Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cs1
Solvent: CCCCO
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cs1
Temperature: 160 °C
Reaction time: 18 h

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide (200 mg, 0.563 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (338 mg, 1.69 mmol) in n-BuOH was stirred at 160° C. in a sealed tube. After 18 hours, additional (R)-tert-butyl piperidin-3-ylcarbamate (113 mg, 0.563 mmol) was added to the mixture and heating at 160° C. was continued for a further 18 hours. The mixture was concentrated in vacuo and purified by C-18 reverse phase column chromatography (Biotage Flash 25 M+ column) on Biotage SP4 unit eluting with a gradient of 10-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-methylthiazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. This material was dissolved in neat TFA (3 mL), stirred at room temperature for 30 minutes and concentrated in vacuo. The oily residue was dissolved in a few drops of methanol and treated with 2M HCl in ether. The resulting precipitate was concentrated under reduced pressure, and the residue was dissolved in a few drops of methanol and CH3CN was added. The precipitate formed was filtered and dried under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide hydrochloride (25 mg, 10% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.87 (s, 1H), 10.64 (s, 1H), 8.34 (br s, 3H), 8.31 (s, 1H), 8.28 (s, 1H), 8.09 (d, 3.85-3.24 (m, 1H), 3.70-3.57 (m, 2H), 3.35-3.28 (m, 1H), 3.09-3.02 (m, 1H), 2.81 (s, 3H), 2.36-2.27 (m, 2H), 1.94-1.86 (m, 1H), 1.63-1.51 (m, 1H); LCMS (APCI+) m/z 435.0, 437.0 (M+H)+, Retention time=2.54 minutes (Method 2).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=O)[C:18](O)=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][C:18](=[O:19])[C:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[N:9]2
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C(O)C(=O)c1cccs1
Product: O=c1[nH]c2ccc(Br)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-bromo-2-nitroaniline and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-bromo-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][O:33][NH2:34]>C(Cl)Cl.CO>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]=[N:34][O:33][CH3:32])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CON
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Solvent: ClCCl
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=NOC)cc4)cc23)CC1
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL) and MeOH (1.5 mL) was added O-methylhydroxylamine (114 mg, 1.71 mmol). The reaction was stirred overnight. The solvent was then concentrated and purified by Gilson Preparatory HPLC to give 38 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)imino]methyl}phenyl)-1H-indole-7-carboxamide (76%).
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])[CH3:5]>>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]([CH:5]=[O:2])=[O:6])[CH:8]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1cccnc1
Product: O=CC(=O)c1cccnc1
Yield: 90.3 %

Procedure:
3-Pyridylglyoxal (5.0 g, crude) was prepared from selenium dioxide (6.82 g, 61.4 mmol) and 3-acetyl pyridine (5.0 g, 41.0 mmol) according to the typical procedure used for Preparation 1.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([C:30](=[O:32])[CH3:31])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CC[C@@H](n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1
Reaction time: 1 h

Procedure:
To a solution of 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (30 mg), acetic anhydride (0.1 mL) in 8 mL of DCM was added DMAP (3 mg, 0.025 mmol). The mixture was stirred for 1 hour. Then 20 mL of DCM and 10 mL of water was added. The organic phase was washed with water and NaHCO3 and then dried over anhydrous Na2SO4. The solvent was evaporated. The residue was purified by preparative-HPLC to afford the title compound (15 mg) as a pale solid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[C@:16]2([CH3:17])[C@H:11]([C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9][C@:8]1([OH:21])[CH3:20])(=O)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:30][CH2:6][C@@H:7]2[C@:16]3([CH3:17])[C@H:11]([C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15]3)[CH2:10][CH2:9][C@@:8]2([CH3:20])[OH:21])[CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cccc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Reaction time: 18 h
Yield: 69 %

Procedure:
A mixture of [(1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-1-yl]methyl methanesulfonate (12) (5.0 g, 16 mmol), 3-methoxybenzenethiol (1.9 mL, 16 mmol), cesium carbonate (15.3 g, 47.2 mmol) in anhydrous CH3CN (200 mL) was prepared under N2. The mixture was heated to reflux and stirred for 18 h. The reaction mixture was filtered and the filtrate concentrated to dryness. The crude product was purified by flash chromatography on silica gel (Hexanes/EtOAc, 10:1) to yield (1R,2R,4aS,8aS)-1-{[(3-methoxyphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (13-1) (4.0 g, 71% yield) as a yellow oil.
Reaction SMILES: C(OCC1C=[C:13]([N:15]([CH3:17])[CH3:16])[CH:12]=[CH:11]C=1)(=O)CCCC.[C:18]([O:21]CC)(=[O:20])[CH3:19]>[Pd]>[CH3:16][N:15]([CH3:17])[CH2:13][CH2:12][CH2:11][CH2:19][C:18]([OH:21])=[O:20]
Reactant: CCCCC(=O)OCc1cccc(N(C)C)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CN(C)CCCCC(=O)O
Yield: 60.4 %

Procedure:
To a solution of 5-(dimethylamino)benzyl pentanoate (0.79 g, 33.6 mmol) in anhydrous ethyl acetate (20 mL) under nitrogen at room temperature was added 10% palladium on carbon (250 mg). The solution was stirred vigorously under a hydrogen atmosphere. After 16 hours additional palladium on carbon (100 mg) was added to encourage the reaction, and at 24 hours hydrogen gas was bubbled through the solution. At 40 hours the solution was filtered through celite and concentrated in vacuo to dryness to afford the product as a yellow oil (295 mg, 60.4%).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>S(Cl)(Cl)=O.ClCCl>[N:1]([C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(F)c(F)cc1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=Nc1cc(F)c(F)cc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 46 %

Procedure:
A solution of 2-azido-4,5-difluoro-benzoic acid (26.2 g, 132 mmol; Grieder A.; Thomas, A. W., Synthesis (2003), (11), 1707-1711) in thionyl chloride (216 ml) was stirred under reflux conditions for 1.5 h. The solvent was removed under reduced pressure to give the corresponding crude acid chloride which was suspended in dichloromethane (200 ml). 4-Chloroaniline (16.8 g, 132 mmol) was added and the mixture was stirred at ambient temperature for 14 h. Under ice cooling saturated NaHCO3 solution was added until pH 8 was reached. The mixture was extracted two times with dichloromethane, the combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown solid which was crystallized from dichloromethane/n-heptane to give the title compound (18.5 g, 60 mmol; 46%) as yellow crystals.
Reaction SMILES: [C:1]1([S:7][CH:8](S(C2C=CC=CC=2)(=NC)=O)[C:9](O)([C:11]2[CH2:15][CH2:14][CH2:13][CH:12]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C(O)(=O)C>C1COCC1>[C:11]1([C:9]([CH2:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH2:10])[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: CN=S(=O)(c1ccccc1)C(Sc1ccccc1)C(C)(O)C1=CCCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=C(CSc1ccccc1)C1=CCCC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of S-[1-phenylthio-2-hydroxy-2-(cyclopent-1-enyl)propyl]-N-methyl-S-phenylsulfoximine (1.05 g, 2.7 mmol) in a mixture of THF (20 mL), H2O (8 mL) and acetic acid (8 mL) is added freshly prepared Al/Hg (1.3 g) in an ice-bath. After stirring at 0° C. for 5 hours, the mixture is filtered through a pad of Celite and the Celite is washed with EtOH (10 mL). The filtrate is concentrated in vacuo to ca. 5 mL. The residue is diluted with H2O (100 mL) and extracted with pentane (40 mL×5). The combined extracts are dried (Na2SO4), and evaporated in vacuo to dryness. The residue is chromatographed over a silica gel column (2×40 cm) using pentane as the eluent. The product is obtained as a syrup, 486 mg (83%). 1H NMR (CDCl3): δ1.73-2.08 (2H, m, CH2 -4), 2.49 (4H, t, J=6.72 Hz, CH2 -3 and -5), 3.78 (2H, s, CH2 --S), 5.01 (2H, d, J=6.86 Hz, CH2 =), 5.90 (1H, brs, CH=), 7.11-7.53 (5H, m, pH).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][CH2:46][C:47]([NH:49][C@@H:50]([C:52]([NH:54][C@H:55]([C:58]([NH:60][C@H:61]([C:66]([O:68]C(C)(C)C)=[O:67])[CH2:62][C:63](=[O:65])[NH2:64])=[O:59])[CH2:56][OH:57])=[O:53])[CH3:51])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])[CH3:11])=[O:8]>FC(F)(F)C(O)=O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][CH2:46][C:47]([NH:49][C@@H:50]([C:52]([NH:54][C@H:55]([C:58]([NH:60][C@H:61]([C:66]([OH:68])=[O:67])[CH2:62][C:63](=[O:65])[NH2:64])=[O:59])[CH2:56][OH:57])=[O:53])[CH3:51])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH3:11])=[O:8]
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O

Procedure:
In 5 ml of trifluoroacetic acid is dissolved 500 mg of pGlu-Ala-Lys(Boc)-Ser-Gln-Gly-(D)-Ala-Ser-Asn-OBut and the mixture is allowed to stand at room temperature. The trifluoroacetic acid is distilled off and the residue is precipitated with ether and recovered by filtration. The resulting powders are dissolved in 50 ml of water and run onto a column of Amberlite IRA-410(acetate-form) (2×5 cm). The effluent is combined with washings and lyophilized. The powdery lyophilizate is dissolved in a small amount of 0.1 N-aqueous acetic acid and put onto a column of Sephadex LH-20 (2.5×125 cm), elution being carried out with 0.1 N-aqueous acetic acid. The fractions from 186 ml through 206 ml are pooled and lyophilized. Yield 310 mg (62%); [α]D24 -47.3°(c=0.35, H2O); Rf4 (Avicel)=0.24; amino acid analysis (acid hydrolyzate); Lys, 1.08(1); Asp, 1.00(1); Ser, 1.90(2); Glu, 1.93(2); Gly, 1.06(1); Ala, 2.00(2); average recovery 89%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[C:25]([Br:29])=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:30]([NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:31][CH3:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[C:25]([Br:29])=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:30]([N:33]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:31][CH3:32])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2sc(Br)c(Br)c2c(=O)n1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1nc2sc(Br)c(Br)c2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (19 mg, 0.085 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-5,6-dibromo-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-7, 45 mg, 0.085 mmol, 1 equiv) and N,N-diisopropylethylamine (11 mg, 0.085 mmol, 1 equiv) in dichloromethane (5 mL), and the resulting reaction mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, then brine, and dried (MgSO4) and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide N-[1-(3-benzyl-5,6-dibromo-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (2-9) as a colorless foam. MS(M+1)=708.9
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][N:3]=1.Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Br.CC([O-])(C)C.[K+]>O1CCOCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][N:3]=1
Reactant: Cc1ncc(CC#N)cn1
Reactant: BrCCOCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(C2(C#N)CCOCC2)cn1
Temperature: 80 °C
Yield: 9.020515659967313e+19 %

Procedure:
A solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (4 g, 0.03 amol) and 1-bromo-2-(2-bromoethoxy)ethane (7.66 g, 0.033 mol) in 1,4-dioxane (60 mL) was added t-BuOK (66 mL, 0.066 mol, 1M in THF) and heated to 80° C. for 4 h. The reaction mixture was cooled to room temperature, quenched by sat.NH4Cl. The 1,4-dioxane was removed under reduced pressure. The residue aqueous layer was extracted with EtOAc (3×150 mL). The organic layer was dried over Na2SO4 and concentracted to give 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile (5.5 g, yield: 90.5%). 1H NMR (CDCl3 400 MHz): δ8.75 (s, 2H), 4.15-4.05 (m, 2H), 3.95-3.85 (m, 2H), 2.75 (s, 3H), 2.15-2.00 (m, 4H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Li]CCCC.Cl[CH2:17][CH2:18][CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1>>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2([CH2:19][CH2:18][CH2:17][N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[O:21][CH2:22][CH2:23][O:24]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: c1ccc2c(c1)CCNC2
Agent: [Li]CCCC
Product: Fc1ccc(C2(CCCN3CCc4ccccc4C3)OCCO2)cc1
Yield: 16 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline, n-BuLi, and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane were allowed to react under conditions analogous to Example 1, Method C. Flash chromatographic purification provided 4A (16% yield) as a yellow oil. 1H NMR(300 MHz, CDCl3, δ): 7.44-7.39 (m, 2H), 7.15-6.98 (m, 6H), 4.08-3.96 (m, 2H), 3.83-3.71 (m, 2H), 3.57 (s, 2H), 2.87 (t, 2H, J=6 Hz), 2.67 (t, 2H, J=6 Hz), 2.47 (t, 2H, J 7 Hz), 1.96-1.91 (m, 2H), 1.69-1.59 (m, 2H).
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]([CH3:55])([CH3:54])[CH2:7][O:8][C:9](=[O:53])[C:10]([CH3:52])([CH3:51])[C:11]([O:13][CH2:14][O:15][C:16]1[N:17]([C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[N:18]=[C:19]([CH:21]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[NH:44])[NH2:43])=[CH:38][CH:37]=2)[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH2:31][CH2:32][OH:33])[C:23]=2[F:34])[N:20]=1)=[O:12].CC(N(C)C)=O.[N+](C1C=CC([O:71][C:72](=O)[O:73][CH2:74][C:75]([CH3:78])([CH3:77])[CH3:76])=CC=1)([O-])=O>C(N(CC)CC)C>[CH3:5][C:6]([CH3:55])([CH3:54])[CH2:7][O:8][C:9](=[O:53])[C:10]([CH3:52])([CH3:51])[C:11]([O:13][CH2:14][O:15][C:16]1[N:17]([C:45]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)[N:18]=[C:19]([C@H:21]([NH:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]([NH2:43])=[N:44][C:72]([O:73][CH2:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:71])=[CH:40][CH:41]=2)[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH2:31][CH2:32][OH:33])[C:23]=2[F:34])[N:20]=1)=[O:12]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Reactant: CC(C)(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethylmalonic acid 5-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-metho xyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester 2,2-dimethylpropyl ester acetate (Example 18e, 70 mg) and DMA (2 mL), carbonic acid 2,2-dimethylpropyl ester 4-nitrophenyl ester [CAS No. 158810-98-1] (70 mg) and triethylamine (0.07 mL) were added, and the resulting mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain a racemate of the captioned compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[N:6]=[CH:5]2.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][NH:29][C:28](=[O:32])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N[C@@H]1CCCC[C@H]1N.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)Cl.[Cu]I>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][N:29]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:6]=[CH:5]3)[C:28](=[O:32])[CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Brc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Yield: 7.2 %

Procedure:
A suspension of 5-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazole (0.21 g, 0.70 mmol) in 1,4-dioxane (10 mL) stirred under nitrogen was treated sequentially with 4-(benzyloxy)pyridin-2(1H)-one (0.14 g, 0.70 mmol), trans-1,2-diaminocyclohexane (0.03 mL, 0.2 mmol), CuI (28 mg, 0.15 mmol) and K2CO3 (0.19 g, 1.4 mmol). After stirring overnight at 110° C., the mixture was allowed to cool to room temperature, diluted with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 95:5 to 90:10) gave the title compound (21 mg, 7%) as an off-white powder: 1H NMR (500 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.66 (d, J=1.4 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.43-7.36 (m, 6H), 7.28 (d, J=7.5 Hz, 1H), 6.09-6.06 (m, 2H), 5.06 (s, 2H), 4.58-4.55 (m, 2H), 3.03 (br m, 2H), 2.61 (br m, 4H), 1.81 (br m, 4H); ESI MS m/z 415 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)(OC(C)(C)C)=O.[H-].[Na+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CN(C=O)C>[CH3:23][S:24]([N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:10]2[CH2:9][NH:8][CH2:20][CH2:19][C:11]1=2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c2c(c3ccccc31)CNCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
N-Boc-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (800 mg, 2.94 mmol) was dissolved in DMF (20 mL) and stirred at room temperature. The vessel was flushed with argon and sodium hydride (235 mg, 5.87 mmol) was added. After 30 minutes, the reaction was cooled to 0° C. and methanesulphonyl chloride (0.46 mL, 5.87 mmol) was added dropwise over 5 minutes. The mixture was stirred and allowed to warm to room temperature overnight and the solvent removed in vacuo. TLC and LCMS showed that the BOC group was removed during this process. Therefore the residue was partitioned between 2M aqueous sodium hydroxide (30 mL) and dichloromethane (2×100 mL) and combined organics treated with brine (30 mL), dried (sodium sulphate), concentrated in vacuo. Flash column chromatography (silica, eluting with 100% dichloromethane/5% methanolic ammonia in 50% ethanol/dichloromethane) gave 5-methanesulphonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a pale yellow brittle solid (135 mg, 18%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Sn](Cl)Cl>>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)NC(=O)CCc1ccccc1
Agent: Cl[Sn]Cl
Product: CCOC(=O)C(Cc1cccc(N)c1)NC(=O)CCc1ccccc1

Procedure:
Corresponding to Example 3b, 3.0 g of (6a) were reduced using tin-(II) dichloride. A white solid was obtained (yield: 1.2 g).
Reaction SMILES: C(OC(N[C:12]1([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][C:12]1([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)C1(NC(=O)OCc2ccccc2)CCC(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)C1(Cl)CCC(=O)O1

Procedure:
A mixture of 80 mg of the Compound (10) obtained in Example 10, 131 mg of triphenylphosphine and 5 ml of carbon tetrachloride was heated under reflux for 4 hours in nitrogen streams. The solvent was evaporated off. The residue was subjected to a flash chromatograph using silica gel, followed by elution with hexane-ethyl acetate (1:2) to give 46 mg of the subject Compound (13) as colorless crystals, m.p. 50.5-51.0° C.