Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:2][C:3]([OH:5])=[O:4])=[CH:13][CH:12]=1)(=[O:10])[CH3:8]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccc(NCC(=O)O)cc1
Yield: 90 %

Procedure:
Chloroacetic acid (40 mmol) was neutralized with aqueous 2N NaOH (50 mmol), then 4-aminoacetophenone was added (25 mmol) was added to the above solution, and the whole reaction mixture was refluxed for 5 hrs. Cooled the reaction mixture, and the solid separated was filtered and washed with water. The solid was recrystallized from aqueous ethanol to get pure 2-((4-acetylphenyl)amino)acetic acid (4.2 g, 90% yield). To a solution of 1-(4-methoxyphenyl)piperazine (0.6 mmol) and 2-((4-acetylphenyl)amino)acetic acid (0.66 mmol) (obtained from the above reaction step) and DMAP (cat) in dichloromethane was added EDCI (0.8 mmol), and the resulting reaction mixture was stirred for 8 h. The reaction mixture was diluted with ethyl acetate and washed with dilute HCl solution, saturated NaHCO3 solution, water and brine solution. Dried the solution with sodium sulfate and concentrated to give crude mass which on silica gel chromatography eluting with 0.6% methanol in dichloromethane provided TG2-150 (70% yield). Similar synthetic procedures were used for making the compounds listed in Table 1 and Table 2.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.CCN(CC)CC.[F:25][C:26]1[C:27]2[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:35]=[CH:34][C:28]=2[S:29][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[F:25][C:26]1[C:27]2[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:35]=[CH:34][C:28]=2[S:29][C:30]=1[C:31]([N:1]1[CH2:2][CH:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:9][CH2:10]2)[CH2:4]1)=[O:32]
Reactant: O=C(Cl)c1sc2ccc(-c3ccccc3)cc2c1F
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nccs1)N1CCN(C2CN(C(=O)c3sc4ccc(-c5ccccc5)cc4c3F)C2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a solution of compound 5e (42.7 mg, 0.131 mmol) and Et3N (0.07 mL, 0.5 mmol) in CH2Cl2 (2 mL) at 0° C. was slowly added a solution of compound 52e (36.3 mg, 0.125 mmol) in CH2Cl2 (1 mL). The reaction was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 2% MeOH/EtOAc) to give compound Cpd 1315 (16.7 mg). 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J=1.2 Hz, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.80-7.86 (m, 1H), 7.73 (dd, J=8.6, 1.7 Hz, 1H), 7.62-7.68 (m, 2H), 7.55 (d, J=3.2 Hz, 1H), 7.46-7.53 (m, 2H), 7.37-7.44 (m, 1H), 4.22-4.67 (m, 5H), 4.05-4.20 (m, 1H), 3.77-4.01 (m, 2H), 3.25-3.37 (m, 1H), 2.42-2.68 (m, 4H). MS m/z (M+H+) 507.0.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH:11]=[N+:12]([CH3:14])[O-:13])C.C(N1C([N+]([O-])=O)=CN=C1C=[N+](C)[O-])CC.CN1C([N+]([O-])=O)=CN=C1C=[N+](CC1C=CC=CC=1)[O-].Cl.C(NO)C1C=CC=CC=1.CN1C([N+]([O-])=O)=CN=C1C=O>>[CH3:1][N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH:11]=[N+:12]([CH3:14])[O-:13]
Reactant: CCn1c([N+](=O)[O-])cnc1C=[N+](C)[O-]
Agent: CCCn1c([N+](=O)[O-])cnc1C=[N+](C)[O-]
Agent: Cl
Agent: Cn1c([N+](=O)[O-])cnc1C=O
Product: Cn1c([N+](=O)[O-])cnc1C=[N+](C)[O-]

Procedure:
The corresponding α-(1-ethyl-5-nitroimidazol-2-yl)-N-methylnitrone, α-(1-propyl-5-nitroimidazol-2yl)-N-methylnitrone, and α[1-(2'-acetoxyethyl)-5-nitroimidazol-2-yl]-N-methylnitrone can be prepared in a similar fashion utilizing the respectively 1-substituted-2-formyl-5-nitroimidazoles disclosed in Examples 3 and 5. The corresponding α-(1-methyl-5-nitroimidazol-2-yl)-N-benzylnitrone can also be prepared using N-benzylhydroxylamine hydrochloride in the above reaction with 1-methyl-2-formyl-5-nitroimidazole.
Reaction SMILES: C([C:3]([C:12]#[N:13])([CH:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])[C:4]([OH:6])=[O:5])C.CO.[OH-].[Na+]>O1CCCC1>[C:12]([CH:3]([CH:7]([CH:9]1[CH2:10][CH2:11]1)[CH3:8])[C:4]([OH:6])=[O:5])#[N:13]
Reactant: CCC(C#N)(C(=O)O)C(C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C1CC1)C(C#N)C(=O)O
Yield: 86.1 %

Procedure:
39.8 g (0.22 mol) of ethyl 2-cyano-3-cyclopropylbutanoic acid were refluxed for 4 hours in a mixture of in each case 150 ml of methanol, tetrahydrofuran and 2 N sodium hydroxide solution. For working-up, 200 ml of 2 N sodium hydroxide solution were added and the mixture was extracted repeatedly with diethyl ether. The aqueous phase was subsequently acidified by adding hydrochloric acid and also extracted with ether. After this organic phase had been dried and concentrated, 29 g (yield 86%) of 2-cyano-3-cyclopropylbutanoic acid were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.CC(O)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCCC3)cc1)C2c1ccc(F)cc1
Reaction time: 8 h
Yield: 26.2 %

Procedure:
To a stirred mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (0.1 g, 0.26 mmol) in anhydrous DCM (4 mL) was added AcOH (94 mg, 1.56 mmol) at 25° C. for 0.5 h, then pyrrolidine (37 mg, 0.52 mmol) was added at 25° C., stirred overnight. NaBH(OAc)3 was added at ice bath, and stirred for 5 h. The mixture was concentrated to give the crude product. The crude product was dissolved in ethyl acetate and to this solution was added 2N HCl (10 mL). The aqueous phase was separated and 20% NaOH (20 ml) was added. The mixture was extracted with ethyl acetate and the organic phase was separated to give the title compound (30 mg, yield 26%). LC-MS (ESI) m/z: 441(M+1)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]O)=O.COC1(C2C(C)[C:27]34C[CH:24]([O:25][C:26]3=[CH:33][C:32](=O)[C:31]([O:35]C)=[CH:30]4)C2)C=CC=C(OC)C1.CCCCCC.C(OCC)(=O)C>ClCCl.C(OCC)(=O)C>[CH2:5]([O:7][C:33]1[CH:32]=[C:31]([OH:35])[CH:30]=[CH:27][C:26]=1[O:25][CH3:24])[C:4]1[CH:3]=[CH:2][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC1=CC=CC(OC)(C2CC3CC4(C=C(OC)C(=O)C=C4O3)C2C)C1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(O)cc1OCc1ccccc1

Procedure:
3-chloroperoxybenzoic acid (9.9 g, 0.0343 mols), in small portions, is added to a stirred solution of 3-benzyloxy-4-methoxybenzaldehyde (201, prepared as described in Example 66) (7.57 g, 0.0313 mols) in dicloromethane (100 ml) over a thirty minute period With vigorous shirring. The reaction flask is fitted with a condensor and the contents is heated to reflux for six hours and monitored by TLC using 2:1 hexane-ethyl acetate as eluant. The reaction is filtered off the 3-chlorobenzoic acid (which precipitates out of solution) and the filtrate is washed with saturated sodium bicarbonate followed by water and dried in vacuo to an oil which eventually solidifies. The solid is subsequently dissolved in distilled methanol (80 ml) and heated to reflux under nitrogen. TLC using hexane-ethyl acetate as the eluant shows almost complete conversion after two hours and forty five minutes. The solvent is removed in vacuo no produce a dark oil which is redissolved in a small amount of ethyl acetate and purified by column chromatography on silica gel (2:1 hexane-ethyl acetate as eluant). The major fraction from the column is combined and concentrated in vacuo to a solid (4.68 g, 64.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[C:43](O)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:23][CH2:24][N:25]([C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:26][CH2:27]2)[C:19]=1[CH3:20])=[O:13]
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Reactant: CC(C)(C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)C(C)(C)C)CC1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(piperidin-4-yl)amino)-4-methyl-4′-(morpholinomethyl)[1,1′-biphenyl]-3-carboxamide (0.2 g, 0.34 mmol) was dissolved in DMSO (2 mL) and pivalic acid (0.107 g, 1.04 mmol) and triethyl amine (0.106 g, 1.04 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (0.27 g, 0.52 mmol) was added to it and stirring was continued for overnight. After completion of the reaction, reaction mixture was poured into ice, extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated to obtain crude; which then purified by column chromatography to afford the title compound (0.14 g, 60.86%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si](C(C)C)(C(C)C)C(C)C)[CH:6]=[CH:5]2.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C1(C)C(C)=CC=CC=1>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:24][CH2:23]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: CN1CCN(c2ccc3[nH]ccc3c2)CC1
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
5-Bromo-1-triisopropylsilyl-indole (5.8 g, 16.4 mmol), N-methylpiperazine (1.8 g, 18 mmol), NaOt-Bu (2.2 g, 23 mmol), Pd(OAc)2 (37 mg, 0.16 mmol), Pt—Bu3 (66 mg, 0.33 mmol) and, xylene (30 mL) were mixed and heated to 130° C. under stirring for 5 h. The crude material was chromatographed on a silica columns using DCM/MeOH 95/5 as eluent. Concentration of the main fractions left 5.6 g of an oil which was dissolved in MeCN (10 mL), 20 mL of a 1 M solution of tetrabutylammonium fluoride in THF was added and the mixture left over-night. The reaction mixture was put on a silica column and eluted, with DCM/MeOH 95/5 to give the product as an oil (2 g, 9.3 mmol; yield 57%) 1H NMR (CDCl3) δ 2.37 (3H, s), 2.64 (4H, t, J=5), 3.19 (4H, t, J=5), 6.44-6.48 (1H, m), 6.95-7.00 (1H, m), 7.16 (1H, d, J=3), 7.18 (1H, d, J=2), 7.29 (1H, d, J=9) and 8.12 (1H, bs).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]=[C:7]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)C.Cl.[OH-].[Na+].C(O)(=O)/C=C\C(O)=O>O.CCO>[CH3:1][NH:2][CH2:4][CH2:5]/[CH:6]=[C:7]1\[C:8]2[C:13]([CH2:14][O:15][C:16]3[C:17]\1=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CN(C)CCC=C1c2ccccc2COc2ccccc21
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNCC/C=C1\c2ccccc2COc2ccccc21
Reaction time: 8 h

Procedure:
(E)-Desmethyldoxepin is prepared from doxepin hydrochloride as follows. Doxepin hydrochloride (E/Z=85/15) (55.0 g, 0.174 mol) is dissolved in 600 mL H2O, made basic with 6M NaOH, and extracted with CHC13 (3×600 mL). The CHC3 extracts are combined, dried over Na2SO4, and solvent removed in vacuo. The resulting oil is dissolved in 250 mL EtOH, then 21.15 g (0.182 mol) of maleic acid dissolved in 100 mL EtOH is added slowly, with stirring, followed by an additional 350 mL EtOH. The resulting cloudy solution is refluxed until it becomes clear, then allowed to stand overnight at room temperature; the resulting crystals are isolated by vacuum filtration. Additional recrystallization from EtOH yields a white crystalline product (E)-Doxepin maleate) with an E/Z ratio of 98/2. (E)-Doxepin maleate (2.50 g, 6.32 mmol) is then partially dissolved in 60 mL H20, made basic with 6M NaOH, and extracted with CHC13 (3×60 mL). The CHC13 extracts are combined, washed with 60 mL brine, dried over Na2SO4, and solvent removed in vacuo. The resulting oil is re-dissolved in 10 mL CHC13, 1.8 mL (13 mmol) of triethylamine added, 1.8 mL (13 mmol) of 2,2,2-trichloroethylchloro-formate added, and reaction stirred under N2 for 3.5 hours. The completed reaction is then diluted with 140 mL Et2O, washed successively with 0.5M HCl (2×140 mL), H20 (140 mL), and brine (140 mL), then dried over MgO4 and solvent removed in vacuo. Resulting material is further purified by silica gel column chromatography, eluting with EtOAc/Hex (20/80), to afford 1.48 g (3.36 mmol) of the desired product as a clear oil. The N-protected (E)-desmethyldoxepin intermediate (1.44 g, 3.27 mmol) is then dissolved in 12 mL THF, 2.88 g of zinc powder added, 2.3 mL of 1M sodium phosphate (pH=5.5) added, and reaction stirred for 17 hours. The reaction mixture is then vacuum filtered, filtrate solvent removed in vacuo, and resulting residue purified by silica gel column chromatography, eluting with THF/MeOH/NH4OH (85/15/0.4), then THF/MeOH/NH4OH (75/25/0.4), to afford 744 mg (2.80 mmol) of the desired product as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28]>C1COCC1>[NH2:20][C:4]1[N:3]=[C:2]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[CH2:34][CH2:33]2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Solvent: C1CCOC1
Product: Nc1nc(N2CCN(c3ccc(Cl)c(Cl)c3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 150 °C
Yield: 5.9 %

Procedure:
To a solution of 2-chloro adenosine (80 mg, 0.27 mmol) in THF (4 mL) was added 4-(3,4-dichlorophenyl)piperazine (122 mg, 0.53 mmol) and the resulting solution heated in a Biotage microwave (150° C., absorption high, pre-stirring 30 s) for 30 min. The solvents were then removed in vacuo and the residue purified twice by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 18 min, product eluted in 80% acetonitrile) and (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 9 min, product eluted in 55% acetonitrile) to yield (2R,3R,4S,5R)-2-(6-amino-2-(4-(3,4-dichlorophenyl)piperazin-1-yl)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol 8 as a white solid (7.9 mg, 6%)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([N:14]3[CH2:19][CH:18]4[CH:16]([C:17]4([C:21]4[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=4)[CH3:20])[CH2:15]3)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][N:14]3[CH2:19][CH:18]4[CH:16]([C:17]4([C:21]4[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=4)[CH3:20])[CH2:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccc4c(c3)OCO4)CC21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3ccc4c(c3)OCO4)CC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a solution of N-(3-{3-[3-(1,3-benzodioxol-5-yl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide (Preparation 120, 96 mg, 0.22 mmol) in anhydrous tetrahydrofuran (2 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.44 ml, 0.44 mmol) and the mixture was stirred at room temperature for 3 h. The rapidly stirred reaction mixture was treated sequentially with water (0.44 ml), sodium hydrogen carbonate (400 mg) and ethyl acetate (10 ml). After 30 min the reaction mixture was filtered and concentrated in vacuo to afford a colourless oil. This was purified by preparative HPLC (condition 8) to give a pale yellow oil which was partitioned between dichloromethane (10 ml) and aqueous potassium carbonate solution (4% w:v, 5 ml). The layers were separated and the organic layer was washed with water (3 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (32 mg, 34%). The free base (23 mg, 0.054 mmol) was dissolved in anhydrous diethyl ether (5 ml) and dichloromethane (1 ml) and the solution was treated with hydrogen chloride (1.0M solution in diethyl ether, 0.06 ml). The heterogeneous suspension was concentrated in vacuo to afford the hydrochloride salt of the title compound as a white solid (20 mg, 80%).
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:51]([O:53][C:54](=[O:75])[C@H:55]([O:57][C:58]1[CH:63]=[C:62](Cl)[N:61]=[C:60]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([F:73])[C:68]=2[F:74])[N:59]=1)[CH3:56])[CH3:52]>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].O1CCOCC1>[CH2:51]([O:53][C:54](=[O:75])[C@H:55]([O:57][C:58]1[CH:63]=[C:62]([NH:10][S:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:9])=[O:8])[N:61]=[C:60]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([F:73])[C:68]=2[F:74])[N:59]=1)[CH3:56])[CH3:52]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of 4-morpholinesulfonamide (prepared according to patent WO 2004/011443, 0.19 g), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (52 mg), cesium carbonate (0.38 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy](2R)-propanoic acid ethyl ester (the product of Example 23 step i) (0.30 g) and dioxane (10 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:1) as eluent to give the subtitle compound as an oil. Yield: 0.34 g
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][N:28]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[C:33]=1[CH3:47])[C:27]2=[O:48].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:18][O:17][C:15]([C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:2]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([N:28]5[C:27](=[O:48])[C:26]6[C:31](=[C:22]([F:21])[CH:23]=[CH:24][CH:25]=6)[N:30]=[CH:29]5)[C:33]=4[CH3:47])=[N:3][CH:4]=[C:5]([C:19]#[N:20])[C:6]=3[NH:7][C:8]=2[CH:9]=1)=[O:16]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1cnc2c(F)cccc2c1=O
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(Cl)c12
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: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(-c3cccc(-n4cnc5c(F)cccc5c4=O)c3C)c12
Temperature: 110 °C
Yield: 34 %

Procedure:
A stirred mixture of methyl 1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate (0.285 g, 0.998 mmol), 8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one (0.379 g, 0.998 mmol), Tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.050 mmol) and Sodium carbonate[2M aqueous] (0.499 mL, 0.998 mmol) in Dioxane (2 mL) was heated at 110° C. for 16 hours overnight. LC-MS showed complete conversion to the desired product mass plus residual starting material[boronic ester] and a byproduct. The reaction mixture was concentrated. The residue was taken up in 10 ml DMF, stirred and filtered. The filtrate was concentrated; the residue triturated with methanol and filtered. The solid residue labeled 89040-079-04 was dried overnight. LC-MS showed the solid residue to be the desired product Methyl-4-cyano-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate as a tan solid [0.172 g, 0.342 mmol, 34% yield]. The product had an HPLC Retention Time=3.510 min [mixture of rotamers][4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 504.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH:25]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:13][C@@H:12]1[CH3:42])(=[O:10])[CH3:9]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:25]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:13][C@@H:12]1[CH3:42])(=[O:10])[CH3:9]
Reactant: CC(=O)N1c2ccc(-c3cn(CCC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1c2ccc(-c3cn(CCC(=O)O)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 16 h
Yield: 78 %

Procedure:
Trifluoracetic acid (1 ml) was added to a solution of 1,1-dimethylethyl 3-{(cis)-4-[1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}propanoate (for a preparation see Example 91) (1.06 g, 2.19 mmol) in DCM (5 mL). The reaction mixture was allowed to stand at room temperature for 16 h then most of the solvent were removed in vacuo. The residue was co-evaporated twice with toluene then triturated with Et2O to give 3-{(cis)-4-[1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}propanoic acid trifluoroacetate (920 mg, 1.696 mmol, 78%) as an off-white solid.