Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][NH:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[NH:23][C:24]2[C:29]([C:30](=[O:32])[N:31]=1)=[C:28]([O:33][CH3:34])[C:27]([O:35][CH3:36])=[C:26]([O:37][CH3:38])[CH:25]=2.CCN(CC)CC.O>CS(C)=O>[C:1]([Si:5]([CH3:19])([CH3:20])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][N:14]([CH3:15])[C:22]1[NH:23][C:24]2[C:29]([C:30](=[O:32])[N:31]=1)=[C:28]([O:33][CH3:34])[C:27]([O:35][CH3:36])=[C:26]([O:37][CH3:38])[CH:25]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2c(OC)c1OC
Reactant: CNCc1cccc(OCCO[Si](C)(C)C(C)(C)C)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2[nH]c(N(C)Cc3cccc(OCCO[Si](C)(C)C(C)(C)C)c3)nc(=O)c2c(OC)c1OC
Temperature: 120 °C
Yield: 82.12 %

Procedure:
{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzyl}-methyl-amine from Step 3 (294 mg, 1.00 mmol) and 2-chloro-5,6,7-trimethoxy-1H-quinazolin-4-one (prepared as described previously) (270 mg, 1.00 mmol) were dissolved in dry DMSO. Et3N (0.14 mL, 1.00 mmol) was added and the mixture was heated to 120° C. overnight. Upon cooling, the mixture was poured into water and extracted with diethyl ether. The ethereal extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by SiO2 eluted with 99:1 CH2Cl2/MeOH to give 435 mg (82.12%) of a white crystalline solid.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH2:16][CH3:17])([CH2:14][CH3:15])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=12.[C:18]([N:20]=[C:21]1[NH:25][CH2:24][CH2:23][S:22]1)#[N:19].O>CN(C)C=O.C(N(CC)CC)C>[C:18]([N:20]=[C:21]1[N:25]([C@@H:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH2:16][CH3:17])([CH2:14][CH3:15])[C@H:2]2[OH:1])[CH2:24][CH2:23][S:22]1)#[N:19]
Reactant: N#CN=C1NCCS1
Reactant: CCC1(CC)Oc2ccc(C#N)cc2C2OC21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 28.9 %

Procedure:
A mixture of 3,4-epoxy-2,2-diethyl-3,4-dihydro-2H-1-benzopyran-6-carbonitrile (1.07 g) and 2-cyanoiminothiazolidine (0.89 g) in N,N-dimethylformamide-triethylamine (2:1, 7.5ml) was heated at 100° C. with stirring for 8 hours and 20 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine, and then dried over anhydrous magnesium sulfate. After the solution was evaporated in vacuo, the residue was purified with silica gel column chromatography using a mixture of ethyl acetate and n-hexane (1:1) as an eluent. The fractions containing the object compound were concentrated in vacuo and the residue was recrystallized from 50% aqueous acetonitrile to give trans-4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-3,4-dihydro-3-hydroxy-2H-1-benzopyran-6carbonitrile (0.48 g).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2)=O.C1(P(=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](/[CH:1]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:11]2)#[N:13]
Reactant: N#Cc1ccc2[nH]c(C=O)cc2c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cc2cc(C#N)ccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
2-Formyl-1H-indole-5-carbonitrile (D28) (230 mg) was dissolved in acetonitrile (50 mL). Ethyl (triphenyl-λ5-phosphanylidene)acetate (522 mg) was added to the solution. The reaction was heated to 60° C. and was stirred at 60° C. for 1 hour. The reaction mixture was concentrated. The residue was purified by Biotage (25%→33% EtOAc in hexane) to afford ethyl (2E)-3-(5-cyano-1H-indol-2-yl)-2-propenoate (D29) (230 mg) as a white solid. MS (ES): C14H12N2O2 requires 240; found 239.1 (M−H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)(=[O:12])=[O:11].C([N-]C(C)C)(C)C.[Li+].[CH:29]([Si:32]([CH:47]([CH3:49])[CH3:48])([CH:44]([CH3:46])[CH3:45])[N:33]1[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[C:35]([CH:42]=[O:43])=[CH:34]1)([CH3:31])[CH3:30].O>O1CCCC1>[F:1][C:2]1[C:7]([CH:42]([OH:43])[C:35]2[C:36]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[N:33]([Si:32]([CH:44]([CH3:46])[CH3:45])([CH:47]([CH3:49])[CH3:48])[CH:29]([CH3:30])[CH3:31])[CH:34]=2)=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)(=[O:11])=[O:12]
Reactant: COc1cccc(S(=O)(=O)Nc2ccc(F)cc2F)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)Nc2ccc(F)c(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncccc34)c2F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To N-(2,4-difluoro-phenyl)-3-methoxy-benzenesulfonamide (91, 0.148 g, 0.494 mmol) in tetrahydrofuran (10.0 mL) cooled in a −78° C. acetone/dry ice bath, under an atmosphere of nitrogen, was added lithium diisopropylamide (0.85 M in tetrahydrofuran, 1.45 mL, 1.23 mmol) dropwise. After 30 minutes, 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (96, 0.15 g, 0.500 mmol, prepared as described in Example 12) was added in tetrahydrofuran (2.0 mL) into the reaction dropwise. Then the reaction was stirred for 1 hour at −78° C. and allowed to reach room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give light yellow solid (92, 0.080 g, 26.8%). MS (ESI) [M+H+]+=602.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].[CH3:20][C:21]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:22]=1[CH2:23]Cl.Cl>C(#N)C.O>[CH3:20][C:21]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:22]=1[CH2:23][NH:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: Cc1ccc(C)c(CCl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C)c(CNc2cccc(S(=O)(=O)O)c2)c1
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a stirred slurry of 52.0 g (0.30 mole) of 3-aminobenzenesulfonic acid in 225 ml of hot (65° C.) water was added 83.0 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. The temperature was stabilized at approximately 67°-68° C. and a solution of 30.93 g (0.20 mole) of 2,5-dimethylbenzyl chloride in 75 ml of acetonitrile added dropwise over 1 hr. The resulting orange solution was refluxed for 31/2 hrs, then acidified with 40 ml of conc. HCl while simultaneously distilling off 80 ml of acetonitrile. After placing the reaction mixture in a refrigerator a flocculent cream-colored precipitate formed which was collected by vacuum filtration, washed with water and air-dried. The collected solids were then slurried in 400 ml of boiling methanol for 20 minutes, then vacuum filtered and then dried in vacuo at about 60° C., which afforded 30.86 g (53.0% yield) of purified 3-(((2,5-dimethylphenyl)methyl)amino)benzenesulfonic acid as a white powder having a melting point greater than 275° C.
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[C:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1)[CH2:4][CH3:5].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.[Pd]>[NH2:1][C:2](=[O:44])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1)[CH2:4][CH3:5]
Reactant: CCC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reaction time: 16 h
Yield: 244.9 %

Procedure:
A suspension of 10% Pd/C (100 mg), tert-butyl 4-(4-((4-((2-(1-amino-1-oxobutan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A1) (167 mg, 0.275 mmol) and Et3N (1.0 mL) in DMF (10 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was diluted with EtOAc (60 mL), filtered through Celite then the solvent removed under reduced pressure to give the title compound A2 as a yellow oil (412 mg, 98%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.67 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.49-7.42 (m, 1H), 7.31 (s, 1H), 7.22-7.14 (m, 5H), 6.87 (s, 1H), 4.06 (d, J=10.5 Hz, 2H), 3.61 (dd, J=8.8, 6.1 Hz, 1H), 3.29-2.94 (m, 4H), 2.88-2.74 (m, obscured by solvent), 2.70-2.59 (m, 1H), 2.04-1.92 (m, 1H), 1.74 (d, J=12.6 Hz, 2H), 1.61-1.43 (m, 3H), 1.41 (s, 9H), 0.83 (t, J=7.3 Hz, 3H). LCMS-A: rt 6.722 min; m/z 612 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[NH:10][NH2:11])=[CH:4][CH:3]=1.[F:13][C:14]([F:27])([F:26])[C:15]1[O:20][C:19](=O)[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[N:16]=1>N1C=CC=CC=1.ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:10][N:11]2[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:16]=[C:15]2[C:14]([F:13])([F:26])[F:27])=[O:12])=[CH:6][CH:7]=1
Reactant: O=c1oc(C(F)(F)F)nc2ccccc12
Reactant: NNC(=O)Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)Nn1c(C(F)(F)F)nc2ccccc2c1=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
4-(p-Chlorophenyl)semicarbazide (1.49 g, 8.03 mmol) is added to a solution of 2-(trifluoromethyl)-4H-3,1-benzoxazin-4-one (1.72 g, 8.00 mmol) in pyridine (27 mL) at 100° C. The reaction mixture is stirred for 15 hours at 100° C., cooled to room temperature and concentrated in vacuo to obtain a solid. The solid is diluted with dichloromethane and the mixture is washed sequentially with 10% hydrochloric acid and water and concentrated in vacuo to obtain a tan solid. The tan solid is washed with dichloromethane and filtered. The filtrate is concentrated in vacuo to obtain a brown foam. The foam is diluted with ether and the mixture is washed sequentially with 10% hydrochloric acid, water and saturated sodium hydrogen carbonate solution, dried over anhydrous MgSO4, decolorized with carbon and concentrated in vacuo to obtain a cream colored foam. Flash chromatography of the cream colored foam using silica gel and a 3:1 dichloromethane/hexanes solution gives the title product as a white solid, 0.36 g, which is identified by 1HNMR spectral analysis.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]/[C@:4]1([CH3:30])[S:10](=[O:12])(=[O:11])[C@H:9]2[N:6]([C:7](=[O:13])[CH2:8]2)[C@H:5]1[C:14]([O:16]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15].C(C(CCCC)C([O-])=O)C.[Na+:41]>C1C(O)=CC=CC=1C.CC(CC(C)C)=O>[Cl:1]/[CH:2]=[CH:3]/[C@:4]1([CH3:30])[S:10](=[O:12])(=[O:11])[C@H:9]2[N:6]([C:7](=[O:13])[CH2:8]2)[C@H:5]1[C:14]([O-:16])=[O:15].[Na+:41]
Reactant: C[C@]1(/C=C/Cl)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1(=O)=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: Cc1cccc(O)c1
Product: C[C@]1(/C=C/Cl)[C@H](C(=O)[O-])N2C(=O)C[C@H]2S1(=O)=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
385 mg (0.86 mmol) of benzhydryl (E)-(2S,3S,5R)-3-(2-chloro-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate are dissolved in 2.3 ml of m-cresol under argon and stirred at 50° C. for 4 hours. Subsequently, the mixture was diluted with 15 ml of isobutyl methyl ketone, treated with 0.50 ml of sodium 2-ethylcaproate (2N solution in ethyl acetate) and extracted three times with 8 ml of water each time. The combined aqueous phases were washed once with 10 ml of isobutyl methyl ketone, lyophilized and the lyophilizate obtained was chromatographed over polymeric hydrophobic gel with water as the eluent.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([S:17](Cl)(=[O:19])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:22][C@H:23]([C@H:26]1[O:30][C:29](=[O:31])[C@H:28]([CH3:32])[CH2:27]1)[CH2:24][OH:25].O1CCCC1>O>[OH:25][CH2:24][C@H:23]([NH:22][S:17]([C:11]1[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=1[N+:14]([O-:16])=[O:15])(=[O:19])=[O:18])[C@@H:26]1[CH2:27][C@@H:28]([CH3:32])[C:29](=[O:31])[O:30]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 2 h
Yield: 56 %

Procedure:
8.66 g of triethylamine (85.7 mmol) and 9.67 g of O-nitrobenzenesulfonyl chloride (41.3 mmol) were added to a solution of (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-methyldihydrofuran-2-one hydrochloride obtained in the above reaction in a mixed solvent of tetrahydrofuran (120 ml) and water (12.0 ml) at 0° C., and the mixture was stirred at the same temperature for two hours. The reaction mixture was concentrated under reduced pressure and 200 ml of water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate). Further, 10 ml of diisopropyl ether and 20 ml of ethyl acetate were added, and the precipitated solid was collected by filtration to obtain 5.27 g of the title compound (total yield over two steps: 56%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=2)[CH:31]=[N:32][CH:33]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3cncc(F)c3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 52.4 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 5-fluoropyridine-3-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.015 g) to obtain the title compound (0.065 g) as a colorless solid. MS (ISP): 485.3 (M+H)+
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][Cl:35]>>[ClH:35].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:32]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(Cc2cccc(C(F)(F)F)c2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 197° C. and MS: m/e=528.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3-trifluoromethylbenzylchloride.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1>N1C=CC=CC=1>[CH2:1]([NH:3][C:4]([N:10]1[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][C:9]1=[O:13])=[O:5])[CH3:2]
Reactant: O=c1cc(O)cc[nH]1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)n1ccc(O)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
A 2.50 ml quantity of ethyl isocyanate was added to a suspension of 3.00 g of 4-hydroxy-2-pyridone in 20 ml of pyridine, and the mixture was stirred at room temperature for one hour. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed twice with 30 ml of water. The ethyl acetate layer was dried on anhydrous sodium sulfate and concentrated. The concentrate was recrystallized from ethanol-ether, thereby producing 1.48 g of the title compound in a yield of 30.1%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36]([C:2]3[CH:3]=[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:15][CH2:14]4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ncnn2c(CN3CCN(C(=O)C(F)(F)F)CC3)cc(Br)c12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Product: Nc1ncnn2c(CN3CCN(C(=O)C(F)(F)F)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 11 %

Procedure:
In a manner similar to the procedure described for step 3 of Example 83 and using 5-bromo-7-{[4-(trifluoroacetyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine and 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole as starting materials, 14 mg, (11%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.05 (s, 1 H) 7.89 (s, 1 H) 7.74-7.81 (m, 2 H) 7.32-7.42 (m, 5 H) 7.24 (dd, 1 H) 6.71 (s, 1 H) 5.80 (br, 2 H) 5.62 (s, 2 H), 4.00 (s, 2 H) 3.59-3.71 (m, 4 H) 2.59-2.69 (m, 4 H). LC-MS [M+H]+=535.2, RT=2.51 min
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10](=[O:18])[C:11](=[N:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]>C(O)(=O)C>[NH2:2][C:1]1[N+:16]([O-:17])=[C:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:18])[NH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)NC(=O)C(CC(C)C)=NO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(=O)c(CC(C)C)[n+]([O-])c1N
Yield: 60.9 %

Procedure:
400 Milliliters of acetic acid was added to 35 g of ethyl 2-cyano-2-(α-hydroxyiminoisocaproylamino)acetate. The mixture was subjected to a reaction for 1 hour at 70° C. Acetic acid was removed by evaporation, then the residue was mixed with toluene, and toluene was removed by evaporation. This procedure was repeated several times. The residue was purified by a silica gel column chromatography (eluting solvent: 50% by volume of ethyl acetate-n-hexane), followed by recrystallization from ethanol to obtain 21.3 g of 5-amino-6-ethoxycarbonyl-3-isobutyl-1,2-dihydropyrazin-2-one 4-oxide (Compound B-9) as yellow needle-like crystals having a melting point of 179°-181° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[NH:7][C:6]=1[CH3:15].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Cl:35][C:36]1[CH:37]=[C:38]([S:43](Cl)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[Cl:42]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[N:7]([S:43]([C:38]2[CH:39]=[CH:40][C:41]([Cl:42])=[C:36]([Cl:35])[CH:37]=2)(=[O:45])=[O:44])[C:6]=1[CH3:15]
Reactant: COC(=O)Cc1c(C)[nH]c2nccc(Cl)c12
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2nccc(Cl)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (58 mg, 0.24 mmol) in DMF (1.2 mL) is added BEMP (113 μL, 0.39 mmol). The reaction mixture is stirred at ambient temperature for 40 minutes. 3,4-Dichloro-benzenesulfonyl chloride (60 μL, 0.39 mmol) is added and the reaction mixture is stirred for 10 minutes at ambient temperature. The reaction mixture is poured into ice cold water, extracted with EtOAc, washed with brine, dried (Na2SO4) and evaporated. The crude product is purified by column chromatography on silica gel using 1:8 EtOAc/iso-hexane as the eluent, furnishing [4-chloro-1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl]-acetic acid methyl ester; MH+=449.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][O:10][C:11]1[C:16]2[C:17](=[O:27])[N:18]3[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:19]3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=[CH:13][C:12]=1[O:28][CH3:29].N1C=CN=C1.O>CN(C=O)C>[CH3:9][O:10][C:11]1[C:16]2[C:17](=[O:27])[N:18]3[CH2:25][C@H:24]([O:26][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23][C@H:19]3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=[CH:13][C:12]=1[O:28][CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Solid TBDMS Chloride (8.22 g, 54.44 mmol) was added in one portion to a solution of 170 (7.23 g, 24.74 mmol) and imidazole (8.42 g, 123.72 mmol) in anhydrous DMF (75 mL) and allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (500 mL) and filtered to afford the crude product (171), which was purified by recrystallisation from EtOH (800 mL) as fine white needles (6.995 g, 17.21 mmol, 70%). 1H NMR (270 MHz, CDCl3) δ10.06 (s, 1H, NH), 7.37 (s, 1H, ArH), 6.68 (s, 1H, ArH), 4.19-4.14 (m, 1H, 2), 4.06-4.01 (m, 1H, 11a), 3.90 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.69-3.63 (m, 2H, 3), 2.85-2.80 (m, 1H, 1), 2.05-2.01 (m, 1H, 1); 13C NMR (67.8 MHz, CDCl3) δ170.4, 170.2, 165.9, 152.1, 145.8, 145.6, 131.1, 130.7, 118.1, 111.9, 104.3, 104.1, 69.2, 69.1, 56.0, 55.9, 55.7, 54.3, 54.0, 35.0, 25.8, 25.7, 25.6, 17.9, −3.0, −3.5, −4.9, −5.0.