Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([O:15][C:11](=[O:14])/[CH:12]=[CH:13]/[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:17]
Reactant: C=CC(=O)OCC
Reactant: O=C(O)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
A solution of 3-iodobenzoic acid (20.2 g, 81.4 mmol), ethyl acrylate (9.0 g, 90.2 mmol), triethylamine (24 mL) and palladium acetate (92 mg, 0.41 mmol) in DMF (130 mL) was stirred at 140° C. for 3 hr. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate and 1N hydrochloric acid, and the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 50:50-0:100) to give the title compound (18.7 g, quant.) as an orange solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O.[BH4-].[Na+].CO>O1CCCC1>[C:18]([O:17][C:15]([N:6]1[CH2:7][C@H:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 80.5 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (8.11 g) in tetrahydrofuran (49 ml) stirring under ice cooling, sodium borohydride (2.36 g) and methanol (20 ml) are added. The mixture is stirred at room temperature for 25 minutes and at 60° C. for 25 minutes. The mixture is cooled with ice and filtered. The filtrate is concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is recrystallized from petroleum ether-ether to give (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (5.96 g). Colorless crystals. Yield: 80%. mp. 95° to 96° C. NMR δ(CDCl3) ppm: 1.48(s, 9H), 1.78 to 2.02(m, 1H), 2.3 to 2.48(m, 1H), 3.05(s, 3H), 3.5 to 3.65(m, 2H), 3.65 to 4.0(m, 2H), 4.03 to 4.25(m, 1H), 5.2(s, 1H). IR ν (CHCl3) cm-1 : 3460, 1680.
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[C:13]([NH:1][CH:2]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(C(=O)O)C1CCC(O)CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C1CCC(C(NC(=O)c2ccccc2)C(=O)O)CC1

Procedure:
Bicyclic diamines of general formula (32), wherein P2 is a nitrogen protecting group, can be prepared as described in (Org. Mass Spectrum. (1984) 19(9), 459-460). Amino(4-hydroxyphenyl)acetic acid, purchased commercially, can be treated with Raney nickel and heat to provide amino(4-hydroxycyclohexyl)acetic acid. Amino(4-hydroxycyclohexyl)acetic acid can be treated with benzoyl chloride and then oxidized with Jones' reagent to provide (benzoylamino)(4-oxocyclohexyl)acetic acid. (Benzoylamino)(4-oxocyclohexyl)acetic acid can be subjected to a Beckmann rearrangement using hydroxyl amine and a sulfonyl chloride such as phenyl sulfonyl chloride to provide (benzoylamino)(7-oxo-4-azepanyl)acetic acid. (Benzoylamino)(7-oxo-4-azepanyl)acetic acid can be treated with concentrated HCl and heat to provide 2-amino-3-(2-aminoethyl)hexanedioic acid. 2-Amino-3-(2-aminoethyl)hexanedioic acid can be distilled at 180-200° C./0.1 torr to provide octahydro[1,7]naphthyridine-2,8-dione. Octahydro[1,7]naphthyridine-2,8-dione can be treated with lithium aluminum hydride and monoprotected with a nitrogen protecting reagent such as acetyl chloride/acetic anhydride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, or benzyl bromide to provide bicyclic diamines of general formula (32).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:30])[CH:24]=1>>[CH2:21]([O:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:29]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[OH:30])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Reactant: O=C(c1cccnc1)c1cccnc1
Product: CCOc1cccc(-c2cc(OC)nc3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Yield: 41.2 %

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-ethoxy-phenyl)-2-methoxy-quinoline (400 mg, 1.11 mmol) and di-pyridin-3-yl-methanone (225 mg, 1.22 mmol) generated the title compound of 37A (212 mg, 41.2% yield).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[CH2:7]([NH:11][C:12]#[N:13])[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C>CCOCC>[C:12]([N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[C:3](=[O:4])[CH:2]([Br:1])[CH3:6])#[N:13]
Reactant: CC(Br)C(=O)Br
Reactant: CCCCNC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCN(C#N)C(=O)C(C)Br
Reaction time: 3 h
Yield: 70.8 %

Procedure:
29.5 g (0.137 mole) of 2-bromopropionyl bromide are added dropwise at 15° C. to 13.4 g (0.137 mole) of butyl cyanamide and 13.8 g (0.137 mole) of triethylamine in 150 ml of ether. The mixture is stirred for 3 hours at 20° to 25° C., then filtered to remove the precipitated salt. The filtrate is extracted with dilute hydrochloric acid and the extract is dried over sodium sulfate and concentrated by evaporation. The oily residue is distilled under high vacuum, affording 22.6 g (70.8% of theory) of 2-bromopropionic acid N-cyano-N-butylamide with a boiling point of 53°-54° C. at 0.0052 mbar.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([N:20]([CH3:40])[C:21](=[O:39])[C:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)([CH3:24])[CH3:23])=[C:16]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=3[CH3:48])[CH:15]=2)[C@H:10]([CH3:49])[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C>[F:38][C:35]([F:36])([F:37])[C:27]1[CH:26]=[C:25]([C:22]([CH3:23])([CH3:24])[C:21]([N:20]([C:17]2[CH:18]=[N:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[CH3:49])=[CH:15][C:16]=2[C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=2[CH3:48])[CH3:40])=[O:39])[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN(Cc3ccccc3)C[C@H]2C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1-c1cc(N2CCNC[C@H]2C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A solution of 0.11 g (0.17 mmol) (R)-N-[6-(4-benzyl-2-methyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml acetic acid was deoxygenated by three cycles of evacuation and flushing with argon. After addition of 0.02 g palladium on charcoal (10%) the reaction vessel was evacuated and filled with hydrogen gas. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 3 h. The reaction mixture was filtered over decalite followed by washing with tert-butyl methyl ether. The filtrate was washed with a 2 M aqueous solution of sodium hydroxide. The aqueous layer was extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 98 mg (98%) of the crude title compound as an off-white solid, which was used in the next step without further purification. MS m/e (%): 597 (M+H+, 100)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([Cl:35])=[CH:33][C:32]([Cl:36])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:35][C:34]1[C:25]([NH:24][C:22]2[C:21]([Cl:37])=[CH:20][N:19]=[C:18]([NH:16][C:13]3[CH:14]=[CH:15][C:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=4[CH:12]=3)[N:23]=2)=[C:26]([CH:31]=[C:32]([Cl:36])[CH:33]=1)[C:27]([NH:29][CH3:30])=[O:28]
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cc(Cl)cc(Cl)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(Cl)cc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
3,5-Dichloro-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,5-dichloro-N-methyl-benzamide in an analogous manner to Example 303c. Product isolated as an off-white foam (47 mg, 25%). LCMS (m/e) 549 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.69 (s, 1H), 7.61 (s, 1H), 7.47 (s 1H), 7.15 (s, 1H), 7.01-6.89 (m, 2H), 6.87 (s, 1H), 6.01-5.92 (m, 1H), 3.56 (t, 2H, J=5.5 Hz), 3.39 (s, 3H), 2.92-2.84 (s, 2H), 2.81-2.65 (m, 8H), 2.75 (d, 3H, J=4.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[C:24]([F:27])([F:26])[F:25])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([O:30]C)=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[C:24]([F:27])([F:26])[F:25])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([OH:30])=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC[C@@H]3C(F)(F)F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC[C@@H]3C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[(2R)-2-(trifluoromethyl)piperidin-1-yl]quinoxaline-6-carboxylate (15 mg, crude) in methanol (15 mL) was added sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted pH to 6 with HCl (1N), then extracted with dichloromethane (4×10 mL) and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. Purification via Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.05% NH3 and CH3CN (10% CH3CN up to 45% in 7 min); Detector, UV 220 nm] afforded 2-(4-fluorophenyl)-3-[(2R)-2-(trifluoromethyl)piperidin-1-yl]quinoxaline-6-carboxylic acid as a yellow solid (9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8](C1C=CC=CC=1)=[C:7]2[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br>>[CH2:7]([C:8]1[N:9]=[N:10][C:11]2[C:6]([C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:36])([F:35])[F:25])[CH:28]=3)[CH:19]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:6]1[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Oc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: FC(F)(F)c1cccc(COc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenol and 3-trifluoromethylbenzyl bromide according the procedure of Example 14. MS (ES) m/z 504.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11]C)[C:8]=1[O:9][CH3:10].OO.[N+]([O-])(O)=[O:17].O>CC(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][O:9][C:8]1[C:7](=[O:11])[CH:6]=[C:5]([CH3:13])[C:4](=[O:17])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: O=[N+]([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: COC1=C(OC)C(=O)C(C)=CC1=O
Temperature: 75 °C
Yield: 175.7 %

Procedure:
To a round-bottom flask (20 mL) equipped with a reflux condenser was added a solution of commercial 3,4,5-trimethoxy-toluene (0.547 g, 3 mmol) in AcOH (3 mL), followed by para-toluenesulfonic acid monohydrate (57 mg, 0.3 mmol) as catalyst. The oxidant H2O2 (30%, 0.65 mL, 6 mmol) was then added. The reaction mixture was stirred and heated at 75° C. for 30 min. The resulting dark-red solution was cooled to 0-5° C., and concentrated HNO3 (90%, 1.5 mmol) was then slowly added. The cold solution was poured into H2O (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with H2O (80 mL) in order to remove traces of AcOH, dried (Na2SO4) and filtered. When the solvent was evaporated under vacuum, the final crude (0.528 g, dark-red oil) was dissolved in boiling hexane (70 mL), filtered, and the solvent was removed to give the pure 2,3-Dimethoxy-5- methyl-[1,4]benzoquinone (0.480 g, 88% yield) as red needles. 1H NMR (400 MHz, CDCl3, ppm): δ2.04 [d, 3H, J=1.6 Hz, CH3], 4.00 [s, 3H, OCH3], 4.02 [s, 3H, OCH3], 6.43-6.44 [q, 1H, Jm=1.6 Hz]. 13C NMR (400 MHz, CDCl3, ppm): δ15.4, 31.1, 61.2, 131.3, 144.0, 144.9, 145.1, 184.1, 184.4. MS m/z (%): 182 (85), 167 (32), 153 (13), 137 (100), 121 (6), 111(23), 96 (12), 83 (67), 69 (31), 53 (15).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[C:16](=[O:27])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cccc(Br)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a solution of (3-bromophenyl)methanol (10 g, 53.5 mmol) and pyridine (8.65 mL, 107 mmol) in DCM (80 mL) at 0° C. was added a solution of 4-nitrophenyl carbonochloridate (12.93 g, 64.2 mmol) in DCM (20 mL) dropwise. Upon the completion of addition, the reaction mixture was stirred at 0° C. for 2 h. After this time, the reaction was quenched with water. The organic layer was separated and washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (19.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.31-8.29 (m, 1H), 8.28-8.25 (m, 1H), 7.61 (t, J=1.6 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.42-7.34 (m, 3H), 7.30 (d, J=7.8 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, benzyl alcohol and DBU in DME. ES-MS m/e (%): 313 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH:27]1[CH2:32][CH2:31][CH2:30][N:29]=[CH:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:30][CH2:31][CH2:32][N:27]=[CH:28]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: C1=NCCCN1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2C=NCCC2)cc1Cl

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1,4,5,6-tetrahydropyrimidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1,4,5,6-tetrahydropyrimidine-1-carbonyl)benzamide. MS (Q1) 454 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:33])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28](OCC)=[O:29])[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].[BH4-].[Li+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:29][CH2:28][CH2:27][CH:24]1[S:23][C:22]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH3:33])[S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:11])=[O:10])=[N:26][CH2:25]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4OC)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a mixture of ethyl (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (140 mg), lithium borohydride (40 mg) and tetrahydrofuran (5 mL) was added methanol (1 mL), and the mixture was stirred at room temperature for 2 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=6:4-10:0), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (87 mg, yield: 69%) as colorless needle crystals. MS: 446 (MH+). melting point 154-155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH:23]=[C:22]([O:24]C)[N:21]=[C:20]([N:26]2[CH2:31][CH2:30][CH:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH2:27]2)[N:19]=1>Br.CC(O)=O>[NH2:32][CH:29]1[CH2:28][CH2:27][N:26]([C:20]2[NH:21][C:22](=[O:24])[CH:23]=[C:18]([C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[CH:10]=4)[NH:14][CH:13]=3)[N:19]=2)[CH2:31][CH2:30]1
Reactant: COc1cc(-c2c[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: Br
Solvent: CC(=O)O
Product: NC1CCN(c2nc(-c3c[nH]c4ccc(-c5c(F)cccc5F)cc34)cc(=O)[nH]2)CC1
Yield: 19 %

Procedure:
A solution of tert-butyl (1-(4-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate (0.1 g, 0.187 mmol) in 33% HBr in HOAc (1.87 mL) was heated at 90° C. for 14 h. The reaction was quenched with aq. NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified with treatment of acid-base to give 2-(4-aminopiperidin-1-yl)-6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrimidin-4(3H)-one (15 mg, 20%). MS (ESI, pos. ion) m/z: 422.1 (M+1); 1H-NMR (DMSO-d6, 400 MHz): δ ppm 11.80 (brs, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.42-7.46 (m, 1H), 7.19-7.25 (m, 3H), 6.15 (s, 1H), 4.42 (d, J=12.8 Hz, 2H), 2.96-3.05 (m, 3H), 1.88 (s, 1H), 1.77 (d, J=10.8 Hz, 2H), 1.23-1.30 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:12]=1[O:13][C:14]1[C:15]([NH:24][S:25]([C:28]2[CH:37]=[CH:36][C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[CH:29]=2)(=[O:27])=[O:26])=[N:16][CH:17]=[N:18][C:19]=1[O:20][CH2:21][CH2:22][OH:23]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:12]=1[O:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][O:23][C:8](=[O:9])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:18][CH:17]=[N:16][C:15]=1[NH:24][S:25]([C:28]1[CH:37]=[CH:36][C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=1)(=[O:27])=[O:26]
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc4c(c3)OCCO4)ncnc2OCCO)c1
Reactant: O=C=Nc1cccnc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc4c(c3)OCCO4)ncnc2OCCOC(=O)Nc2cccnc2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
57 mg of 3-pyridyl isocyanate were added to 121.5 mg of N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-2,3-dihydro-1,4-benzodioxin-6-sulfonamide dissolved in 1 ml of dry toluene. The reaction mixture was stirred at 100° C. for 1 hour. Then, the solution was added to a silica gel column and it was eluted with EtOAc. There was obtained pyridin-3-ylcarbamic acid 2-[5-(2-chloro-5-methoxy -phenoxy]-6-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonylamino) -pyrimidin-4-yloxy]-ethyl ester, white powder, MS: m/e =630.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:12][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCN
Product: CCNCc1ccc(Cl)nc1

Procedure:
Using 6-chloro-3-pyridylmethyl chloride and 70% aqueous ethylamine solution, the reaction according to Reference Example 11 was carried out to give the title compound as a brown oil.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>C(O)C>[CH:21](=[N:10]/[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)\[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCCCCCC=O
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: C=CCCCCCCCC/C=N/NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of 1a (1.50 g, 11.0 mmol) and 10-undecenal (2.80 g, 16.5 mmol) in ethanol (28 ml) was heated under reflux for 2 h. After cooling to room temperature, the product was concentrated, washed with hexane and dried under vacuum (0.20 mbar) to give 2.78 g (88%) of a white solid.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N:23]([O-])=[O:24].[Na+]>C(OC(=O)C)(=O)C>[N:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(S(=O)(=O)N(Cc2ccccc2)N=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of N-benzyl-p-toluenesulphonamide (21 g, 80 mmol) and acetic acid (100 ml) in acetic anhydride (400 ml) was added solid sodium nitrite (120 g, 1.7 mol) in portions over a period of 12 hours at 5° C. The temperature was kept below 10° C. all the time. After the addition was finished the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured over an excess of ice water and stirred for 1 hour. The pale yellow precipitate was filtered and washed several times with water. The crude product was recrystallized from ethanol to give the title compound as a tiny yellow needles (19.1 g, 82% yield, m.p. 92°-93° C., (Lit.1 89°-90° C.). δH (CDCl3): 7.80(2H,m); 7.25(7H,m); 4.95(2H,s); 2.40(3H,s)ppm.