Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([O:27]C)[CH:20]=3)[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH:1]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([OH:27])[CH:20]=3)[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCN(CCC3CCCc4ccccc43)CC2)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(C2CCN(CCC3CCCc4ccccc43)CC2)cc1O
Reaction time: 3 h

Procedure:
A mixture of 4.1 g of 1-(2-(tetralin-1-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine (fumarate, m.p. 154°-156°) 3.2 g of pyridine hydrochloride and 80 ml of pyridine is boiled for 3 hours. It is cooled, evaporated and worked up in the customary manner and gives 1-(2-(tetralin-1-yl)ethyl)-4-(3,4-dihydroxyphenyl)piperidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[C:33][CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:4][N:3]=1.N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(O)C.N1C=CC=CC=1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: CCN(CC)CC#Cc1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Solvent: c1ccncc1
Product: CCN(CC)C/C=C\c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Yield: 37.6 %

Procedure:
A solution of N-(4-{4-amino-7-[3-(diethylamino)prop-1-ynyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.135 g, 0.251 mmol) in ethanol/pyridine (15 mL/10 mL) was treated with Lindlar's catalyst (0.027 g), quinoline (0.05 g, 0.38 mmol), and hydrogen (55 psi) in a Parr Hydrogenator. The reaction mixture was shaken for 1H. The catalyst was filtered through celite. The solvent was removed under reduced pressure. The crude material was purified by preparative HPLC to afford 0.051 g (38%) of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.00-7.98 (d, 1H), 7.81 (s, 1H), 7.71-7.69 (d, 1H), 7.60-7.57 (m, 2H), 7.35-7.33 (m, 2H), 7.21-7.21 (m, 1H), 7.17-7.13 (t, H), 7.10-7.08 (d, 1H), 6.56-6.53 (d, 1H), 5.90-5.88 (dt, 1H), 5.60 (brs, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.30-3.28 (m, 2H), 2.49-2.44 (q, 4H), 0.93-0.89 (t, 6H); LCMS (conditions a) Rt 3.28 min (95%), MH+ 540.3.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:2][C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH:13]=[CH2:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(NC(C)=O)cc1

Procedure:
4-Acetamidophenol (383 g, 2.53 mole), allyl bromide (338 g, 2.79 mole), and anhydrous potassium carbonate (350 g, 2.53 mole) were added to acetone (2250 ml). Under intense stirring, the heterogeneous mixture was refluxed overnight. After cooling, the inorganic salts were filtered off and the filtrate concentrated under reduced pressure. The obtained solid was used for step 2 without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[S:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[S:13][C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(NC(=S)NCCCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2sc(NCCCO)nc2c1
Yield: 72.2 %

Procedure:
A mixture of 21 parts of N-(2-chloro-5-nitrophenyl)-N'-(3-hydroxypropyl)thiourea, 10 parts of potassium carbonate and 180 parts of N,N-dimethylformamide is stirred and refluxed for 30 minutes. After cooling, 300 parts of water are added and the product is allowed to crystallize. It is filtered off and washed with water, yielding 13.3 parts (72.2%) of 3-[(5-nitro-2-benzothiazolyl)amino]-1-propanol; mp. 140°-144° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:16][CH2:15]1)[C:7]2=[O:30])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:18][CH2:19]1)[C:7]2=[O:30]
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CCN(Cc2c[nH]c3ccccc23)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)N(C1CCN(Cc3c[nH]c4ccccc34)CC1)C2=O

Procedure:
5-Nitro-2-[1-(indol-3-ylmethyl)piperid-4-yl]-1H-isoindole-1,3-(2H)-dione (0.8 g, 1.98 mmol) was hydrogenated in methanol over Pd/C (5%, 0.15 g) at atmospheric pressure. The catalyst was filtered off and the filtrate evaporated. The solid product was recrystallised from chloroform to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][C@@H:22]4[CH2:26][CH2:27][CH2:28][C@@H:21]34)[N:17]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]3)[C:4]=2[C:5]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=2)=[N:6][C:7]=1[C:8]#[N:9].[CH3:37]B1OB(C)OB(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:16][C:14]1[CH:15]=[C:10]([C:5]2[C:4]3[N:17]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:18]([N:20]4[CH2:25][CH2:24][O:23][C@@H:22]5[CH2:26][CH2:27][CH2:28][C@@H:21]45)=[N:19][C:3]=3[C:2]([CH3:37])=[C:7]([C:8]#[N:9])[N:6]=2)[CH:11]=[N:12][CH:13]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Br)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C#N)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Temperature: 100 °C

Procedure:
A vial was charged with 7-bromo-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (40 mg, 0.07 mmol), trimethylboroxine (10 μL, 0.07 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mg, 0.007 mmol), K3PO4 (37.2 mg, 0.175 mmol), dioxane (0.8 mL), and water (0.2 mL). The mixture was sparged with N2, the vial was sealed, and the reaction was heated at 100° C. for 90 minutes. The reaction was then cooled to room temperature, diluted with EtOAc (40 mL), and washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column with 0 to 100% EtOAc/hexanes to afford 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methyl-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C28H33ClN6O [M+H]+=505. found=505.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:38])[C:34]([OH:37])([CH3:36])[CH3:35])[NH:28][C:27](=[O:39])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:38])[C:34]([OH:37])([CH3:36])[CH3:35])[NH:28][C:27](=[O:39])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)C(C)(C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 63.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide as starting materials to give N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide (46 mg, 63.3%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16](=O)(OC)OC>>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH3:16])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)OC
Product: COS(=O)(=O)C(F)(F)F
Yield: 197.7 %

Procedure:
731 g (2.59 mol) of trifluoromethanesulfonic anhydride and 232 g (2.58 mol) of dimethyl carbonate are added to the residue, and the process described above is repeated. 837 g of methyl trifluoromethanesulfonate having a purity of greater than 99% are isolated (yield: 99.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8](C)[C:9](=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][CH3:9]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
3.6 g (12.7 mmol) of tert-butyl (3-bromophenyl)-N-methylcarbamate, prepared in a manner analogous to Example 1b), are dissolved in 15 ml of dichloromethane. 5 ml of trifluoroacetic acid are added and the reaction mixture is stirred at ambient temperature for 1 hour. The reaction is halted by the addition of 50 ml of a saturated sodium hydrogencarbonate solution and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 50/50). 2.14 g of 3-bromo-N-methylaniline are obtained in the form of an oil. Yield=90%.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:55][OH:56])[CH:53]=[O:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:55][OH:56])[CH2:53][OH:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of (2R,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl) phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 17j (4.80 g, 6.04 mmol) in methanol (50 mL) was added sodium borohydride (326 mg, 8.62 mmol) at −5° C. The mixture was stirred for 30 min at −5° C. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and concentrated in vacuo to remove most of the solvent. To the residue was added water (50 mL). The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 17k as light yellow oil (2.7 g, 56.3%, HPLC: 89.2%). This material was not further purified. The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.53 (d, 2H), 7.40 (d, 1H), 7.33 (d, 2H), 7.31-7.22 (m, 12H), 7.08-7.01 (m, 4H), 6.89 (d, 2H), 4.90 (s, 1H), 4.85-4.74 (m, 3H), 4.71-4.63 (m, 3H), 4.52 (d, 1H), 4.30 (s, 1H), 4.05 (m, 3H), 3.99-3.85 (m, 3H), 3.79 (m, 2H), 3.54 (d, 1H), 3.19 (d, 1H), 3.09 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:28])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.00 g (8.59 mmol) 4-benzyloxy-1-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 15b) in 20 mL of DCM and 20 mL THF is added 0.81 mL (8.59 mmol) phosphorus tribromide at 0° C. The cooling bath is removed and the mixture is stirred 1 h at RT in an ultrasound bath.
Reaction SMILES: Cl/[C:2](=[N:8]\[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(S[C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)C=C.C(N(CC)CC)C>O1CCOCC1>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:22]2=[N:26][CH:25]=[CH:24][N:23]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]1
Reactant: C=CCSc1ncc[nH]1
Reactant: CCOC(=O)/C(Cl)=N/NCc1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2nccn12

Procedure:
Ethyl (2Z)-chloro[(2-fluorobenzyl)hydrazono]acetate (750 mg, 2.90 mmol) from example 2A, 2-allylthio-1H-imidazole [U.S. Pat. No. 3,574,593; Chem. Abstr. 75, 49078] (1.20 g, 7.25 mmol) and triethylamine (293 mg, 2.90 mmol) are dissolved in dioxane (10 ml) and heated under reflux for 4 h. This is followed by dilution with water and extraction with ethyl acetate. The organic phase is dried over sodium sulfate, and the crude product is purified by chromatography on silica gel (eluent: dichloromethane/methanol 50:1). 410 mg (41% of theory) of the desired product are obtained with 84% purity.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:24])[C:10]1[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[O:22][CH3:23].[C:25]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][C:9](=[O:24])[C:10]2[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:20])([F:21])[F:19])=[CH:12][C:11]=2[O:22][CH3:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCCC1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCCC1NC1CCCC1

Procedure:
The title compound, light yellow solid, MS: m/e=431.3 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate I) and cyclopentanone.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13])=[O:22]
Reactant: O=C=Nc1ccccc1Br
Reactant: COC(=O)c1ccc(N)c(O)c1
Product: COC(=O)c1ccc(NC(=O)Nc2ccccc2Br)c(O)c1
Yield: 32.9 %

Procedure:
The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.12 g, 33%). EI-MS m/z 363(M-H)-
Reaction SMILES: C([N:8]([CH2:16][CH2:17][C:18]1[CH:41]=[CH:40][C:21]([C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:26]([OH:28])=[O:27])=[O:23])=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(OC(C)(C)C)=O.[ClH:42].O1CCOCC1>CO>[ClH:42].[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:26]([OH:28])=[O:27])=[O:23])=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(C(=O)N[C@@H](CCCNCc2ccccn2)C(=O)O)cc1)Cc1ccccn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCCNCc1ccccn1)C(=O)O)c1ccc(CCNCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The compound obtained in Example 10-1 (13.9 mg) was dissolved in methanol (0.28 ml) and 4 mol/l hydrochloric acid/dioxane solution (0.28 ml) was added to the solution. The mixture was stirred for 75 minutes at room temperature. After the completion of the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (0.5 g, chloroform/methanol/water=7/3/0.5). The obtained product was added with aqueous solution of hydrochloric acid, concentrated and then azeotropically distilled with water. The resulting solid was washed with ether to obtain a hydrochloride of the title compound (13.8 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH2:19][CH2:20][O:21][CH3:22])[C:11]=12)[NH2:5].Cl[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]=[C:26]([NH2:34])[N:25]=1.Cl.N1C=CC=CC=1N.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[N:27]=[C:26]([NH2:34])[N:25]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH2:19][CH2:20][O:21][CH3:22])[C:11]=12
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: COCCc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Agent: Nc1ccccn1
Agent: [Na+]
Solvent: O
Product: COCCc1c[nH]c2nccc(Oc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12
Reaction time: 8 h

Procedure:
53 mg (0.18 mmol) of 3-fluoro-4-{[3-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}aniline and 42 mg (0.21 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 4 ml of water. 0.23 ml (0.23 mmol) of 1N hydrochloric acid is added, and the mixture is heated at reflux overnight. Another 22 mg (0.11 mmol) of 4-chloro-6-trifluoromethyl)pyridine-2-amine are then added, and the mixture is again heated overnight. By addition of 1N aqueous sodium hydroxide solution, the pH is adjusted to 10, resulting in the precipitation of crystals. The crystals are filtered off with suction and washed with water. The product is purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[S:10](=O)(=[O:13])([OH:12])[OH:11]>O>[Cl:1][C:2]1[CH:8]=[C:7]([CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4])[S:10]([OH:13])(=[O:12])=[O:11]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: Nc1c(Cl)cc(S(=O)(=O)O)cc1Cl
Temperature: 170 °C

Procedure:
2,6-Dichloroaniline (22.0 g; 0.136 mol) was added cautiously to concentrated sulphuric acid (50 ml) under nitrogen, with cooling and stirring. When addition was complete the reaction mixture was heated under nitrogen at 170° C. for 5 hr, then allowed to cool to 50° C. before pouring into cold water (4° C.). The precipitate was filtered and then heated with decolourising charcoal (2 g) in boiling water (500 ml) for 15 min. After filtration the solvent was removed and the crude product was recrystallised from water to give a crystalline solid, which was dried over silica gel overnight, to give 3,5-dichlorosulphanilic acid as a white powder. Yield 13.7 g (42%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13])(=O)=O.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH3:15][O:14][C:12]([C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[O:13]
Reactant: COC(=O)c1sccc1OS(=O)(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1C#C[Si](C)(C)C
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 2.07 g of 2-methoxycarbonyl-3-thienyl trifluoromethane sulfonate, 2.02 ml of trimethylsilylacetylene, 1.57 g of tetrakis (triphenylphosphine)palladium(0), 272 mg of cuprous iodide, 2.98 ml of triethylamine and 30 ml of N,N-dimethylformamide was stirred at 65° C. for 3 hours in a nitrogen atmosphere. Silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to silica gel column chromatography using 6% ethyl acetate/hexane, to give 1.78 g of the target compound.
Reaction SMILES: [CH3:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].Cl[CH2:19][CH2:20][O:21]C1CCCCO1>>[OH:21][CH2:20][CH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1=[O:11]
Reactant: ClCCOC1CCCCO1
Reactant: CC1(c2ccccc2)C(=O)Nc2ccccc21
Product: CC1(c2ccccc2)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-methyl-3-phenyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[N:18]=[CH:17]2)([C:5]1[CH:6]=[N:7][C:8]([O:12]C)=[C:9]([CH3:11])[CH:10]=1)[OH:4].Cl.[NH+]1C=CC=CC=1>CCOCC.O>[CH3:11][C:9]1[C:8](=[O:12])[NH:7][CH:6]=[C:5]([C:3]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)([OH:4])[C:2]([F:1])([F:30])[F:31])[CH:10]=1
Reactant: COc1ncc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c[nH]c1=O
Temperature: 125 °C

Procedure:
A mixture of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(5-methyl-6-methoxypyridin-3-yl)ethanol (0.679 mmol) and pyridinium hydrochloride (6.79 mmol) was warmed at 125° C. in a sealed tube for 20 minutes, cooled to room temperature and diluted with ether and water. The organic layer was washed with brine and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue triturated with petroleum ether to provide the title compound.