Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1C
Reactant: N
Solvent: CO
Product: Cc1ccccc1C(C)Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O

Procedure:
In a similar manner as described for example A9, 1.25 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-methylphenyl)ethoxy]thiophene-2-carboxylate and 60 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:5]=1.[C:20]1([CH2:26]CO)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S([O-])(O)(=O)=O.[K+].CO>C1(C)C=CC=CC=1>[C:4]1([CH2:3][CH2:19][O:18][CH:3]([O:2][CH2:1][CH2:26][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH:5]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(OC)c1cccc(OC(=O)OC(C)(C)C)c1
Reactant: OCCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)Oc1cccc(C(OCCc2ccccc2)OCCc2ccccc2)c1
Reaction time: 2 h

Procedure:
One g (3.73 mmol) of 3-tert.-butoxycarbonyloxy-benzaldehyde dimethylacetal was dissolved in 40 ml of dried toluene. After addition of 0.91 g (7.46 mmol) of 2-phenylethanol and 18 mg of potassium hydrogen sulfate, the resulting mixture was stirred for 2 hours under reflux. The methanol formed was then distilled off slowly, while more toluene was added to the mixture. After complete removal of the methanol, the mixture was cooled down and the potassium hydrogen sulfate was filtered off. The filtrate was concentrated in a rotary evaporator. This gave a yellowish, viscous oil, which was dried in an oil pump vacuum.
Reaction SMILES: [C:1]([S:5]([NH:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.I[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:20]([C:11]1[S:10][C:9]([NH:8][S:5]([C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:6])=[CH:13][CH:12]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCI
Reactant: CC(C)(C)S(=O)(=O)Nc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(NS(=O)(=O)C(C)(C)C)s1
Temperature: -20 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 2-(t-butylsulfonamido)thiophene (3.42 g, 15.6 mmol) in anhydrous THF cooled to -78° C. under N2 was added 2.5M n-BuLi (15.6 mL, 2.5 equiv). The reaction was warmed to -20° C. over 3.5 h. After stirring at -20° C. for an addional h, iodopentane (2.4 mL, 1.2 equiv) was added. The ice bath was removed and the reaction was stirred at rt overnight. The next day the reaction was quenched with sat'd NH4Cl solution and the THF was removed in vacuo. The residue was extracted with Et2O/EtOAc and washed with water and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo. The product was purified by flash chromatography on a silica column eluting with Hex/EtOAc (15:1). Removal of the solvent afforded 2.72 g (60%) of the titled compound as a yellow oil. Rf=0.4 (6:1 Hex/EtOAc).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[F:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: Nc1ccccc1F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccccc3F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 2-fluorophenylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=373.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:6]=2[CH:23]=1.[CH2:24]([N:26]([CH2:28][CH3:29])O)[CH3:25].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]([CH2:28][CH3:29])[CH2:24][CH3:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reactant: CCN(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 15, 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a] [1,4]-benzodiazepine is treated with a cold mixture of N,N-diethylhydroxylamine and sodium hydride in dimethylformamide to give 8-bromo-1-[(diethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo [4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].CO>C1COCC1>[O:11]=[C:6]1[N:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: Oc1nccc2ncccc12
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cn1ccc2ncccc2c1=O
Temperature: 100 °C
Yield: 95 %

Procedure:
1,6-naphthyridin-5-ol (1.00 g, 6.8 mmol), ethyl iodoacetate (1.6 ml, 14 mmol) and cesium carbonate (4.5 g, 14 mmol) were dissolved in 25 mL of THF then stirred and heated at 100° C. for 2 h until the reaction was complete. The reaction was concentrated and purified via MPLC using a gradient to 90% DCM: 10% MeOH to afford ethyl 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)acetate (1.5 g, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH:24]=[CH:25][CH:26]=[C:27]([OH:28])[C:20]5=[N:19][C:18]=4[CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H][H]>[C].[Pd].C(O)(=O)C>[CH3:29][C:18]1[N:19]=[C:20]2[N:21]([CH2:24][CH2:25][CH2:26][CH:27]2[OH:28])[C:22](=[O:23])[C:17]=1[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O

Procedure:
A mixture of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one (formula-11) (5 grams), acetic acid (25 ml) and palladium carbon (4 grams) was taken in an autoclave. Hydrogen gas with a pressure of 3.0 Kg/cm2 was applied to the above mixture at 32° C. for 9 hrs. The reaction mixture was filtered through a hyflow bed. The filtrate was treated with water (100 ml) and the pH of the filtrate was adjusted to 10 using aqueous sodium hydroxide solution. The solid formed was filtered, washed with water and dried at 50° C. to yield the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13](O)[N:12]2[N:16]=[CH:17][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:36])=O>>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([Cl:36])[N:12]2[N:16]=[CH:17][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CCCCCc1cnn2c(O)nc(SCc3ccccc3)nc12
Solvent: CN(C)c1ccccc1
Product: N#CCCCCc1cnn2c(Cl)nc(SCc3ccccc3)nc12

Procedure:
A solution of compound (4) (6.0 g, 17.7 mmol) and N,N-dimethylaniline (2.24 mL, 17.7 mmol) in phosphorus oxychloride (20 mL) was heated to reflux in a sealed tube for 1 h. Solvent was removed and the residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3, dilute HCl, followed by brine, dried over anhydrous Na2 SO4, filtered and concentrated to give 5-(2-benzylsulfanyl-4-chloro-pyrazolo[1,5-a][1,3,5]triazin-8-yl)-pentanenitrile (5), which was used directly for the next step.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:19]1([CH2:25][CH:26]([CH3:29])[CH2:27]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH:26]([CH3:29])[CH2:27][O:1][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Reactant: CC(CCl)CN1CCCCC1
Product: CC(COc1c2c(oc(=O)c1-c1ccccc1)CCCC2)CN1CCCCC1
Yield: 82 %

Procedure:
Prepared according to the method of Example 13 by alkylation of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin with 3-piperidino-2-methyl-1-chloropropane. A thick oil is obtained which cannot be crystallised. Yield 82%.
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][OH:10]>>[CH2:1]([S:8][C:1]1[C:9](=[O:10])[CH2:4][CH2:3][CH:2]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CO
Reactant: CCCCCCCS
Product: CCCCCCCSC1=CCCC1=O
Yield: 49 %

Procedure:
Cyclopentenone (3.40 g) was oxidized in 15 ml of methanol using 4.4 ml of an aqueous solution of hydrogen peroxide and 4 ml of a 3 N aqueous solution of sodium hydroxide to afford crude 2,3-epoxycyclopentanone. To the crude product was added dropwise slowly 30 ml of a solution of 3.20 g of n-heptylmercaptan in methanol at room temperature over the course of 1.5 hours. Thirty minutes after the end of addition, the reaction mixture was concentrated under reduced pressure, and diethyl ether was added. The organic layer was washed with water, and treated in a customary manner to afford 5.21 g of a crude product. The crude product was chromatographed with cyclohexane/ethyl acetate (=8/2) to afford 2.50 g of 2-n-heptylthiocyclopent-2-en-1-one in a yield of 49%. The product had the following characteristics.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](=O)[CH2:26][CH3:27]>>[CH2:1]([N:8]([CH2:25][CH2:26][CH3:27])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: NC(=O)OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Product: CCCN(Cc1ccccc1)c1ccc(-c2cc(COC(N)=O)on2)cc1

Procedure:
An experiment was performed using the compound carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester in Example 74 as a starting material and propionaldehyde in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(benzyl-propyl-amino)-phenyl]-isoxazol-5-ylmethyl ester.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19]C)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].[OH-].[K+].Cl>CO.O>[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:10][CH2:11][C:12]([C:17]([OH:19])=[O:18])([CH2:13][CH2:14]1)[CH2:15][CH2:16]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCCC12CCC(C(=O)OC)(CC1)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)CCCC12CCC(C(=O)O)(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfone 11-7 (3.1 g, 10 mmol) was dissolved in 9:1 MeOH/water (50 mL) and treated with potassium hydroxide (3 g). The solution was stirred at room temperature overnight, then the mixture was acidified with 1 N HCl and extracted four times with 50 mL of methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford 4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]octane-1-carboxylic acid (11-8) which was used without purification in the next step. 1H NMR (500 MHz, CDCl3): δ 3.03 (2H, q, J=7 Hz), 2.94 (2H, dd, J=7.5 Hz), 1.84 (8H, m), 1.45 (8H, m), 1.30 (2H, m) ppm.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH3:10][O:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([NH:18][C:19](=[O:21])[CH3:20])=S)=[CH:14][CH:13]=1.Cl.Cl.[NH2:26][CH:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:28]([NH:30][C:31]1([C:38]#[N:39])[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:29].C(N(CC)C(C)C)(C)C>ClCCl>[C:19]([N:18]=[C:16]([NH:26][CH:27]([CH2:40][CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)[C:28]([NH:30][C:31]1([C:38]#[N:39])[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1)=[O:29])[C:15]1[CH:22]=[CH:23][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc(C(=S)NC(C)=O)cc1
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=NC(C)=O)NC(CC2CCCCC2)C(=O)NC2(C#N)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-N-methylpyridinium iodide (660 mg, 2.58 mmol), was added to a solution of N-(4-methoxy-thiobenzoyl)acetamide (420 mg, 2.01 mmol), 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt (730 mg, 2.00 mmol), and N,N-diisopropylethylamine (1.05 mL, 6.02 mmol) in dichloromethane (8.0 mL). The reaction mixture was stirred at room temperature for 2 h, then diluted with dichloromethane (100 mL)and washed with 2×150 mL of saturated sodium bicarbonate. The organic phase was dried (MgSO4) and concentrated. The resulting residue was chromatographed over 100 g of flash silica first using EtOAc, then dichloromethane/methanol 9:1 as the eluant to provide the desired product as an off white solid (377 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ 0.70-0.90 (m, 2H), 1.00-1.30 (m, 4H), 1.35-1.65 (m, 8H), 1.72 (s, 3H), 1.85-2.20 (m, 6H), 2.48-2.60 (m, 1H), 3.78 (s, 3H), 4.20-4.35 (m, 1H), 6.95-6.99 (m, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H). MS, m/z 468=M+1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH3:21][CH:22]([CH3:26])[CH2:23][C:24]#[CH:25]>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>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:25]#[C:24][CH2:23][CH:22]([CH3:26])[CH3:21])[CH:4]=1
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: C#CCC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)c1ccc(OC)cc1C#CCC(C)C
Yield: 98.3 %

Procedure:
Coupling of methyl 4-(methyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (77) (1.0 g, 3.18 mmol) with 4-methyl pentyne (0.78 mL, 6.36 mmol) using Pd(PPh3)2Cl2 and CuI gave 0.77 g (98%) of compound 102 as a brown oil. 1H NMR (400 MHz, CDCl3): δ 1.06 (d, J=6.8 Hz, 6H), 1.90-2.00 (m, 1H), 2.37 (d, J=6.4 Hz, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.82 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.00 (d, J=2.7 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 247 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([NH:18]C(=O)C)[NH:15][N:14]=1)(=[O:12])=[O:11].Cl>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([NH2:18])[NH:15][N:14]=1)(=[O:12])=[O:11]
Reactant: CC(=O)Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Yield: 84.9 %

Procedure:
A solution of 45.0 g (0.13 mol) of N-(2,6-dichlorophenyl)-5-acetamido-1,2,4-triazole-3-sulfonamide, 60 ml of 6N aqueous hydrochloric acid, and 500 ml of THF was heated at reflux for 4 hrs. The reaction mixture was cooled and the solvent was removed by rotary evaporation in vacuo. The crude solid was triturated with 5 ml of cold ethanol and then recrystallized from water. The desired product was collected by filtration and dried to yield 34.0 g (86 percent) of the desired product as a white solid, mp 262°-264° C. (decomposition). IR, 1H NMR, and 13C NMR were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccccc1-c1cc(CCl)ccn1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3ccccc3OC)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(2-methoxyphenyl)pyridine (234 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23](O)=[O:24])=[CH:15][CH:14]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:23]([C:16]3[C:17]4[N:18]=[CH:19][CH:20]=[N:21][C:22]=4[C:13]([C:3]4[C:4]([F:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])=[CH:14][CH:15]=3)=[O:24])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(F)c(OC)cc(OC)c4F)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1), and stirring the reaction mixture for 48 h at rt and for 5 h at 50° C. after addition of further 1.2 equiv of TBTU. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 549.1 [M+H]+; tR=3.39 min (System 1); TLC: Rf=0.24 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.COP([CH2:17][C:18](=[O:20])[CH3:19])(=O)OC.C([O-])([O-])=O.[K+].[K+]>O>[O:20]=[C:18]([CH3:19])/[CH:17]=[CH:1]/[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: COP(=O)(CC(C)=O)OC
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)/C=C/c1ccc(C#N)cc1
Temperature: 0 °C
Yield: 71.9 %

Procedure:
A two necked flask was charged with 4-formyl-benzonitrile (20.0 g, 0.152 mol) and (2-oxo-propyl)-phosphonic acid dimethyl ester (30.4 g, 0.18 mol) and cooled down at 0° C. K2CO3 (42.16 g, 0.305 mol) in H2O (45 mL) was added dropwise. Stirring was continued over night at RT. The product was extracted with EtOAc, and the organic phase was dried over Na2SO4. Flash chromatography (SiO2, Heptane/EtOAc 1:1) afforded 18.7 g (72%) of the title compound as alight yellow solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:13]1([C:24]2[C:25]([O:30][CH2:31][CH3:32])=[N:26][CH:27]=[CH:28][CH:29]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[NH:15][C:14]1=[O:23].Cl>CN(C)C=O.ClCCl>[Cl:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:23])[C:13]2([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[C:24]1[C:25]([O:30][CH2:31][CH3:32])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(C(C(=O)OC)C(=O)OC)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
11.2 ml (98 mmol) of dimethyl malonate were slowly added dropwise to a suspension, cooled to 10° C., of 3.56 g (89 mmol) of sodium hydride (60% dispersion in mineral oil) in 150 ml of dimethylformamide, and the mixture was then stirred at room temperature for 30 minutes. Subsequently, 9.6 g (30 mmol) of 3,5-dichloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one from example 1.1 were added in portions, and the mixture was stirred at room temperature for 15 min. To work up the reaction it was stirred into cold 1N HCl, and dichloromethane was added. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water and saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was recrystallized from dichloromethane/pentane. 9.01 g of the title compound were obtained as a yellowish solid.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)=[CH:22][CH:21]=1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-n2cnc3ccc(O)nc32)cc1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 4-methoxyphenylboronic acid, prepared in a similar manner as the one described in Example 1.25, Steps A and B, the title compound was obtained as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 3.9 (s, 3H), 6.92 (d, J=8.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 8.10 (d, J=8.8 Hz, 1H), 9.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH:19]=[CH:20][C:21]([O:23]C(C)(C)C)=[O:22])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:21]([CH:20]=[CH:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[F:30])=[N:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18])([OH:23])=[O:22]
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A solution of 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline (581 mg, 1.31 mmol) in a mixture of methylene chloride/TFA (2.5 ml/2.5 ml) was stirred at ambient temperature for 1.5 hours. After removal of the volatiles under vacuum, the residue was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH3 with 0.5M sodium hydroxide. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to give 7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (430 mg, 85%).