Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=O)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C=O)c2)c1F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CN2CCOCC2)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (40 mg, 0.071 mmol) and morpholine (6.18 mg, 0.071 mmol) were mixed in 1,2-dichloroethane (2 mL) and treated with sodium triacetoxyborohydride (21 mg, 0.099 mmol) and acetic acid (4.06 μl, 0.071 mmol). The mixture was stirred at RT for 1 h then TFA (2 ml, 26.0 mmol) was added to the solution and stirred for 30 min. The solvent was removed under vacuum and the crude product was purified by Reverse Phase HPLC (MeCN/water 0.1% formic acid) to give 30 mg (84%) of the title compound as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 8.08 (s, 1H), 7.61-7.81 (m, 1H), 7.46 (s, 1H), 7.29-7.41 (m, 2H), 7.24 (s, 1H), 7.08-7.19 (m, 1H), 4.63 (s, 2H), 3.52-3.84 (m, 4H), 2.53 (m., 4H). LC-MS (ES+) m/z 502.9 [M+1].
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][S:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([C:18]3[CH:23]=[C:22]([O:24][S:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)(=[O:27])=[O:26])[CH:21]=[N:20][CH:19]=3)[NH:8]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cncc(OS(=O)(=O)N3CCCC3)c2)cc2ccc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Oc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1)N1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Chloro-2-[5-(pyrrolidine-1-sulfonyloxy)-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester is dissolved in DCM (2 mL), and the mixture is cooled to 0° C. TFA (2 mL) is added and the mixture is stirred at room temperature for 1 h. Saturated sodium bicarbonate is then added and the mixture is extracted with DCM. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford pyrrolidine-1-sulfonic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester as an oil which is taken onto the next step without further purification. MS (ESI) m/z 376.2 (M+H)+.
Reaction SMILES: CN([CH:4]=[O:5])C.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].IC>O>[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:5][CH3:4])=[O:10]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 40 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
With reference to FIG. 4, DMF (130 mL) was added to a well mixed 2-methyl-3-nitrobenzoic acid 2 (50 g, 0.28 mol) and KHCO3 (84 g, 0.84 mol) solution. Since the mixture became highly viscous, it was heated to 40° C. with manual shaking. Iodomethane (79 g, 0.56 mol) was added via syringe after the gas evolution had ceased. The resulting orange colored solution was stirred for 12 hours at room temperature. The reaction mixture was poured into water (800 mL), and the resulting precipitate collected by filtration and dried over P2O5 to give pure methyl 2-methyl-3-nitrobenzoate 3 (56 g, 100%) as a white solid: mp. 64.2–65.5° C.; 1H-NMR (CDCl3) δ 8.00 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 3.95 (s, 3H), 2.63 (s, 3H); IR (KBr, cm−1) 1724, 1548, 1279; MS (EI): 195 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:21][O:22][C:23]([C:25]1[CH2:26][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:28][CH2:29][C:30]=1OS(C(F)(F)F)(=O)=O)=[O:24].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:21][O:22][C:23]([C:25]1[CH2:26][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:28][CH2:29][C:30]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)=[O:24]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(OCc3ccccc3)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a sol. of 4-benzoxy-bromo-benzene (18.4 g, 70.0 mmol) in THF (450 mL) at −78° C. was added BuLi (1.6M in hexane, 50.0 mL, 80.0 mmol). The mixture was stirred for 30 min at −78° C., and ZnCl2 (1M in THF, 86 mL, 86 mmol) was added. The mixture was allowed to warm up to rt. A sol. of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957; 19.5 g, 50.0 mmol) in THF (20 mL) and Pd(PPh3)4 (1.43 g, 1.23 mmol) were added. The mixture was quickly heated to 50° C., and stirred at this temperature for 40 min. Aq. sat. NH4Cl was added, and the mixture was extracted with EtOAc (3×). The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:9→2:8) yielded the title compound (20.8 g, 98%). LC-MS: tR=1.12 min; ES+: 424.25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:21]1C=CN=C1)=O.[OH-].[NH4+]>>[NH2:21][C:16]([CH:14]([O:13][C:10]1[N:11]=[CH:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=1)[CH3:15])=[O:18]
Reactant: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Product: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(N)=O
Yield: 53.5 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 37, 2.6 g of carbonyldiimidazole and 0.7 g of ammonium hydroxide. The product was recrystallized from ethanol to obtain 1.6 g of the desired product, m.p. 179°-181°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=[O:20])[NH:18][CH3:19])=[CH:14][C:13]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=O)=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:39]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17]([NH:18][CH3:19])=[O:20])=[CH:14][C:13]([C:21]2[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:26])[NH:48][C:39]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([CH3:41])[CH3:40])[CH:22]=2)=[CH:12][CH:11]=3)=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-1H-indol-5-yl)benzoic acid (12 mg, 0.031 mmol) and DIPEA (20 μL, 0.115 mmol) in 1,2-dichloroethane (0.5 mL)/DMF (0.1 mL) was added cumylamine (15 μL, 0.10 mmol) and HATU (15 mg, 0.039 mmol). The reaction was stirred at r.t. for 30 min, then the volatiles were evaporated and the residue was purified directly by prep HPLC. Concentration afforded the title compound as a white powder (11 mg, 68% yield). 1H NMR (500 MHz, MeOD) δ ppm 8.52 (s, 1H) 8.09 (d, J=7.93 Hz, 2H) 7.85 (d, J=7.63 Hz, 1H) 7.66-7.77 (m, 3H) 7.49-7.57 (m, 3H) 7.47 (d, J=8.24 Hz, 2H) 7.31 (t, J=7.78 Hz, 2H) 7.23 (t, J=8.85 Hz, 2H) 7.19 (t, J=7.32 Hz, 1H) 2.89 (s, 3H) 1.78 (s, 6H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=3 min, stop time=4 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.49 min, (ES+) m/z (MH+)=506. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=15.29 min, purity=97%; column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=11.59 min, purity=98%.
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1Br)[CH3:5])#[N:2].[NH2-].[Na+]>N>[C:1]([CH:3]1[C:11]2=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=[C:6]2[CH:4]1[CH3:5])#[N:2]
Reactant: COc1ccc(C(C)CC#N)c(Br)c1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: COc1ccc2c(c1)C(C#N)C2C

Procedure:
The bromo compound of Step 3. above (60.4 g) is added dropwise to a refluxing solution of sodium amide (39.0 g) in liquid ammonia (600 ml) over a period of 30 min. The mixture is refluxed for three hours, quenched with ammonium chloride (50.8 g) and evaporated. The residue is taken up in H2O, extracted with CHCl3, the CHCl3 extract is washed with 5% aq. HCl, sat'd NaCl, dried and filtered. The filtrate is stirred with silica gel, filtered and the filtrate evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(Cl)c(N)c1
Yield: 98.3 %

Procedure:
The title compound was prepared using the method of example 32, starting with 4-chloro-3-nitro-benzonitrile (Fluka, 11.0 g, 60 mmol), tin chloride dihydrate (Aldrich, 67.8 g, 300 mmol). 9.0 g (98%) of crude compound 242 was obtained as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([O:15]CC)=O)=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>CCO>[CH3:38][C:28]1[CH:29]=[CH:30][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:32][CH:33]=1.[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:13]([C:11]1[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:9][N:10]=1)=[O:15])[CH2:20]2
Reactant: CCOC(=O)c1ncc(-c2cccc(Cl)c2)o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: O=C(N[C@H]1CN2CCC1CC2)c1ncc(-c2cccc(Cl)c2)o1
Reaction time: 64 h
Yield: 70.9 %

Procedure:
A mixture of the product from Step 79c (0.419 g, 1.66 mmol, 1.0 eq), (R)-(+)-3-aminoquinuclidine (0.221 g, 1.75 mmol, 1.05 eq) and EtOH (4.0 mL) is heated under reflux. After 64 h, the mixture is cooled and the contents are filtered through glass wool into p-toluenesulfonic acid monohydrate (0.315 g, 1.65 mmol, 1.0 eq). The resulting solid is filtered and dried in vacuity to afford the title compound (0.59 g, 65%). HRMS (FAB) calculated for C17H18ClN3O2+H1 332.1165, found 332.1180.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[CH:8][N:9]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])[C:10](=[O:13])[C:11]=2[CH:12]=1.[BrH:21]>>[BrH:21].[OH:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[CH:8][N:9]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])[C:10](=[O:13])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)C(C)n1ccc2ncc(OC)cc2c1=O
Agent: Br
Product: CC(C(=O)O)n1ccc2ncc(O)cc2c1=O
Temperature: 130 °C
Reaction time: 20 h
Yield: 100.5 %

Procedure:
A resealable pressure-resistant bottle was charged with ethyl 2-(3-methoxy-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoate (0.83 g, 3.0 mmol) (Example 515) and conc. HBr (0.16 ml, 3.0 mmol). The vessel was sealed and the mixture was stirred at 130° C. for 20 hours. The reaction mixture was then concentrated to afford 2-(3-hydroxy-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrobromide (0.95 g, 100% yield) as brown solid. This was carried through crude in the next step. Free base material MS m/z=235.0 [M+1]+. Calc'd for C11H11BrN2O4: 315.1.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([O:17][CH3:18])[C:6](=[O:16])[CH:7]=[C:8]1[C:12](=O)[O:11]C(C)(C)[O:9]1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([O:17][CH3:18])[C:6](=[O:16])[CH:7]=[C:8]([OH:9])[C:12]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[O:11]
Reactant: CON(Cc1ccc(F)cc1Cl)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CS(N)(=O)=O
Product: CON(Cc1ccc(F)cc1Cl)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 45.8 %

Procedure:
Reaction of N-(2-chloro-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide (0.175 g, 0.51 mmol) with methanesulfonamide (0.073 g, 0.77 mmol) as described in the preparation of compound 22 gave 0.089 g (45% yield) of the title amide as a white solid after crystallization from ethyl acetate-hexane; mp=144° C. (decomposition). 1H NMR (400 MHz, CDCl3) δ: 3.36 (3H, s, SO2CH3), 3.71 (3H, s, OCH3), 4.96 (2H, s, NCH2), 6.60 (1H, s, CH), 6.95-7.32 (3H, m, aromatics), 8.96 (1H, broad s, NH). Anal. calcd for C13H14ClFN2O6S: C, 41.00; H, 3.70; N, 7.35; found: C, 41.03; H, 3.61; N, 7.29.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C@@H:4]1[CH3:13].C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C@@H:4]1[CH3:13])[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: CN[C@H]1c2ccccc2CC[C@@H]1C
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@H]3c4ccccc4CC[C@@H]3C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1R,2S)-1,2,3,4-tetrahydro-N,2-dimethyl-naphthalenamine and its enantiomer (0.043 g, 0.25 mmol) (prepared by the method described from Example 6, Step A) and triethylamine (0.104 mL, 0.74 mmol) in 2 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (85 mg, 0.2 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 60-100% of ethyl acetate in hexanes as eluant to give 43 mg of the title compounds, compounds of the present invention as white foam.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]3=[O:24])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCCNS(=O)(=O)c1ccc(N2CCCCCC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCCN1S(=O)(=O)c1ccc(N2CCCCCC2)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
4 g of product obtained in Stage B are heated to reflux for 1 hour with 4 g of sodium acetate in 80 cm3 of acetic anhydride. The mixture is cooled to room temperature and evaporated to dryness, the residue is taken up in 60 cm3 of water, filtered and dried and 3.5 g of expected product are obtained. After crystallization in isopropanol, 2.3 g of product are obtained. M.p. 164°- 165° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:9]=2)[C:4]2[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:48].[ClH:48].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:9]=2)[C:4]2[CH2:25][CH2:26][NH:27][CH2:28][C:3]1=2
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CN(C(=O)OC(C)(C)C)CC5)c(=O)c2)cn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CNCC5)c(=O)c2)cn1
Yield: 23 %

Procedure:
tert-Butyl 9-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (208 mg, 0.442 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (40.6 mg, 23%) as a yellow solid: mp 305-313° C.; 1H NMR (500 MHz, CD3OD) δ 8.80 (d, J=8.1 Hz, 1H), 8.11 (dd, J=8.2, 2.5 Hz, 1H), 7.79 (d, J=7.0 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.11 (dd, J=8.3, 1.8 Hz, 1H), 6.93 (d, J=1.9 Hz, 1H), 6.85 (dd, J=7.1, 2.0 Hz, 1H), 4.40 (s, 2H), 3.71 (s, 3H), 3.46 (t, J=5.9 Hz, 2H), 3.04 (t, J=5.9 Hz, 2H), 2.62 (s, 3H); ESI MS m/z 371 [M+H]+; HPLC (Method B)>99% (AUC), tR=8.9 min.
Reaction SMILES: CN1C(S[C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)(=[O:22])=[O:21])/[CH:9]=2)=NN=N1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=[O:33].N1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[N:19][S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH:9]=[C:8]1[NH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=[O:33]
Reactant: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Reactant: Nc1cccc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(NC2=CC(=NS(=O)(=O)c3cccs3)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
33.8 mg (E)-N-(3-(1-methyl-1H-tetrazol-5-ylthio)-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (12a) was dissolved in 3 ml THF, to which was added 13.7 mg 3-aminobenzoic acid. The resulting orange solution was stirred at r.t. for 30 min and 0.2 ml THF solution containing 1 eq. pyridine was added. The reaction was continued for 30 min. The mixture was diluted to 50 ml with ethyl acetate and washed with 0.5 N NaHSO4 solution, water and brine. Dried over Na2SO4, the organic phase was filtered and the filtrate was concentrated. The residue was washed with dichloromethylene/hexane (1:1) affording the title compound 32.5 mg (74.2%) as a red solid, m.p.: 230° C. (dec.).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[S:37][CH2:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])C(=O)OC(C)(C)C)=[CH:5][CH:4]=1>CCOCC.C(Cl)Cl>[ClH:1].[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:10][NH:11][CH:19]([CH3:21])[CH3:20])[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[S:37][CH2:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:5][CH:4]=1
Reactant: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)NCC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
HCl (4N in dioxane) was added to a solution of tert-butyl 2-(4-fluorophenyl)-3-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (50 mg, 0.092 mmol) in Et2O (4 mL) and DCM (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was taken up into DCM (1 mL), and precipitated with Et2O (15 mL), and the solids were filtered under nitrogen to give 2-(4-fluorophenyl)-3-(isopropylamino)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (30 mg, 63% yield) as a mixture of 2 diastereomers. LCMS (APCI+) [M+H]+ 444.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:18].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[CH:4][C:3]=2[F:18])[CH:21]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)c(F)c1
Product: COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-chloro-2-methoxybenzene boronic acid.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C[O-].[Na+].[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([CH2:17][C:18]#[N:19])=O)=[CH:13][CH:12]=1>C(O)C>[NH2:19][C:18]1[N:3]([C:4]([NH2:6])=[O:5])[N:2]=[C:15]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:21][CH:20]=2)[CH:17]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: NNC(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)n1nc(-c2ccc(F)cc2)cc1N
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
To a stirred solution of 12.0 g of semicarbazide hydrochloride in 200 ml of ethyl alcohol is added 5.35 g of sodium methoxide. The reaction mixture is stirred for 15 minutes and 16.3 g of p-fluorobenzoylacetonitrile added. The reaction mixture is heated at reflux for 2 hours, cooled and concentrated in vacuo to a separated solid which is filtered and washed with water and air dried. The solid is dissolved in 200 ml of ethyl alcohol and 5 ml of triethylamine followed by reflux for 1 hour. The volatiles are evaporated in vacuo to a solid which is filtered, washed with water and air dried to give 8.0 g of the desired product as a solid, m.p. 140° C.