Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1C=C(C2C=CC=CC=2OC)N2[C:10]=1C=NC(NC1C=CC(N3CCN(C)CC3)=CC=1)=N2.Br[C:34]1[CH:35]=[C:36]([C:57]2[CH:62]=[CH:61][C:60]([S:63]([CH3:66])(=[O:65])=[O:64])=[CH:59][CH:58]=2)[N:37]2[C:42]=1[CH:41]=[N:40][C:39]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]3)=[CH:46][CH:45]=1)=[N:38]2>>[CH3:66][S:63]([C:60]1[CH:59]=[CH:58][C:57]([C:36]2[N:37]3[C:42]([CH:41]=[N:40][C:39]([NH:43][C:44]4[CH:45]=[CH:46][C:47]([N:50]5[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]5)=[CH:48][CH:49]=4)=[N:38]3)=[C:34]([CH:2]=[CH2:10])[CH:35]=2)=[CH:62][CH:61]=1)(=[O:64])=[O:65]
Reactant: CN1CCN(c2ccc(Nc3ncc4c(Br)cc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Reactant: COc1ccccc1-c1cc(Br)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Product: C=Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc12
Yield: 63 %

Procedure:
The tited compound was prepare in an analogous fashion to Example 103 replacing [5-Bromo-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine with [5-Bromo-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine to give [7-(4-Methanesulfonyl-phenyl)-5-vinyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (45 mg, 63%). LCMS (E/I+) 489.21 (M+H). NMR 1H (DSMO-d6)-9.23 (s, 1H), 8.99 (s, 1H), 8.48 (d, 2H, J=8.44 Hz), 8.07 (d, 2H, J=8.56 Hz), 7.66 (d, 2H, J=9.01 Hz), 7.00-7.18 (m, 2H), 7.00 (d, 2H, J=8.88 Hz), 5.82 (d, 1H, J=16.95 Hz), 5.21 (d, 1H, J=12.21 Hz), 3.80 (s, 3H), 3.02 (t, 4H, J=4.60 Hz), 2.44 (t, 4H, J=4.72 Hz), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[C:29]([F:33])[C:30]=1[CH2:31][F:32].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([O:21][C:27]4[CH:26]=[C:25]([F:24])[C:30]([CH2:31][F:32])=[C:29]([F:33])[CH:28]=4)=[O:20])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)CC1
Reactant: Oc1cc(F)c(CF)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(=O)Oc4cc(F)c(CF)c(F)c4)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
First, 1.5 g (4.8 mmol) of 4-(trans-4-(trans-4-ethylcyclohexyl)cyclohexyl)benzoic acid, 0.8 g (4.8 mmol) of 3,5-difluoro-4-fluoromethylphenol, 0.2 g (1.4 mmol) of DMAP, and 25 ml of dichloromethane were mixed. To this mixture was added dropwise 5 ml of dichoromethane solution containing 1.2 g (5.7 mmol) of DCC at room temperature in 5 minutes, and reacted as they were while stirring for 12 hours. The crystal thus precipitated were filtered off. Toluene in an amount of 30 ml was added to the filtrate, and washed with 2N-sodium hydroxide 5 times and water thrice, and then dried over anhydrous magnesium sulfate. Solvent was distilled off at a reduced pressure and the residue was subjected to a silica gel column chromatography (eluent: toluene) to obtain 2.1 g of a crude 3,5-difluoro-4-fluoromethylphenyl 4-(trans-4-(trans-4-ethylcyclohexyl) cyclohexyl)benzoate. This product was recrystallized from a mixed solvent of heptane/ethyl (1/1) acetate to obtain 1.9 g (yield: 86.3%) of the subject compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:13].CN(C)C(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([Br:1])[N:3]=2)=[CH:18][CH:17]=1)[CH3:13]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Nc2nc(Br)cn3ccnc23)cc1
Temperature: 160 °C

Procedure:
A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (0.18 mol), 4-aminobenzoic acid ethyl ester (2) (0.18 mol), and N,N-dimethylacetamide (30 mL) is heated at 160° C. for 30 min. The mixture is cooled to room temperature, treated with ethyl acetate (150 mL), stirred, and filtered to afford an orange/brown solid. This solid is slurried with ethyl acetate and saturated sodium bicarbonate solution to give 4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid ethyl ester (18) freebase.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[S:25])[NH2:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.O.O.[OH-].C(=O)(O)[O-].[Mg+2].[O:37]1[C:41]2[CH:42]=[CH:43][C:44]([C@@H:46]([CH2:53][C:54](=O)[CH2:55]Cl)[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:45][C:40]=2[O:39][CH2:38]1>O1CCOCC1>[O:37]1[C:41]2[CH:42]=[CH:43][C:44]([C@@H:46]([CH2:53][C:54]3[N:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[S:25][CH:55]=3)[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:45][C:40]=2[O:39][CH2:38]1
Reactant: CC(C)(C)[Si](OCCCCC(N)=S)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C[C@H](CC(=O)CCl)c1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C[C@H](Cc1csc(CCCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n1)c1ccc2c(c1)OCO2
Temperature: 60 °C

Procedure:
Dissolve 5-{[tert-butyl(diphenyl)silyl]oxy}pentanethioamide (4.97 g, 13.37 mmol) in 1,4-dioxane (50 mL). Add magnesium carbonate hydroxide pentahydrate (3.25 g, 0.5 mmol) and (3S)-ethyl 3-(1,3-benzodioxol-5-yl)-6-chloro-5-oxohexanoate (see Scheme 2, Example M) (4.18 g, 13.37 mmol). Heat to 60° C. for 5 hrs. Upon cooling, the reaction was filtered through a pad of celite and concentrated in vacuo, and purified via silica gel chromatography (eluent: 9:1 Hexane:Ethyl Acetate) to give the product as a yellow oil. Yield: 6.55 g (78%) 1H NMR (DMSO-d6) δ7.64–7.58 (m, 4H), 7.48–7.39 (m, 6H), 6.95–6.93 (m, 1H), 6.85–6.82 (m, 1H), 6.73–6.69 (m, 1H), 5.92 (s, 2H), 3.93–3.85 (q, 2H), 3.70–3.64 (t, 2H), 3.46–3.38 (m, 1H), 3.00–2.85 (m, 4H), 2.68–2.53 (m, 2H), 1.83–1.74 (m, 2H), 1.62–1.53 (m, 2H), 1.08–0.99 (t, 3H), 0.99 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[F:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:24][C:25]1[N:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[N:8][C:7]=4[C:6]=3[CH:23]=2)=[CH:27][CH:26]=1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: OB(O)c1ccc(F)nc1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc(F)nc3)cc1-2
Yield: 30 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 6-fluoropyridin-3-ylboronic acid were reacted to give 495 (0.346 g, 30%). 1H NMR (500 MHz, DMSO) δ 8.68 (d, J=2.3, 1H), 8.55 (s, 1H), 8.28 (td, J=8.3, 2.5, 1H), 8.13 (s, 1H), 7.68 (dd, J=8.4, 2.3, 1H), 7.35 (dd, J=8.6, 2.7, 1H), 7.22 (d, J=8.4, 1H), 5.77 (dt, J=13.1, 6.6, 1H), 4.43 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 1.51 (dd, J=54.9, 6.6, 6H). MS (ESI(+)): m/z 408.1 (M+H)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[N:8]([CH:21]1[CH2:24][CH2:23][CH2:22]1)[C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:21]1([N:8]([C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]2[NH:2][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[C:9](=[O:20])[C:10]2[C:11]([O:18][CH3:19])=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:24][CH2:23][CH2:22]1
Reactant: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1

Procedure:
To a solution of N-[(1S,2S)-2-aminocyclopentyl]-N-cyclobutyl-2,6-dimethoxybenzamide hydrochloride (Intermediate 18; 200 mg, 0.56 mmol) in dry DMSO (1.9 ml) was added 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 153 mg, 0.85 mmol) and DIPEA (295 μl, 1.69 mmol). The reaction subjected to microwave irradiation at 150° C. for 2 hours and then was partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. This was then purified using column chromatography (silica, 0-100% ethyl acetate/petrol) and then further purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.[CH3:25]CO.[ClH:28]>>[CH2:1]([O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[NH2:7])[CH3:25].[ClH:28]
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](O)CN(N)Cc1ccc(Br)cc1

Procedure:
A solution of (R)-3-[N-(4-bromobenzyl)-N′-t-butoxycarbonylhydrazino]-2-hydroxypropionic acid methyl ester (25 g, 62 mmol) in EtOH/HCl (1M, 310 mL, 0.3 mol) was stirred overnight until the reaction was complete. The mixture was then concentrated and the residue was washed with EtOAc (120 mL) and filtered. The solids were collected to yield the title compound as a white solid HCl salt (15 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[CH:27]=[O:28].[CH3:32][N:33]([CH3:36])[CH:34]=[S:35]>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:27]([OH:28])[C:34](=[S:35])[N:33]([CH3:36])[CH3:32])[CH:29]=1
Reactant: COc1ccc(F)cc1C=O
Reactant: CN(C)C=S
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1ccc(F)cc1C(O)C(=S)N(C)C
Temperature: -78 °C
Yield: 28000.7 %

Procedure:
To a solution of lithium diisopropylamide, 2M in THF/n-heptane (210 mL, 583 mmol) was added THF (100 mL) and the solution cooled to −78° C. under nitrogen. This was then added dropwise over 1 h to a solution of the 5-fluoro-2-methoxybenzaldehyde (50 g, 0.32 mmol) and N,N-dimethylthioformamide (34.7 g, 389 mmol) in dry THF (200 mL). This was warmed to −5° C. and quenched with water (400 mL). The solution was filtered and washed with diethyl ether, the aqueous layer was extracted with ether (1 L). The combined organic layers were washed with water (500 mL), dried (MgSO4) and the solvent removed in vacuo to give a crystalline suspension in oil. This was triturated in ether and filtered to give a crystalline solid (21.8 g, 28%); δH (300 MHz, CDCl3) 7.16-6.81 (3H, m, ArH), 5.81-5.75 (1H, m, CHOH), 5.31-5.22 (1H, m, OH), 4.89 (3H, s, OCH3), 3.50 (3H, s, N(CH3)2) and 3.08 (3H, s, N(CH3)2).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>>[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:39]=[CH:38][C:36]([NH:37]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(-c2ncc[nH]2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2ncc[nH]2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(imidazol-2-yl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C26H20N4O3
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:38])(=[O:37])[N:26]([CH2:32][CH2:33][CH2:34][C:35]#[N:36])[CH2:27][CH2:28][CH2:29][C:30]#[N:31])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[C:30]([CH2:29][CH2:28][CH2:27][N:26]([CH2:32][CH2:33][CH2:34][C:35]#[N:36])[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:23][CH2:22]2)(=[O:38])=[O:37])#[N:31]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)N(CCCC#N)CCCC#N)C4(CC4)C3)ncnc21
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N#CCCCN(CCCC#N)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-{4-[Bis-(3-cyano-propyl)-sulfamoyl]-4,7-diaza-spiro[2.5]oct-7-yl}-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 19) was dissolved in THF (1 mL), added TFA (0.5 mL) and then stirred at rt for 2 h. The crude reaction mixture was concentrated in vacuo and redissolved in MeOH (0.5 mL). The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [C:1]1([S:7]/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>C(O)(=O)C.O>[C:1]1([S:7](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: CCOC(=O)C[C@@H](NC(=O)/C=C/Sc1ccccc1)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C[C@@H](NC(=O)/C=C/S(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 36 h
Yield: 63 %

Procedure:
Diethyl N-[3-phenylthio-2(E)-propenoyl]-(R)-aspartate (3.51 g, 10 mmol) was dissolved in glacial acetic acid (30 ml) and a 30% solution of hydrogen peroxide (1.4 ml) was added and the mixture was stirred at room temperature for 36 hours, then diluted with water (100 ml) and extracted twice with dichloromethane (50 ml each). The organic phase was dried over anhydrous sodium sulfate, the solvents were evaporated and the residue was suspended in carbon tetrachloride and filtered to give a crude product which was recrystallised from toluene, yielding the desired product (2.3 g, 63%).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([C:4]3[N:3]=[C:2]([C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH:5]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: CN1CCC(c2ccc(-c3cc4nccn4c(Cl)n3)cc2)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cn[nH]c4)n3)cc2)CC1
Temperature: 100 °C
Yield: 23.6 %

Procedure:
5-Chloro-7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidine (0.120 g, 0.367 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.107 g, 0.551 mmol) and potassium carbonate (0.152 g, 1.10 mmol) were suspended in a mixture of DME (5 mL) and water (2 mL) and purged with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.02121 g, 0.01836 mmol) was added and the reaction sealed and heated at 100° C. for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with water and filtered. The solids were washed with acetone and then dried under high vacuum to afford 7-(4-(1-methylpiperidin-4-yl)phenyl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.0310 g, 0.0865 mmol, 23.55% yield). MS (apci) m/z=359.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].C1COCC1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2c1cccc(Br)c1

Procedure:
The title compound was synthesized from methyl 4-(3-bromophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.315 g, 0.98 mmol) and lithium hydroxide (0.415 g, 9.9 mmol), according to General Procedure 7. A 1:1 mixture of THF and methanol (8 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound. 0.119 g (40% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.16 (ddt, J=12.67, 8.50, 6.30, 6.30 Hz, 1H), 2.67-2.93 (m, 3H), 4.13 (t, J=7.20 Hz, 1H), 6.54 (s, 1H), 7.11-7.17 (m, 2H), 7.26-7.32 (m, 2H); LCMS (ESI+) 328.0 (M+Na); HPLC (UV=93.7%), (ELSD=99.9%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Clc1ccc(I)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and l-chloro-4-iodobenzene according to the general procedure C. Obtained as a yellow solid (779 mg).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][N:13]2[C:31]([O:32][CH3:33])=[O:34])=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: COC(=O)C1CCNC(c2ccc(S(C)(=O)=O)cc2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 107.5 %

Procedure:
Methyl 2-(4-(methylsulfonyl)phenyl)piperidine-4-carboxylate hydrochloride (5.2 g, 15.58 mmol) and DIPEA (6.78 mL, 38.94 mmol) were dissolved in DCM (40 mL) and methyl carbonochloridate (1.472 mL, 18.69 mmol) added. The reaction was stirred at room temperature for 50 min. DCM (160 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo yielding crude dimethyl 2-(4-(methylsulfonyl)phenyl)piperidine-1,4-dicarboxylate (5.95 g, 108%). MS m/z 356 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccc(F)cc3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 4-fluoro-benzenesulfonyl chloride (73 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide (121 mg, 81.3%) as a white solid. MS (ESI+APCI) M+1=479.1.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[C:28]([N+:30]([O-])=O)[CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[C:17]([F:33])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>O.CC(C)=O.[Zn]>[NH2:30][C:28]1[CH:29]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][C:17]=2[F:33])[CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cc([N+](=O)[O-])c3[nH]ccc3c2)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cc(N)c3[nH]ccc3c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
Zn dust (123 mg, 1.88 mmol) was added to a solution of N-(tert-butyl)-3′-fluoro-4′-(7-nitro-1H-indol-5-yl)-[1,1′-biphenyl]-2-sulfonamide (23 mg, 0.19 mmol) and NH4Cl (101 mg, 1.88 mmol) in water (0.75 mL) and acetone (3.76 mL). The mixture was stirred at rt for 1 hour and then filtered through Celite. The resulting filtrate was concentrated to dryness and then taken up in water and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated to dryness to give the title compound (23 mg, 28%). MS (ESI): mass calcd. for C24H24FN3O2S, 437.16; m/z found, 438.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=8.0, 1.3, 1H), 8.17-8.10 (m, 1H), 7.63-7.56 (m, 2H), 7.54-7.48 (m, 1H), 7.42 (s, 1H), 7.38 (dd, J=7.8, 1.7, 2H), 7.32 (dd, J=11.4, 1.8, 1H), 6.86 (m, 1H), 6.62 (dd, J=3.2, 2.0, 1H), 3.78-3.68 (m, 2H), 1.05 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].[OH-].[Na+]>>[C:15]([NH:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1)(=[O:17])[CH3:16]
Reactant: CN1CCc2c(N)ccc(Cl)c2CC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(Cl)c2c1CCN(C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 10.5 g. (0.05 mole) of 9-amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 50 ml. of acetic anhydride is stirred and heated at 60°-65° C. for 4 hours. The resulting solution is poured into ice/water and stirred at 25° C. for 16 hours, then it is made alkaline by addition of sodium hydroxide at 5°-10° C. The precipitate is immediately filtered to give 9-acetamido-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.