Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][N:17]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O.Cl>[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][N:17]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C(CN(Cc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CN(Cc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
Lithium hydroxide (62.4 mg) was added to a solution of the product of step (b) (1.0 g) in tetrahydrofuran/water (30 ml). The resulting solution was stirred at room temperature for 4 hours, diluted with 1N HCl (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless foam (990 mg). NMR δH (360 MHz, CDCl3) 1.44 (9H, s), 3,49 (2H, m), 4.51 (3H, m), 5.17 (2H, m), 5.79 (1H, br s), 7.20-7.42 (8H, m). m/e (CI+) 497 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6](SC)=[N:7][CH:8]=1)#[N:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([NH:14][NH2:15])=[N:7][CH:8]=1)#[N:2]
Reactant: NN
Reactant: CNc1nc(SC)ncc1C#N
Solvent: O
Solvent: CCO
Product: CNc1nc(NN)ncc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-cyano-4-methylamino-2-methylsulfanyl-pyrimidine (25.86 g) from Example 3 and hydrazine hydrate (52 mL) in ethanol (250 mL) was heated at reflux with stirring for 3 hours. The reaction mixture was cooled to room temperature and the insoluble product was collected by filtration, washed with cold aqueous ethanol (1:1) to give 23 g of the title compound. Crystallization from ethanol afforded an analytically pure sample of 5-cyano-2-hydrazino-4-methylamino-pyrimidine; mp 247-249° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CC(C)=O>[O:27]=[C:20]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To an ice-cooled solution of 3-(trifluoromethyl)aniline (64.5 g, 0.40 mol) and triethylamine (60 ml) in acetone (700 ml) was added dropwise, ethyl 3-chloro-3-oxopropanoate (63.6 g, 0.42 mol) in acetone (50 ml). After the addition was complete (approx. 30 minutes), stirring was continued at RT overnight. The solvents were removed and water (1200 ml) was added. The resulting precipitate was filtered off, thoroughly washed twice with water and then dried to afford ethyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate as a yellow powder (109 g, 99%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]12[NH:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][C:15]1[CH:14]=[CH:13][C:12]([NH2:21])=[CH:11][C:10]2=1>C(#N)C>[Cl:1][C:11]1[C:10]2[CH:9]3[NH:20][CH:17]([CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1[NH2:21])[CH2:18][CH2:19]3
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Solvent: CC#N
Product: Nc1ccc2c(c1Cl)C1CCC(C2)N1
Yield: 15 %

Procedure:
N-chlorosuccinimide (172 mg, 1.3 mmol) was added to a solution of 12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (150 mg, 0.86 mmol) in acetonitrile (10 mL) at 60° C. in one portion. The reaction was then heated at reflux for 5 h. The resulting mixture was concentrated, diluted with CH2Cl2 (10 mL), washed with 10% ammonium hydroxide (5 mL) and brine (5 mL) before drying over MgSO4 and filtering. Concentration and purification with silica gel chromatography (0-20% MeOH in CH2Cl2) gave 3-Chloro-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine as a brown solid (27 mg, 16%). 1HNMR (400 MHz, CDCl3) δ 6.8 (d, 1H, J=8.1 Hz), 6.6 (d, 1H, J=8.1 Hz), 4.7 (d, 1H, J=5.3 Hz), 4.0-3.8 (m, 4H), 3.2 (dd, 1H, J=16.5, 4.8 Hz), 2.5 (d, 1H, J=16.5 Hz), 2.2-2.1 (m, 2H), 1.9 (m, 1H), 1.6 (m, 1H); MS (m/e) 209 (M+1); mp 220-224° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\C(C2C=CC3C=CSC=3C=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][C:45]=1[O:53][CH3:54]>>[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](/[N:31]=[C:14]2/[N:13]([C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:2])[CH3:3])[CH2:12][CH2:11]3)[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/2)=[O:50])=[CH:46][C:45]=1[O:53][CH3:54]
Reactant: COc1cc(C(=O)O)ccc1F
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: COc1cc(C(=O)/N=c2\[nH]c3cnc(OCCN4CCCCC4)cc3n2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)ccc1F

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 4-fluoro-3-methoxybenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-methoxybenzamide (43.1% yield). MS m/z=581.4 [M+H], calc 580.69 for C31H41FN6O4.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]3[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23.C[Sn](C)(C)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(#N)C>C(O)C.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>[N:28]1[CH:29]=[CH:30][C:25]([C:2]2[C:3]([F:22])=[CH:4][C:5]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]4[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=2[C:6]=34)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cn2c3c(c(Br)c(F)cc3c1=O)OC[C@@H]2C
Reactant: C[Sn](C)(C)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)c1cn2c3c(c(-c4ccncc4)c(F)cc3c1=O)OC[C@@H]2C
Temperature: 150 °C

Procedure:
Ethyl (S)-10-bromo-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (U.S. Pat. No. 4,839,355, Example 5f) (3.50 g), 2.97 g of 4-(trimethylstannyl)pyridine and 0.155 g of dichlorobis(triphenylphosphine)palladium were combined in a Parr apparatus in 200 ml of absolute ethyl alcohol and the mixture under nitrogen was heated at 150° C. for 41/2 hours, allowed to cool slowly and concentrated in vacuo. The concentrate was taken up in chloroform and residues were removed by filtration. The filtrate was extracted with sufficient 1M hydrochloric acid to extract all the product and the aqueous extract was poured onto ice and saturated sodium acetate was added. The resulting mixture was extracted with chloroform and the chloroform extract was washed with brine followed by sodium bicarbonate, dried over magnesium sulfate and concentrated to give, after recrystallization from acetonitrile, 2.56 g of a mixture of the title compound with its corresponding 6-carboxylic acid (73.5% yield); m.p. 249°-252° C. This was combined with 100 mg of the same product obtained previously by an analogous procedure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].S(Cl)([Cl:20])(=O)=O.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([Cl:20])[C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-oxo-5-phenyl-pentanoic acid ethyl ester (1.6 g, 7.76 mmol) in methylene chloride (18 mL) is added sulfuryl chloride (1.15 g, 8.53 mmol) dropwise. After stirred at room temperature for 6 hours, the reaction mixture is poured into water, extracted with methylene chloride, is washed water and brine, dried over sodium sulfate. Concentration gave the crude title compound, which is used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:1]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc(C#N)cn1
Temperature: 130 °C

Procedure:
To a stirred solution of 6-aminonicotinonitrile (L-1) (8.7 g, 73 mmol) in DMF (35 mL) was added N,N-dimethylformamide dimethyl acetal (35 mL, 294 mmol). The reaction mixture was heated to 130° C. overnight. After cooled to room temperature, the volatiles were removed under reduced pressure to afford the desired intermediate N′-(5-cyanopyridin-2-yl)-N,N-dimethylformamidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:13])[CH:11]([N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(O)C(N(Cc2ccccc2)Cc2ccccc2)C1
Yield: 15.8 %

Procedure:
3.7 g (0.02 mole) of 1-t-butoxycarbonyl-3,4-epoxypyrrolidine (prepared as described in Preparation 8) were dissolved in 15 ml of ethanol. 7.88 g (0.04 mole) of dibenzylamine were added to the solution, and the mixture was heated under reflux for 10 hours. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel, eluted with a 12:88 by volume mixture of ethyl acetate and toluene, to give 1.21 g of 1-t-butoxycarbonyl-3-dibenzylamino-4-hydroxypyrrolidine as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=O.Cl.[Cl:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][NH2:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][N:18]=[CH:3][C:2]([CH3:6])([CH3:5])[CH3:1]
Reactant: NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(C)(C)C=O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(C)(C)C=NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a mixture of 0.07 g of trimethylacetaldehyde and 5 ml of pyridine was added 0.30 g of O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.31 g (yield, 96.8%) of trimethylacetaldehyde O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-pentyl)oxime, nD23.0 1.5178.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:23][C:24]([F:38])([F:37])[O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:32](=[O:33])[CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([O:25][C:24]([F:37])([F:23])[F:38])=[CH:27][CH:28]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: O=C(O)COc1ccc(OC(F)(F)F)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(OC(F)(F)F)cc3)CC2)c2nc(-c3cccnc3)sc2n1
Yield: 45 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-trifluoromethoxyphenoxyacetic acid in a yield of 45%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.[F:33][C:34]([F:42])([F:41])[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:27]=[CH:28][C:29]([O:32][S:37]([CH2:36][CH2:35][C:34]([F:42])([F:41])[F:33])(=[O:39])=[O:38])=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Solvent: c1ccncc1
Product: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(2-Chloro-4-fluorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (0.223 g, 0.49 mmol) was co-concentrated with pyridine twice and put under nitrogen. Pyridine (2.5 ml) was added and the reaction mixture cooled to 0° C. with an ice-bath followed by addition of 3,3,3-trifluoropropane-1-sulfonyl chloride (0.153 g, 0.78 mmol). The reaction mixture was stirred at 0° C. for 3 h adding more 3,3,3-trifluoropropane-1-sulfonyl chloride (0.171 g, 0.87 mmol) after 1 h 10 min. The ice bath was removed and the reaction mixture evaporated. The crude product was purified by hplc to yield the product as a beige solid after freeze-drying (0.19 g, 63%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([Br:15])[C:11](N)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)(C)C)=[O:17]>CN(C=O)C.O>[CH2:1]([C:8]1[CH:9]=[C:10]([Br:15])[C:11](=[O:17])[NH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc(Cc2ccccc2)cc1Br
Reactant: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cc(Cc2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-benzyl-3-bromopyridin-2-amine 3 (0.2 g, 0.7 mmol) in DMF (4 mL) was added water (2 drops) followed by t-butyl nitrite (0.378 g, 3.6 mmol) and the reaction mixture stirred at RT for 30 min. DMF and the excess reagent were distilled off, and the residue purified by flash chromatography on silica gel (EtOAc:hexane, 1:1). Yield 7.3 g (86%), white solid, mp 151-152° C. 1H NMR (CDCl3, 500 MHz): δ 3.77 (s, 2H, CH2), 7.17-7.36 (m, 6H, Ar—H and CH), 7.76 (d, 1H, CH, J=1.5 Hz) 13.25 (bs, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 37.3, 115.4, 121.0, 126.9, 128.8, 128.8, 128.9, 128.9, 132.4, 138.5, 145.3, 161.0; HRMS (M+H)+ calcd for C12H11BrNO 264.0024, found 264.0014.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[O:12][CH2:13][C:14]3[CH:15]=[N:16][S:17][C:18]=3[C:5]2=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[O:12][CH2:13][C:14]3[CH:15]=[N:16][S:17][C:18]=3[C:5]2=[CH:4][CH:3]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OCc1cnsc1-2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1cnsc1-2
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a stirred solution of methyl 7-amino-4H-chromeno[3,4-d]isothiazole-6-carboxylate (Intermediate 74, 0.300 g) in DCM (15 mL) was added pyridine (2.5 mL), followed by 2-bromo-4-fluorobenzenesulfonyl chloride (0.468 g). The resultant mixture was stirred at room temperature overnight. A further amount of 2-bromo-4-fluorobenzenesulfonyl chloride (0.300 g) was added and stirring was continued overnight. The mixture was diluted with DCM and washed with 0.5M hydrochloric acid and aqueous sodium bicarbonate. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 15-45% to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-chromeno[3,4-d]isothiazole-6-carboxylate (0.460 g) as a cream solid.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[S:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:40])=[C:26]([CH:39]=1)[C:27]([NH:29][C:30]1[N:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1)=[O:28].[OH-].[Na+]>ClCCl>[NH:1]1[C:5]2[C:6]3[S:13][CH:12]=[CH:11][C:7]=3[N:8]([C:36]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[C:26]4[CH:39]=[C:22]([F:21])[CH:23]=[CH:24][C:25]=4[CH3:40])=[N:35][CH:34]=3)=[O:37])[CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1
Reactant: c1cc2c(s1)-c1[nH]ncc1CCN2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)cn1
Reaction time: 8 h

Procedure:
To a solution of 2 mmol of 1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 4.2 mmol of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. After stirring overnight, the mixture is worked-up as described for Example 1, and the initial solid treated with 1N NaOH as described for Example 1 to give the product as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15]O)[CH2:2][CH2:3][CH3:4].[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOc1c(NCCCO)c(=O)c1=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCOc1c(NCCCS(C)(=O)=O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of 1-butoxy-2-(3-hydroxypropylamino)-1-cyclobutene-3,4-dione [prepared in Example 7] (1.0 g, 4.4 mmol) in 5 mL of pyridine was cooled to 0° C. and treated dropwise with 0.36 mL (4.6 mmol) of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 1 hour then poured into 80 mL of water and extracted with 20 mL of ethyl acetate. The organic phase was washed 4 times with water, dried and evaporated to give 0.84 g of title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])C(O)=O)=[O:4].C(Cl)(=O)[C:17]([Cl:19])=[O:18]>ClCCl.CN(C)C=O>[F:15][C:2]([F:1])([F:14])[C:3]([NH:5][CH2:6][CH2:10][CH2:11][CH2:12][CH2:13][C:17]([Cl:19])=[O:18])=[O:4]
Reactant: CCCCC(NC(=O)C(F)(F)F)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCNC(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
735 mg(3 mmol) (2,2,2-trifluoro-acetylamino)-hexanoic acid were dissolved in 5 mL dried dichloromethane and stirred under argon flux at 0° C. Then, 0.6 mL (6.6 mmol) oxalyl chloride were added dropwise at 0° C., a few drops of dried dimethylformamide were also added dropwise which lead to gas development and yellow colouring of the previously white mixture. The mixture, was stirred at room temperature for 70 min. Then the mixture was repeatedly evaporated with dichloromethane. The crude product was used directly in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1)=[O:6].CC1C=C(C)C=C(C)C=1S([NH:29]O)(=O)=O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:11]([NH2:29])[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: CCOC(=O)c1ccc(C(=O)OC)[nH]1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(=O)OC)n1N
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 90 mg) was added to a solution of 1H-pyrrole-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester (100 mg) in N,N-dimethylformamide (2 mL) and the resulting mixture was stirred for 5 minutes. 2,4,6-Trimethyl-benzenesulfonylhydroxylamine (prepared from 0.5 g of mesitilene oxamate as described in JOC 1973, 1239) was then added and the mixture was stirred for 5 minutes. The reaction mixture was then quenched by addition of water and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 90/10) to afford 100 mg of 1-amino-1H-pyrrole-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][OH:33])[CH2:26]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2([C:45](O)=[O:46])[CH2:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>C(Cl)Cl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2([C:45]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][OH:33])[CH2:26]3)=[O:46])[CH2:44][CH2:43][CH2:42]2)=[CH:39][CH:40]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: OCC1CCCCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 95 %

Procedure:
iPrEtN (1.78 mL, 10.2 mmol) and pyBrOP (2.39 g, 5.12 mmol) were added at room temperature to a stirring solution of azepan-3-yl-methanol (0.4392 g, 3.41 mmol) and 1-(4 Chlorophenyl)-cyclobutanecarboxylic acid (1.0778 g, 5.12 mmol) in CH2Cl2 under N2. When the reaction was complete, the reaction was subjected to aqueous work-up. Silica gel purification (4:1 to 2:3 Hexanes:Ethyl acetate) provided the desired product in 95% yield (1.0395 g). LRMS: 321.91.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11](=O)[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH3:20])#[N:2].[OH-:22].[Na+].OO>CCO>[CH3:20][O:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[C:11]1[NH:2][C:1](=[O:22])[C:3]2[C:4](=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:10]=1
Reactant: [OH-]
Reactant: COc1cccc(C)c1C(=O)Nc1cc(C)ccc1C#N
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C)c1-c1nc2cc(C)ccc2c(=O)[nH]1
Yield: 6.4 %

Procedure:
N-(2-Cyano-5-methyl-phenyl)-2-methoxy-6-methyl-benzamide (25 g, 0.09 mol) was suspended in 500 mL EtOH, and 121.3 g of 33% aq. NaOH (1 mol, 11 equiv) was added. To this was added a 35% H2O2 solution (50 mL, 0.58 mol), and the reaction was heated to reflux. Additional H2O2 was added dropwise until the reaction mixture became clear. EtOH was removed under reduced pressure, and the precipitate formed was removed by filtration. The solution was acidified with acetic acid to pH 5, and the precipitate formed was collected by filtration. The precipitate was washed twice with water and once with diethyl ether. The product was purified over alumina using EtOAc/heptane (1:1) as an eluent. Another purification was performed, over silica gel with the same eluent to yield 2-(2-methoxy-6-methyl-phenyl)-7-methyl-3H-quinazolin-4-one (1.61 g).