Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[CH2:9][CH2:10][CH:11]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:14](=[O:25])[CH2:13][NH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>>[CH2:1]([N:8]([CH3:26])[CH2:9][CH2:10][CH:11]1[CH2:16][N:15]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:14](=[O:25])[CH2:13][N:12]1[C:31]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCC1CN(Cc2ccc(F)cc2)C(=O)CN1)Cc1ccccc1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1CCN(C)Cc1ccccc1
Reaction time: 0.25 h

Procedure:
The title compound was prepared from 5-{2-[benzyl(methyl)amino]-ethyl}-1-(4-fluorobenzyl)piperazine-2-one (1.15 g, 3.23 mmol) and isopropyl isocyanate (0.412 g, 4.84 mmol) essentially according to the procedure described in Example 6, Step 8. The crude product was purified by silica gel chromatography (120 g RediSep column, 85 mL/min, gradient elution with EtOAc for 4 min, then with 0-10% MeOH-EtOAc over 15 min, then with 10% MeOH-EtOAc for 11 min) to afford the title compound as a viscous, light orange oil. 1H NMR (400 MHz, CDCl3): δ 7.34-7.19 (br m, 7 H), 7.03-6.98 (m, 2 H), 5.59 (m, 1 H), 4.75 (d, J=11.6 Hz, 1 H), 4.58 (d, J=14.8 Hz, 1 H), 4.28 (d, J=11.6 Hz, 1 H), 4.18 (m, 1 H), 4.12 (d, J=6.0 Hz, 1 H), 3.93-3.87 (m, 1 H), 3.70 (d, J=14.8 Hz, 1 H), 3.54 (d, J=10.4 Hz, 1 H), 3.49-3.46 (br m, 1 H), 3.24 (d, J=10.4 Hz, 1 H), 2.83 (dd, J=1.2, 10.0 Hz, 1 H), 2.34-2.29 (m, 1 H), 2.18-2.14 (m, 4 H), 1.71-1.65 (m, 1 H), 1.47-1.42 (m, 1 H), 1.08 and 1.05 (d, J=5.2 Hz, rotamers, 6 H). ES MS (M+1)=441.6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2cc(F)ccc12
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cnc(F)c2cc(F)ccc12
Temperature: 145 °C
Yield: 49.8 %

Procedure:
To a solution of 1-chloro-7-fluoro-4-methoxyisoquinoline (3.7 g, 17.48 mmol) in DMSO was added cesium fluoride (10.26 g, 69.9 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (1.7 g, 49%) as white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.20-8.18 (m, 1H), 7.69-7.66 (m, 1H), 7.54-7.47 (m, 1H), 7.46 (s, 1H), 4.04 (s, 3H); 19F NMR: δ ppm 109.65 (1 F), −78.53 (1 F); MS: MS m/z 196.1 (M++1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1.[CH:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CCCCCC>[CH3:13][O:14][C:15](=[O:24])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)[C:31]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:32]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C(=O)C1CCCCC1)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
A solution of 2.88 mL (20.5 mmol) of diisopropylamine (iPr2NH) in 50 mL of tetrahydrofuran (THF) was flushed with argon and cooled to −78° C. To this solution was added dropwise 8.2 mL (20.5 mmol) of n-butyllithium (nBuLi) 2.5 M solution in hexane, and the resulting mixture was stirred at −78° C. for 20 min, after which time a solution of 4.5 g (16.3 mmol) of (4-iodo-phenyl)-acetic acid methyl ester in 25 mL of THF was added dropwise. The mixture was allowed to warm up to rt for 40 min, then it was cooled again to −78° C., and 2.62 mL (19.6 mmol) of cyclohexanecarbonyl chloride was added dropwise, and the resulting mixture was allowed to warm up to rt, and stirred at rt overnight under argon. The reaction mixture was quenched on ice by the addition of saturated ammonium chloride solution, and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate and concentrated to give 7 g of a burgundy oil which was chromatographed on silica gel (Biotage; 10% ethyl acetate in hexane) to afford 5.06 g (80% yield) of desired 3-cyclohexyl-2-(4-iodo-phenyl)-3-oxo-propionic acid methyl ester as a pale yellow solid as indicated by 1H NMR (1:2.6 keto: enol ratio). LC-MS—calcd for C16H19IO3 [M++H]+: 387.04, found: 387.0.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[NH:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[N:20][C:15]=2[C:14](=O)[O:13]C1=O>O>[NH2:11][C:16]1[C:15]([C:14]([NH:4][O:2][CH3:3])=[O:13])=[N:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2cccnc2c(=O)o1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CONC(=O)c1ncccc1N
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A solution of Methoxylamine hydrochloride (1.02 g, 12.2 mmol) in H2O (5.0 mL) was treated with Potassium carbonate (0.421 g, 3.05 mmol) followed by 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione (J. Med. Chem., 1996, 39, 4962-4703, 1.0 g, 6.1 mmol). This mixture was allowed to stir at 50° C. for ˜1 hour forming a suspension. The ppt was collected via filtration and the filtrate was stored in the freezer O/N allowing an additional 35 mg to be collected. The solids were combined to afford 257 mg of the title compound (22%). 1H NMR (400 MHz, DMSO-d6) d 11.62 (s, 1H), 7.75 (dd, J=1.4, 4.2 Hz, 1H), 7.23 (dd, J=4.2, 8.5 Hz, 1H), 7.15 (dd, J=1.4, 8.5 Hz, 1H), 6.74 (br. s., 2H), 3.65 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][C:20]4=[O:25])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22](=[O:38])[CH2:21][C:20]4=[O:25])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCSCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCS(=O)CC1=O
Temperature: -12.5 °C
Reaction time: 1 h

Procedure:
204 mg (0.48 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide are dissolved in a mixture of 12 ml dichloromethane and 1.2 ml acetic acid at −15° C. and combined with 110 mg (0.48 mmol) 3-chloroperbenzoic acid. The mixture is then stirred for one hour at −15 to −10° C., heated to ambient temperature and stirred for a further 3 hours. Then the reaction mixture is combined with semi-concentrated sodium hydrogen carbonate solution and extracted with a solvent mixture dichloromethane/methanol 19:1. The combined organic phases are washed with water, dried over magnesium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluting gradient: ethyl acetate/(ethanol/conc. ammonia solution 19:1)=1:0->4:1).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[NH:10][C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=2)[C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccc(CBr)c1
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc2c(c1)N(Cc1cccc(F)c1)C(=O)C(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
A suspension of 3-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (2.0 g, 6.86 mmol), 3-fluorobenzyl bromide (1.68 mL, 13.72 mmol) and Cs2CO3 (4.48 g, 13.72 mmol) in acetonitrile (20 mL) was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness, the residue dissolved in water and extracted with DCM. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated to dryness. Thus obtained crude product was purified by flash chromatography on silica gel column eluted with ethyl acetate/n-hexane (30% of ethyl acetate in n-hexane). The title compound (2.10 g, 77%) was obtained as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[CH:7].I[C:10]1[C:18]([N+]([O-])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[C:7][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: C#CCNC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (71.3 mg, 0.63 mmol) (see below) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.3 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (11 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 25 mg, 23%).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][S:11](=[O:25])(=[O:24])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[CH:5]=1.[OH-].[Na+]>CO>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][S:11]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])(=[O:25])=[O:24]
Reactant: COC(=O)c1cccc(CS(=O)(=O)NCc2ccc(OC)cc2OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CNS(=O)(=O)Cc2cccc(C(=O)O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 3-[(2,4-dimethoxybenzylsulfamoyl)methyl]benzoic acid methyl ester (5 g) in methanol (20 ml) was added 2M NaOH (20 ml), and the solution was stirred at room temperature for 16 h. The methanol was removed under reduced pressure and the aqueous solution was washed with ethyl acetate, acidified with HCl and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This gave the product (4.1 g) with a molecular weight of 365.4 g/mol (C17H19NO6S).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(C#N)cc2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Cyano-benzoic acid.
Reaction SMILES: [OH:1][C@H:2]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:27][CH2:26][C:20]4([C:24](=[O:25])[O:23][CH2:22][CH2:21]4)[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[OH:1][C@H:2]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@@H:3]1[NH:4][C@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:18][CH2:19][C:20]4([C:24](=[O:25])[O:23][CH2:22][CH2:21]4)[CH2:26][CH2:27]3)=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCC4(CCOC4=O)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)N1CCC2(CCOC2=O)CC1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 28 mg (0.05 mmol) of the title compound from Step A above in 1 ml anhydrous dichloromethane at ambient temperature was added 0.3 ml trifluoroacetic acid. The solution was stirred for 1 h. It was then evaporated and purified by reverse-phase HPLC (TMC Pro-Pac C18; 5-65% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give 18 mg (80%) of the title compound as a white solid. LC/MS 449.2 (M+1). 1H NMR (DMSO): δ 7.27-7.32 (m, 8H), 7.19-7.22 (m, 1H), δ 5.15 (bs, 1H), δ 4.28 (t, J=6.8 Hz, 2H), δ 4.23 (d, J=7.2 Hz, 1H), δ 4.20 (bs, 1H), δ 3.60 (bs, 1H), δ 3.27 (t, J=7.0 Hz, 1H), δ 3.21 (m, 2H), δ 3.11 (q, J=7.1 Hz, 1H), δ 2.71 (qd, J=13.1, 6.8 Hz, 2H), δ 2.23 (s, 2H), δ 1.52-1.65 (m, 5H), δ 1.38-1.44 (m, 1H), δ 1.28-1.34 (m, 2H).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:12]1([C:18](=[C:23]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([C:18](=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH:19]=[CH:20][CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CCCCC1
Reaction time: 2.5 h
Yield: 71.2 %

Procedure:
The dianion of t-butyl acetoacetate (13 mL of 1M solution, 13 mmol; prepared as described in Example 6) was added to a solution of 4-cyclohexyl-5,5-bis(4-fluorophenyl)-2,4-pentadienal (3.75 g, 11 mmol) in tetrahydrofuran at -50° C. After stirring for 2.5 hours the solution was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 0.5% methanol in methylene chloride to give 4.0 g of the title compound as an oil.
Reaction SMILES: [C@@H:1]1([N:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([C:18]([NH2:20])=[O:19])[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].O=O.C(=O)([O-])[OH:24].[Na+]>O.[Pt]>[C:18]([C:13]1[N:12]=[CH:11][N:10]([C@@H:1]2[O:7][C@H:6]([C:8]([OH:24])=[O:9])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:14]=1[C:15](=[O:16])[NH2:17])(=[O:19])[NH2:20]
Reactant: O=C([O-])O
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1C(N)=O
Agent: [Pt]
Agent: O=O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ncn([C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H]2O)c1C(N)=O
Reaction time: 48 h

Procedure:
20 g. of 1-β-D-ribofuranosyl-imidazole-4,5-dicarboxamide [see, for example, J. Chem. Soc. 1949, 232] are dissolved in 2 litres of water at 80° C. Platinum (obtained by hydrogenating 10 g. of platinum oxide) is added. Oxygen is blown into the suspension with vigorous stirring. The temperature is held at 80° C. 8.6 G. of sodium hydrogen carbonate are added in several portions so that the mixture always remains alkaline. After 2 days, the catalyst is filtered off, the filtrate concentrated to 100 ml. and acidified with trifluoroacetic acid while cooling with ice-water. The crystallizing solution is left to stand overnight in a refrigerator and the product is then filtered off. 12.4 G. of 1-desoxy-1-(4,5-dicarbamoylimidazol-1-yl)-β-D-ribofuranuronic acid are obtained.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[O:7])C>CO.O>[CH3:16][C:12]1[N:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1nc2cccc(C)n2c1-c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc2nc(C(=O)O)c(-c3cccc(C(F)(F)F)c3)n12
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Potassium hydroxide (0.2 g, 0.003 mol) was added to a suspension of 5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (compound p, 0.35 g, 0.0010 mol) in methanol (0.4 mL) and water (4.7 mL). Stirred at 80° C. for 1 hour. The methanol was removed and 6N HCl added to the residue until pH approx. 5. The white solid that formed was filtered to give 290 mg of 5-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-2-carboxylic acid as a white solid. Rf 0.20, 100% ethyl acetate; MS m/z 319 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)=[O:5])[CH3:2].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:14][CH:15]2[CH2:17][CH2:16]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cccc(S)n1
Product: CCOC(=O)c1cccc(SCC2CC2)n1
Yield: 81 %

Procedure:
6-Mercapto-pyridine-2-carboxylic acid ethyl ester (0.54 g, 2.94 mmol) obtained in Step A and bromomethyl cyclopropane were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.568 g, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Br-].[C:12]([CH2:14][CH2:15][CH2:16][Zn+])#[N:13]>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>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([CH2:16][CH2:15][CH2:14][C:12]#[N:13])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: N#CCCC[Zn+]
Reactant: Brc1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: N#CCCCc1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A mixture of 5-bromoindole (0.25 g, 1.25 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.12 mmol) was stirred under a nitrogen atmosphere for 10 minutes. 3-cyanopropyl zinc bromide [0.5 M in THF] (5.0 mL, 2.50 mmol) was added to the mixture and heated in the microwave at 100° C. for 15 minutes. The solvent was removed and the crude mixture was purified via column chromatography with silica gel, eluting with hexane/ethyl acetate (4/1) to afford the title compound in 63% yield. 1H NMR (CDCl3) δ 8.22 (br, 1H), 7.43 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 2.86 (t, J=7.3 Hz, 2H), 2.28 (t, J=7.2 Hz, 2H), 2.02 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C12H13N2 185.1 (M+H); found 185.1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([CH3:30])([CH3:29])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1)=[O:12].O>CN(C)C=O>[CH3:9][C:10]([CH3:30])([CH3:29])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Br:1])[CH:26]=2)[NH:21]1)=[O:12]
Reactant: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccccc1C1Cc2cc(Br)ccc2N1
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A solution of 4.0 g N-bromosuccinimide in 40 ml anhydrous DMF (dimethylformamide) was added dropwise at 5° C. (ice bath) over 20 minutes to a solution of 6.0 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2-yl)phenyl]propanamide in 60 ml DMF. After stirring for one hour additionally, the resulting solution was poured into excess water and the precipitated solid was collected, washed, and taken up in Et2O. The extract was washed with water and brine, dried (MgSO4) and concentrated to give 7.2 g solid. Recrystallization from cyclohexane gave 2.2 g needles, m.p. 173°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20]#[N:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]([CH3:23])([CH3:22])[C:7]=2[CH:24]=1.C1C(=O)N([Br:32])C(=O)C1.O>CC#N>[Br:32][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[C:20]#[N:21])[NH:10][C:9]1[C:8]([CH3:22])([CH3:23])[C:7]3[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[C:18](=[O:19])[C:17]2=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)c(Br)cc3c1C2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A5-2, 50 mg, 0.158 mmol) was dissolved in CH3CN (1 mL), added with NBS (56 mg, 2 eq.), and stirred at 80° C. overnight. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with MeOH and the solid remained after dissolution was filtered to obtain the target compound (yellow powder, 20 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:80]1[S:81][CH:82]=[CH:83][N:84]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.CN(C)C(=O)C>[S:81]1[CH:82]=[CH:83][N:84]=[C:80]1[NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: Brc1nccs1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Oc2ccc3nc(Nc4nccs4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
A mixture of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (165 mg, 0.4 mmol), tris(dibenzylideneacetone)dipalladium (0) (37 mg, 0.04 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (46 mg, 0.03 mmol), sodium t-butoxide (77 mg, 0.8 mmol), 2-bromothiazole (98 mg, 0.6 mmol) and N,N-dimethylacetamide (2 mL) was heated to 70° C. under nitrogen atmosphere, and the mixture was stirred for 2 hr. After allowing the reaction mixture to cool to room temperature, ethyl acetate was added to the mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone) to give the title compound (10 mg, 5%) as a light blue solid.