Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])[CH3:27]>CN(C=O)C.[Cu]I>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1/[C:26](/[CH3:27])=[CH:25]\[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccc(F)cc1F
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(2-Bromo-1-methyl-vinyl)-2,4-difluoro-benzene (279 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-2% MeOH-DCM. The product was further purified by HPLC. Yield: 16 mg. 1H NMR (CDCl3, freebase) δ (ppm): 7.10 (s, 1H), 7.0 (d, 1H), 6.90 (m, 2H), 6.70 (m, 2H), 6.58 (t, 1H), 3.60 (s, 2H), 2.65 (t, 2H), 2.50 (m, 5H), 2.40 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][CH3:17])[C:3]=1[C:18]([O:20]CC)=[O:19]>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][CH3:17])[C:3]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1c(CC)nc2c(C(F)(F)F)cccc2c1O
Solvent: CCO
Product: CCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Yield: 96.7 %

Procedure:
A solution of 5 g of the product of Step D in 25 ml of 36° Be sodium hydroxide solution and 50 ml of ethanol was refluxed for 31/2 hours and was then cooled. The ethanol was evaporated and 100 ml of ice water were added thereto. The mixture was washed with methylene chloride and was acidified slowly by addition of 2N hydrochloric acid under 15° C. The mixture was filtered and the filtrate was washed with water until the wash water pH was 6 to obtain 4.4 g of 4-hydroxy-2-ethyl-8-trifluoromethyl-quinoline-3-carboxylic acid melting at 174° C which was used as is for the next step.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1.C1(=O)OC(=O)C2=CC=CC=C12.[OH-].[Na+]>O.CN(C)P(=O)(N(C)C)N(C)C.CCCCCC.C(OCC)C>[CH2:14]([CH:21]1[CH2:22][CH2:23][CH2:24][C:19](=[O:25])[CH2:20]1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C1C=CCCC1
Reactant: [Li]CCCC
Agent: CCCCP(CCCC)CCCC
Agent: O=C1OC(=O)c2ccccc21
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CCCCC1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To 30 ml of anhydrous diethyl ether were added 3.8 g (20 mmol) of cuprous iodide and 4.0 g (20 mmol) of tri-n-butylphosphine, and the mixture was stirred for about 1 hour at room temperature in an atmosphere of nitrogen and then cooled to -78° C. Then, 25.6 ml (40 mmol) of a 15% by weight hexane solution of n-butyllithium was added, and the mixture was stirred for 30 minutes, and 1.92 g (20 mmol) of 2-cyclohexenone was added. The mixture was further stirred for 1 hour at -78° C. Then, 5 ml of hexamethylphosphoric triamide was added, and the mixture was stirred for about 10 minutes. Phthalic anhydride (2.96 g, 20 mmol) was further added, and the mixture was stirred for 3 hours at room temperature. After the reaction, a solution of 4 g (100 mmol) of sodium hydroxide in 50 ml of water was added, and the mixture was stirred for about 1 hour. It was extracted with ether, washed, and dried to afford 6.22 g of a crude product. The crude product was distilled to afford 1.62 g (10.5 mmol) of 3-n-butylcyclohexanone in a yield of 53%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:51]([CH3:60])[CH:52]([CH2:57][CH2:58][CH3:59])[C:53](=[O:56])[NH:54][N:55]=2)=[CH:46][C:45]=1[OH:61]>C(Cl)Cl>[OH:61][C:45]1[CH:46]=[C:47]([C:50]2[CH:51]([CH3:60])[CH:52]([CH2:57][CH2:58][CH3:59])[C:53](=[O:56])[NH:54][N:55]=2)[CH:48]=[CH:49][C:44]=1[NH:43][C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: CCCC1C(=O)NN=C(c2ccc(N)c(O)c2)C1C
Reactant: Cn1cccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC1C(=O)NN=C(c2ccc(NC(=O)c3cccn3C)c(O)c2)C1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
240 mg (1.92 mmol) 1-methyl-1H-pyrrol-2-carboxylic acid is placed in 20 mL DCM. 760 mg (2.00 mmol) HATU, 1.50 mL (8.76 mmol) DIPEA and 600 mg (2.30 mmol) 6-(4-amino-3-hydroxy-phenyl)-5-methyl-4-propyl-4,5-dihydro-2H-pyridazin-3-one are added and the mixture is stirred for 3 h at RT. The reaction mixture is extracted successively with 0.5% acetic acid, 10% sodium carbonate solution and saline solution. Then the organic phase is dried and the solv. is eliminated i.V.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:29]
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC3CC3)c2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g, 8.3 mmol) in dry CHCl3 (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.
Reaction SMILES: [C:1]([NH2:6])(=O)[CH:2]([CH3:4])[CH3:3].[P:7]([OH:10])([OH:9])[OH:8].Cl>>[NH2:6][C:1]([P:7]([OH:10])(=[O:8])[OH:9])([P:7]([OH:10])(=[O:9])[OH:8])[CH:2]([CH3:4])[CH3:3]
Reactant: OP(O)O
Reactant: CC(C)C(N)=O
Agent: Cl
Product: CC(C)C(N)(P(=O)(O)O)P(=O)(O)O

Procedure:
Into a mixture of 87 gm of isobutyric acid amide and 82 gm of phosphorous acid, hydrogen chloride gas was introduced for 8 hours. During this time the mixture was stirred and the temperature was held at 155° -160° C. By further processing of the reaction mixture analogously to Example 1, the 1-amino-2-methylpropane-1,1 -diphosphonic acid was isolated and purified. The yield was 8 gm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:19][C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:24][CH:25]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[CH3:34][N:35]([CH3:44])[CH2:36][CH2:37][N:38]1[CH:42]=[C:41]([NH2:43])[CH:40]=[N:39]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:29]([O:28][C:27](=[O:33])[NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[N:7]=[C:2]([NH:43][C:41]3[CH:40]=[N:39][N:38]([CH2:37][CH2:36][N:35]([CH3:44])[CH3:34])[CH:42]=3)[N:3]=2)[CH:21]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CN(C)CCn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(Cl)nc3c2ccn3COCC[Si](C)(C)C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCn1cc(Nc2nc(Oc3cccc(NC(=O)OC(C)(C)C)c3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Temperature: 140 °C

Procedure:
To a solution of tert-butyl {3-[(2-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}carbamate (300 mg, 0.61 mmol) in 1,4-dioxane (4 mL) in a microwave vial was added 1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-amine (94.1 mg, 0.61 mmol) followed by Cs2CO3 (298 mg, 0.915 mmol), Pd2(dba)3 (8.2 mg, 0.009 mmol) and Xantphos (5.4 mg, 0.009 mmol) and the mixture heated in the microwave to 140° C. for 45 min. The reaction was cooled to rt and brine (20 mL) was added and the mixture was extracted with EtOAc (three×10 mL). The combined extracts were dried over MgSO4, filtered and stripped to give the title compound as a dark oil that was taken on to the next step with no purification. m/z (ESI+) for C30H44N8O4Si 609.25 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C@@H:11]([NH:14][CH3:15])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([N:22]([CH2:29][C:30](O)=[O:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:9]1[CH2:13][CH2:12][C@@H:11]([N:14]([CH3:15])[C:30](=[O:31])[CH2:29][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN[C@@H]1CCN(C(=O)c2ccccc2)C1
Reactant: O=C(O)CN(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C(=O)CN(c1ccccc1)c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of (R)-(1-benzoyl-pyrrolidin-3-yl)-methyl-amine(0.32 g, 1.68 mmol) in dry CH2Cl2 (20 ml) was added diphenylaminoacetic acid (0.38 g, 1.68 mmol) under nitrogen. To the reaction was added EDC (0.65 g, 3.36 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give 0.68 g of desired product.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][O:28][CH:29]([O:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH:29]([O:35][CH3:36])[O:28][CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: COC(=O)CC(OC)OC
Agent: Cl
Product: COC(CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)OC

Procedure:
The title compound, white solid (71 mg, 64%), MS (ISP) m/z=443.4 [(M+H)+], mp 148° C., was prepared in accordance with the general method of example 46 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and methyl 3,3-dimethoxy-propanoate.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[CH:30]=[C:29]2[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[O:49][CH3:50])=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([CH:2]([CH2:3][CH3:4])[CH:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[CH:30]=[C:29]2[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[O:49][CH3:50])[OH:25])([OH:6])=[O:5]
Reactant: CCCC(=O)O
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C(O)C(CC)C(=O)O)ccc21
Temperature: 25 °C

Procedure:
A solution of the dianion of butyric acid (5.6 mmol) [prepared from butyric acid (5.6 mmol) and lithium di-isopropylamide (5.6 mmol) in tetrahydrofuran (THF) (30 ml) and dimethylpropyleneurea (11.2 mmol)]was added to a solution of methyl 4-[5-formyl-1-propylindol-3-ylmethyl]-3-methoxybenzoate (2.0 g) in THF (15 ml) cooled in an ice-bath, under a nitrogen atmosphere, at such a rate as to maintain the temperature of the reaction below 10°. The mixture was allowed to warm to room temperature, stirred for an additional hour, poured into 20% (w/v) citric acid solution (150 ml), and extracted with ethyl acetate. The organic extracts were washed (water (twice), brine), dried (MgSO4) and evaporated to give a yellow oil. The product was purified by flash chromatography, eluting with 80:20:2 toluene:ethyl acetate:acetic acid, to give methyl 4-[5-(2-carboxy-1-hydroxybutyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (1.25 g, 48%, as a separable mixture of diastereomers), as a foam; isomer A partial NMR (300 Mz, DMSO-d6): 0.66(t, 3H, CH3), 0.81 (t, 3H, CH3), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.53(d, 1H, CHOH), 5.23(br s, 1H, CHOH); isomer B partial NMR (300 Mz, DMSO-d6): 0.85(m, 6H, 2×CH3), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.62(d, 1H, CHOH), 5.20(br s, about 1H, CHOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[H-].[Na+].[C:16]([O:22][CH2:23]Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([O:22][CH2:23][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH3:13])([CH3:12])[C:6]1=[O:11])=[O:21]
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCN1C(=O)C(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g of 5-bromo-3,3-dimethyl-1,3-dihydroindol-2-one was dissolved in 100 ml of dimethylformamide, and 217 mg of sodium hydride (60% dispersion in mineral oil) were added. The mixture was then stirred at room temperature for 30 minutes. Then the reaction mixture was cooled to 0° C. in an ice bath, and 941 mg of chloromethyl pivalate were added. The ice bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was diluted by adding 250 ml of ethyl acetate, and 50 ml of water were added. The organic phase was removed and washed once with 100 ml of saturated sodium chloride solution, dried over MgSO4 and then concentrated under reduced pressure. This gave 1.5 g of 5-bromo-3,3-dimethyl-2-oxo-2,3-dihydroindol-1-ylmethyl 2,2-dimethylpropionate.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][CH2:19][CH:20]([N:27](C)[C:28](=O)OC(C)(C)C)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:10]1(=[O:37])=[O:36].Cl>CCOCC>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][CH2:19][CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:27][CH3:28])[S:10]1(=[O:36])=[O:37]
Reactant: CN(C(=O)OC(C)(C)C)C(CCN1c2ccccc2N(c2cccc(F)c2F)S1(=O)=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CNC(CCN1c2ccccc2N(c2cccc(F)c2F)S1(=O)=O)c1ccccc1
Yield: 79.7 %

Procedure:
tert-butyl {3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-phenylpropyl}methylcarbamate (0.10 g, 0.19 mmol) was treated with an excess of 2N HCl in ether. The precipitated amine salt was collected to give 65 mg of 3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-1-phenylpropan-1-amine.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)CC1
Temperature: 100 °C
Yield: 16.9 %

Procedure:
200 mg of product obtained in stage 1 above are mixed with 5 ml of DMSO and 790 mg (5 equivalents) of 4-aminomethyl-N-Boc-piperidine, and the mixture is then heated at 100° C. for approximately 3 days. The mixture is allowed to return to ambient temperature. The DMSO is concentrated to dryness and the dry product is taken up in CH2Cl2. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 95-5-0.33 mixture for eluent. 56 mg of expected product are thus obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[C:16]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:12]
Reactant: CCOC(=O)C=Cc1cccnc1
Reactant: Brc1ccc2cc[nH]c2c1
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2cc[nH]c2c1

Procedure:
3-(1H-Indol-6-yl)-3-pyridin-3-yl-acrylic acid ethyl ester CLVII was prepared from 6-bromo-1H-indole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C@@H:16]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1)[CH2:17][N:18]([CH3:31])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH3:31][NH:18][CH2:17][C@@H:16]([NH:15][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([C:39]([F:41])([F:40])[F:42])[CH:33]=1
Reactant: Cc1ccc([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1C(F)(F)F
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(C)c(C(F)(F)F)c1

Procedure:
Compound 76 was prepared following general synthetic scheme 11 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-methyl-3-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide. LC-MS [405 (M+1)]; 1H NMR (400 MHz, DMSO-d6) d 9.95 (d, J=3.4 Hz, 1H), 9.21 (d, J=8.5 Hz, 1H), 9.00 (d, J=4.6 Hz, 1H), 8.54 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.16 (d, J=3.5 Hz, 1H), 7.80 (s, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 5.51 (s, 1H), 3.15 (dd, J=12.4, 8.4 Hz, 1H), 2.92 (dd, J=12.3, 5.5 Hz, 1H), 2.40 (s, 4H), 2.30 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1C(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 30 ml of N,N-dimethylformamide was dissolved 5.0 g of 2-amino-5-chloro-2'-hydroxybenzophenone, as obtained in Example 123 (1), to which were added 4.2 g of potassium carbonate and 2.9 ml of benzyl bromide; the mixture was then stirred for 2 hours at room temperature. The mixture was subjected to extraction with 150 ml of water and 200 ml of ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (eluent, hexane:ethyl acetate=10:1 to 5:1) to yield 6.4 g of 2-amino-2'-benzyloxy-5-chlorobenzophenone as prism crystals, m.p. 110° to 111° C.
Reaction SMILES: C[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:15](Cl)Cl>[O-2].[O-2].[Mn+4]>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:2][C:3]([O:5][CH3:15])=[O:4])=[CH:8][CH:9]=1)=[O:14]
Reactant: ClCCl
Reactant: CC(Cc1ccc(CO)cc1)C(=O)O
Agent: [Mn+4]
Agent: [O-2]
Product: COC(=O)CCc1ccc(C=O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of Intermediate B (300 mg, 1.54 mmol) in DCM (25 mL) was added manganese dioxide (2.98 g, 34 mmol). The mixture was stirred for 15 minutes, and then filtered through Celite and washed with additional DCM (100 mL). The filtrate was concentrated to yield the desired product. This was used directly in the next stage without further purification or characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[C:23]2[CH:27]=O>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[C:23]2/[CH:27]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cccc2c(C=O)c[nH]c12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c[nH]c3c(OC)cccc23)cc(OC)c1OC
Yield: 48.3 %

Procedure:
Substantially the same procedure as in Example 39 was repeated using 3',4',5'-trimethoxyacetophenone (1.74 g) and 7-methoxyindole-3-carboxaldehyde (1.45 g) to give Compound 46 (1.47 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[S:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>>[CH3:13][C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[S:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)cc(C)nc2n1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2cc(C)nc3nc(C)ccc23)c1

Procedure:
The product from Example 14b (60 mg, 0.31 mmol) was reacted with the product from Example 4c (72 mg, 0.31 mmol) for 12 h following the procedure from Example 1g giving the title compound as a crude solid which was purified by HPLC with TFA giving the product as a trifluoroacetic acid salt (45 mg, 37%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.23 (s, 3H) 2.75 (s, 3H) 3.43 (s, 3H) 6.10 (s, 1H) 6.68 (d, J=8.82 Hz, 2H) 6.99-7.20 (m, 3H) 7.20-7.38 (m, 2H) 7.75 (d, J=8.82 Hz, 1H) 8.96 (d, J=8.82 Hz, 1H) 9.86 (s, 1H) 10.78 (s, 1H) 14.21 (s, 1H); MS (APCI) m/z 386 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:17]1[CH:24]=[CH:23][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:21][C:18]=1[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH:23]=[CH:24][C:17]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)#[N:20]
Reactant: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1Oc1cc(CC(=O)O)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 44 step (i).