)+=485, (2M+H)+=969.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH2:29])[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH:29][CH2:32][CH2:31][C:30]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: NC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)CCNC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Temperature: 100 °C

Procedure:
1-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-cyclopropanamine (0.067 g, 0.167 mmol) and methyl acrylate (0.5 mL, 5.5 mmol) were combined in a sealed tube and heated neat at 100° C. for 1 day, during which LC-MS indicated completion of reaction. The cooled reaction mixture was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 5% to 20% EtOAc/Hexanes afforded methyl 3-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)cyclopropylamino)propanoate as a light golden yellow oil. MS (ESI) m/z: Calculated: 487.6; Observed: 488.1 (M++1).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(I)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.0 g of 4-iodoaniline (9.13 mmol) in 40 ml of acetonitrile there are added 1.48 ml of pyridine (18.26 mmol) and then, dropwise, a solution of 1.28 ml of benzenesulphonyl chloride (10 mmol) in 20 ml of acetonitrile. The reaction mixture is stirred overnight at ambient temperature and the acetonitrile is evaporated off under reduced pressure. The residue is taken up in 1N HCl and extracted with ethyl acetate. The organic phase is washed with brine, dried (MgSO4) and evaporated under reduced pressure. The oily residue obtained is triturated in isopropyl ether until the title product crystallises.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([S:38]([C:41]1[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH:33]=[C:32]2I>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([S:38]([C:41]1[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=1)(=[O:39])=[O:40])[CH:33]=[C:32]2[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(Cl)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Temperature: 105 °C
Yield: 90.4 %

Procedure:
Argon was bubbled through a slurry of CuI (0.036 g, 0.190 mmol), Pd(PPh3)4 (0.110 g, 0.095 mmol), 2-chloro-6-(tributylstannyl)pyrazine (1.151 g, 2.85 mmol), 5-(2-chloro-6-fluorophenyl)-3-iodo-1-tosyl-1H-indole (1.00 g, 1.902 mmol) in 9 mL DMF for 2 min. The reaction was sealed and heated to 105° C. for 2 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 0-30% EtOAc/hexane. The product-containing fractions were concentrated to afford 5-(2-chloro-6-fluorophenyl)-3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indole (0.88 g, 1.72 mmol, 91% yield) as a light-yellow solid. MS (ESI, pos. ion) m/z: 512 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([CH3:10])[CH:3]=1.CC(C[Al]CC(C)C)C.CO.[OH:22]S(O)(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:22])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(Br)ccc1C#N
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(Br)ccc1C=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To 4-bromo-2-methylbenzonitrile (2 g, 10.2 mmol) in toluene (60 mL) cooled to 5 C under argon was added Dibal-H (11.2 mL, 1M solution in toluene, 11.2 mmol) dropwise. The reaction was stirred at 5° C. for 30 minutes then MeOH (3 mL) and 2 M H2SO4 (10 mL) were added dropwise. The mixture was stirred for ˜19 h then concentrated in vacuo. The residue was re-dissolved in water/EtOAc. The organic layer was dried and concentrated to give the crude title compound as a brown oil (1.81 g) which was used in the next step without further purification. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.65 (1H, d), 7.50 (1H, dd), 7.43 (1H, m), 2.64 (3H, s).