Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[NH:13]1[CH:17]=[N:16][C:15]([C:18]#[N:19])=[N:14]1>N1C=CC=CC=1.CCOC(C)=O.[Cu]I>[CH3:12][O:11][C:5]1[CH:4]=[N:3][C:2]([N:13]2[CH:17]=[N:16][C:15]([C:18]#[N:19])=[N:14]2)=[C:7]2[NH:8][CH:9]=[CH:10][C:6]=12
Reactant: COc1cnc(Cl)c2[nH]ccc12
Reactant: N#Cc1nc[nH]n1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cnc(-n2cnc(C#N)n2)c2[nH]ccc12
Temperature: 150 °C
Yield: 38 %

Procedure:
7-Chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridine (4 g, 21.90 mmol), 1H-1,2,4-triazole-3-carbonitrile (6.18 g, 65.7 mmol) and copper (I) iodide (1.252 g, 6.57 mmol) were combined in pyridine (6 mL) in a sealed tube. The mixture was heated to 150° C. for 6 hrs. After cooling to room temperature, the mixture was diluted with EtOAc (3000 mL), washed with 5% NaHCO3 (100 mL), brine (100 mL) and concentrated. The residue was purified by silica gel column using 30% EtOAc in hexanes mixture to give 1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazole-3-carbonitrile (2 g, 8.33 mmol, 38.0% yield). LCMS: m/z 241.1 (M+H), 1.67 min (method 8).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]2[N:7]3[CH:25]=[CH:24][CH:23]=[C:8]3[C:9]3([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[O:10][C:5]=2[CH:4]=1)#[N:2].O1CCOCC1>Cl>[NH:13]1[CH2:14][CH2:15][C:9]2([O:10][C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:27]=[CH:26][C:6]=3[N:7]3[CH:25]=[CH:24][CH:23]=[C:8]23)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C#N)ccc1-n1cccc12
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Yield: 107 %

Procedure:
A solution of tert-butyl 7′-cyanospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (1.1 g, 3.1 mmol) in HCl in dioxane (3.1 mL of 4.0 M, 12 mmol) was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness to yield spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carbonitrile (880 mg, 94%). ESI-MS m/z calc. 265.3, found 266.1 (M+1)+. Retention time: 0.92 minutes (3 min run).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=[CH:11][CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc(CO)n2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cccc(COS(C)(=O)=O)n2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-yl]-methanol (729 mg, 3.74 mmol) in dry CH2Cl2 (10.0 mL) was treated at 0° C. with Et3N (0.67 mL, 4.83 mmol) followed by DMAP (46 mg, 0.37 mmol) and Ms-Cl (0.37 mL, 4.72 mmol). After stirring at 0° C. for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (70:30 to 50:50 hept-EA) gave the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.79 min; [M+H]+=274.39.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:17]=[CH:16][C:6]([C:7](=O)[CH2:8][N+]2C=CC=CC=2)=[CH:5][CH:4]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:21][CH:20]=1.C([O-])(=O)C.[NH4+:42]>C(O)(=O)C>[CH3:35][N:34]([CH3:36])[C:31]1[CH:32]=[CH:33][C:28]([C:27]2[CH:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[N:42]=[C:7]([C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:17][CH:16]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: [NH4+]
Reactant: CN(C)c1ccc(C=CC(=O)c2ccc(F)cc2)cc1
Reactant: O=C(C[n+]1ccccc1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Product: CN(C)c1ccc(-c2cc(-c3ccc(F)cc3)nc(-c3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
10.06 parts of 1-(4'-fluorophenacyl)-pyridinium chloride and 10.76 parts of 1-(4-fluorophenyl)-3-(4'-dimethylaminophenyl)-1-oxoprop-2-ene are heated at 130° C. for 81/2 hours together with 34 parts of ammonium acetate in 50 parts of glacial acetic acid. The mixture is stirred for 17 hours at room temperature, after which the precipitated colorless crystals are filtered off under suction, washed with methanol and water and dried at 60° C. in a drying oven to give 10.5 parts of 4-(4-dimethylamino-phenyl)-2,6-bis-(4'-fluorophenyl)-pyridine, which dissolves in glacial acetic acid to give an orange yellow coloration (λmax: 431 nm).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]1([OH:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=P(Cl)(Cl)Oc1cccc2ccccc12
Temperature: 25 °C
Yield: 90 %

Procedure:
Phosphorus oxychloride (1.94 mL, 1 equiv) and α-naphthol (Aldrich, 3 g, 1 equiv) were stirred in anhydrous diethyl ether (20 mL). Anhydrous triethylamine was added (2.90 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min. The triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow oil (4.88 g, 90%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:3]=1.Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:12]1([CH2:11][NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:30]3[CH2:29][CH:28]=[C:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH2:32][CH2:31]3)[N:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:5]=2)[CH2:14][CH2:13]1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCC2CC2)nc(NCCO)nc1N1CC=C(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41b) was treated with 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-(cyclopropylmethyl-amino)-6-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=409.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:45]=[C:46]([NH2:59])[C:47]4[C:51]([CH:52]=3)=[N:50][N:49](C3CCCCO3)[CH:48]=4)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:52]=[C:51]4[C:47]([CH:48]=[N:49][NH:50]4)=[C:46]([NH:59][C:8]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[O:10])[CH:45]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: Cc1cccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.08 h
Yield: 24.9 %

Procedure:
3-Methyl-2-pyridinecarboxylic acid (11 mg, 0.08 mmol) in DMF (0.20 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) in DMF (0.20 ml) and DIPEA (0.030 ml). The reaction mixture was shaken for five minutes then treated with 6-(1H-Indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.20 ml). The reaction mixture was shaken then left to stand at room temperature overnight. Solvent was removed in vacuo and the product re-dissolved in methanol (1 ml) then applied to an SCX cartridge (1 g) which had been pre-rinsed with methanol. After 1 h, the cartridge was eluted with ammonia in methanol (2M, 2×3 ml). Fractions containing product were combined, dried and then further purified by Mass Directed Automated Preparative HPLC (Method D). Fractions containing product were combined and dried to give the title compound (5.5 mg) as a pale yellow gum.
Reaction SMILES: Br.[Br:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](=O)([O-])[O-:11].[K+].[K+]>O.C(OC)=O>[CH:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][Br:2])[CH2:5][CH2:6]1)=[O:11]
Reactant: BrCC1CCNCC1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [K+]
Solvent: COC=O
Solvent: O
Product: O=CN1CCC(CBr)CC1
Reaction time: 20 h

Procedure:
To a solution of 4-bromomethylpiperidin hydrobromide (12.8 g, 0.05 mole) in water (5 ml), methyl formate (25 ml) and potassium carbonate (10 g) were added and the mixture stirred for 20 hours. The solvent was decanted, and the residue was extracted with two 25 ml portions of ether. The combined organic phases were washed with water, dried and evaporated to give (A) as a colourless oil. The IR spectrum (chloroform) showed a strong band at 1650 cm-1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[CH2:14]1[S:16][CH2:15]1>O>[CH3:9][S:10]([O-:13])(=[O:12])=[O:11].[CH3:1][S:2][C:3]1[CH:8]=[CH:7][N+:6]([CH2:14][CH2:15][SH:16])=[CH:5][CH:4]=1
Reactant: C1CS1
Reactant: CS(=O)(=O)O
Reactant: CSc1ccncc1
Solvent: O
Product: CS(=O)(=O)[O-]
Product: CSc1cc[n+](CCS)cc1

Procedure:
4-Methylthiopyridine (2.75 g, 22.0 mmol) was added slowly to methanesulfonic acid* (0.65 mL, 10.5 mmol) by cooling in an ice-bath. To this solid was added ethylene sulfide* (0.66 mL, 11.0 mmol, Aldrich) and the mixture was heated at 50°-60° C. for 21 h. As reaction proceeds the solid went to solution. After cooling, the reaction mixture was dissolved in H2O (5 mL) and washed with Et2O (5×4 mL). The cloudy aqueous layer was filtered over Celite and the filtrate was purified by reverse phase silica gel column chromatography (C18 micro bondapack 10 g) eluting with H2O. Each fraction of 10 mL was collected. Fractions 2 and 3 were combined and repurified by the reverse phase column. Fraction 2 gave 1.258 g (4.48 mmol, y. 42.6%) of the title compound as a viscous oil: 1Hmr (DMSO-d6, CFT-20) δ: 2.32 (3H, s, MeSO3⃝), 2.72 (3H, s, --SMe), 2.68 (1H, m, SH), 2.9-3.2 (3H, m, --CH2S--), 4.59 (2H, t, J=6.4 Hz, --CH2N⊕), 7.97 (2H, "d", J=7.2 Hz, aromatic-Hs) and 8.72 ppm (2H, "d", J=7.2 Hz, aromatic-Hs); ir (neat) νmax : 1630, 1200 (br, --SO3⃝), 785 and 770 cm-1.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[NH:6][C:7]([CH3:29])=[C:8]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:10]=1[C:11]([O-:13])=[O:12].C(O)(=O)C.O>CO>[CH3:4][C:5]1[NH:6][C:7]([CH3:29])=[C:8]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC1=C(C(=O)[O-])C(c2cccc([N+](=O)[O-])c2)C(c2ccncc2)=C(C)N1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(c2ccncc2)=C(C)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.35 g (25 mmol) of sodium methoxide was dissolved in 20 ml of anhydrous methanol. To this solution was added, with ice-cooled, 2.02 g (5 mmols) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(4-pyridyl)pyridine-3-carboxylate. The reaction mixture was stirred at room temperature for 5 hours and neutralized with acetic acid. To this reaction mixture was added 400 ml of water. Crystals were separated from the reaction mixture, which were collected, washed with water and dried under reduced pressure, whereby the captioned compound was obtained. The yield was 1.71 g (98%).
Reaction SMILES: C1(S(C2(SC)[CH2:15][C@@H:14]3[C@@:12]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.[CH3:28][OH:29].Cl>C(OCC)(=O)C.CCCCCC>[C:16]1([C@@:12]23[CH2:13][C@@H:14]2[CH2:15][C:28](=[O:29])[CH2:11]3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CO
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Yield: 99 %

Procedure:
(1R,5R)-3-Benzenesulfonyl-1-(1-naphthyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (620 mg, 1.6 mmol), methanol (4 mL) and concentrated hydrochloric acid (0.7 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)) The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (50 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 458 mg of crude oil, which was purified by preparative HPLC to yield 135 mg (39%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3) 0.76-0.79 (1H,t, J=4 Hz), 1.38 (1H,m), 2.01 (1H,m), 2.49-2.56 (1H,d, J=10Hz), 2.75 (2H,d,J=6 Hz), 3.05-3.15 (2H,dd,J=10 Hz), 7.40-7.45 (1H,m), 7.50-7.56 (3H,m), 7.76-7.79 (1H,d,J=9 Hz), 7.88-7.90 (1H,m), 8.13-8.15 (2H,d ,J=6 Hz). 13CNMR(CDCl3)δ: 218.25, 139.12, 134.01, 128.96, 127.80, 126.77, 126.17, 125.78, 125.33, 124.0, 48.18, 42.46, 27.80, 20.62, 20.05.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([N:16]2[CH2:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)[N:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C@H:64]1[CH2:69][CH2:68][C@H:67]([OH:70])[CH2:66][CH2:65]1>CN(C=O)C.O>[OH:70][C@H:67]1[CH2:68][CH2:69][C@H:64]([NH:63][C:13]([C:12]2[C:7]([NH:6][CH2:5][C:4]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:2]([Cl:1])[CH:3]=3)=[N:8][C:9]([N:16]3[CH2:24][C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[N:10][CH:11]=2)=[O:15])[CH2:65][CH2:66]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(CNc2nc(N3Cc4cccnc4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(N3Cc4cccnc4C3)ncc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1Cl
Reaction time: 0.33 h

Procedure:
In DMF (10 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(5H-pyrrolo[3,4-b]pyridin-6(7H)yl)-5-pyrimidine formic acid (0.8 g, 1.94 mmol). The solution was cooled in an ice bath. HATU (1.11 g, 2.91 mmol) and DIPEA (0.37 g, 2.87 mmol) were added. After 20 min, trans-4-aminocyclohexanol (0.27 g, 2.3 mmol) was added in batches. The reaction was conducted overnight. LC-MS was used to monitor the reaction. The reaction mixture was poured into water (50 mL) and filtrated. The solid was recrystallized with acetone (20 mL) to give N-((trans)-4-hydroxycyclohexan-1-yl)-4-((3-chloro-4-methoxybenzyl)amino)-2-(5H-pyrrolo[3,4-b]pyridin-6(7H)yl)-5-pyrimidine formamide (300 mg, 30.3% yield).
Reaction SMILES: [O:1]([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.[S:14](Cl)([Cl:17])(=[O:16])=[O:15].[NH:19]1[C:27]2[CH:26]=[CH:25][N:24]=[C:23]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[C:22]=2[CH:21]=[CH:20]1>>[ClH:17].[O:1]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[C:23]([N:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[C:22]=3[CH:21]=[CH:20]2)(=[O:16])=[O:15])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3[nH]ccc23)CC1
Product: Cl
Product: O=S(=O)(c1ccc(Oc2ccccc2)cc1)n1ccc2c(N3CCNCC3)nccc21

Procedure:
(4-Phenoxy)benzene)sulfonyl chloride (34.7 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (12.8 mg). LC/MS RT: 1.839 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 95%. MS: 436 (M+1) 1HNMR (CD3OD) δ ppm 3.50 (m, J=3.96 Hz, 4H) 4.09 (m, J=4.45 Hz, 4H) 7.05 (dd, J=8.16, 6.43 Hz, 2H) 7.26 (m, 2H) 7.44 (t, J=7.79 Hz, 2H) 7.90 (m, 3H) 8.01 (d, J=3.71 Hz, 2H) 8.07 (d, J=8.91 Hz, 2H).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:61][CH2:60][N:59]([C:62]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)=[O:63])[CH2:58][CH2:57]2)[CH2:52][CH2:51]1.C(N(CC)CC)C>CN(C)C=O>[F:48][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38](=[O:47])[NH:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:36][CH2:37]1)=[O:34])[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:50]2[CH2:55][CH2:54][CH:53]([N:56]3[CH2:57][CH2:58][N:59]([C:62]([O:64][CH2:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[O:63])[CH2:60][CH2:61]3)[CH2:52][CH2:51]2)=[O:12])[CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 147.2 %

Procedure:
To a solution of a crude product of [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (300 mg) in N,N-dimethylformamide (4.5 ml) were added benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (684 mg) and triethylamine (0.629 ml), followed by stirring at room temperature for 20.5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to provide a crude product of benzyl 4-{1-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-ylcarbamoyl]piperidin-4-yl}piperazine-1-carboxylate as a pale yellow oil (501 mg). This was dissolved in ethanol(10 ml) and N,N-dimethylformamide (5.0 ml). 1,4-cyclohexadiene (0.633 ml) and 10% palladium on carbon (144 mg) were added thereto, followed by stirring at 65° C. for 1.5 hr. The reaction mixture was allowed to cool down to room temperature. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=10:1, then 5:1). Fractions containing the target compound were concentrated to give the residue (56.3 mg). The residue was purified by LC-MS. Fractions containing the target compound were concentrated, which were partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed, and to the residue was added diethyl ether to suspend a solid. This was collected by filtration, and dried under aeration to provide the titled compound as pale yellow powder (12.7 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7](S([O-])(=O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1S([O-])(=O)=O.[K+].[K+].[OH-:21].[K+].[OH2:23]>>[OH:21][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([OH:23])[CH:6]=2)[CH:1]=1
Reactant: [OH-]
Reactant: O
Reactant: O=S(=O)([O-])c1ccc2cc(S(=O)(=O)[O-])ccc2c1
Agent: [K+]
Product: Oc1ccc2cc(O)ccc2c1
Temperature: 310 °C
Yield: 92.6 %

Procedure:
Dipotassium 2,6-naphthalenedisulfonate (364 g) was added to 560 g of a 50% aqueous solution of potassium hydroxide, and the mixture was stirred. Then, 2500 g of a hydrogenated triphenyl mixture was mixed, and the resulting mixture was heated to 310° C. in a nitrogen stream and dehydrated with stirring. The mixture was then stirred at 310° C. for 3 hours. After cooling, 2 liters of water was added to the reaction mixture to separate the hydrogenated triphenyl layer. The aqueous layer was decolorized with activated carbon, and precipitated with dilute sulfuric acid to give 148.2 g (yield 92.6%) of 2,6-dihydroxynaphthalene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([F:17])([F:16])[F:15])[CH2:12][N:11]2[N:18]=[C:19]([I:24])[C:20]([C:21](O)=[O:22])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:21]([C:20]1[C:19]([I:24])=[N:18][N:11]2[CH2:12][CH:13]([C:14]([F:17])([F:16])[F:15])[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][C:10]=12)(=[O:22])[NH2:28]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC1C(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a solution of Intermediate 346E (0.12 g, 0.260 mmol) in DMF (1 mL) was added NH4Cl (0.028 g, 0.520 mmol), HATU (0.099 g, 0.260 mmol) and DIPEA (0.136 mL, 0.781 mmol) under nitrogen and the resulting solution was stirred at RT for 16 h. The reaction mixture was poured into water and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 3% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 346F as a white solid (0.07 g, 50%). MS(ES): m/z=460.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:32])[NH:6][C:7]([C:15]1[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:23][CH2:22]3)[CH:18]=[CH:17][CH:16]=1)=[N:8]2.[OH-].[Li+]>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:32])[NH:6][C:7]([C:15]1[N:20]=[C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][CH2:26]3)[CH:18]=[CH:17][CH:16]=1)=[N:8]2
Reactant: COC(=O)CN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CC(=O)O)CC4)n3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate (0.156 g, 0.35 mmol) in THF (10 mL), water (5 mL) and methanol (3 mL) was added lithium hydroxide (0.043 g, 1.77 mmol). The reaction was stirred for 2 h at rt. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (5 mL) and acidified with 1N HCl to pH 4.5-5.0. The precipitated solids were collected by filtration, washed with water and dried under high vacuum to give 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetic acid (0.135 g, 91%) as a yellow solid: mp 225° C. dec.; 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.72-7.79 (m, 1H), 7.67-7.72 (m, 1H), 7.07 (d, J=8.59 Hz, 1H), 6.78 (d, J=1.56 Hz 1H), 6.58 (d, J=1.56 Hz, 1H) 3.91 (s, 3H), 3.86 (s, 3H), 3.63-3.74 (m, 4H), 3.23 (s, 2H), 2.65-2.74 (m, 4H); ESI MS m/z 426 [M+H]+.