Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](I)=[N:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.Cl>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.O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:18](=[O:20])[CH3:19])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2ccc(I)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc2ccc(Br)cc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a stirred slurry of 7-bromo-2-chloro-quinoline (obtained from AstaTech, Inc.), (8.10 g, 33.4 mmol) and sodium iodide (50.0 g, 334 mmol) in acetonitrile (27 mL) was slowly added acetyl chloride (3.56 mL, 50.0 mmol). The flask was stoppered and sealed and heated at 80° C. for 3 h before being allowed to cool. The mixture was treated sequentially with 10% w/w aqueous potassium carbonate solution (80 mL), 5% w/w aqueous sodium sulfite solution (80 mL) and saturated aqueous sodium thiosulfate solution (80 mL) and the mixture extracted with dichloromethane (2×). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to give a crude 7-bromo-2-iodo-quinoline. To the quinoline was added tributyl(1-ethoxyvinyl)tin (13.6 mL, 40.1 mmol), 1,4-dioxane (67 mL) and bis(triphenylphosphine)palladium(II) dichloride (2.37 g, 3.34 mmol) and the reaction mixture heated at 100° C. for 5 h before being allowed to cool. 2 M aqueous hydrochloric acid (67 mL) was added and the reaction stirred for 1 h. The mixture was filtered and the solids washed with ethyl acetate and the filtrate evaporated to remove organics. The residue was extracted with ethyl acetate (3×) and the combined organic extracts were dried over sodium sulfate, filtered and evaporated. The product was purified on silica gel doped with 10% w/w potassium carbonate eluting with a gradient of 0% to 6% ethyl acetate in iso-hexanes to afford the title compound (5.5 g, 66%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.86 (s, 3H), 7.72-7.80 (m, 2H), 8.21 (ABq, ΔδAB=0.11, JAB=8.5 Hz, 2H), 8.42 (s, 1H). LCMS (m/z) 250.1/252.1 [M+H], Tr=2.90 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13]>>[Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: Cc1cc(Cl)c(C#N)c(Cl)c1
Reactant: O=S(=O)(O)O
Product: Cc1cc(Cl)c(C(N)=O)c(Cl)c1
Temperature: 0 °C
Yield: 59 %

Procedure:
To stirred, cooled concentrated sulfuric acid (40 ml) was added in portions 2,6-dichloro-4-methylbenzonitrile (13.2 g, 71.0 mmol). The mixture was heated on a steam bath for 3 hours with occasional shaking, cooled, poured into ice-water, and extracted twice with dichloromethane. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was chromatographed on a column of silica gel (390 g) eluted with 4:1 (v/v) dichloromethane-diethyl ether to provide 8.6 g (59%) of 2,6-dichloro-4-methylbenzamide, m.p. 101°-107° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[C:12]([CH3:18])[C:13](OCC)=[O:14]>C(O)C>[CH3:9][N:8]([CH3:10])[C:6]1[CH:7]=[C:2]2[C:3]([CH:11]=[C:12]([CH3:18])[C:13](=[O:14])[NH:1]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(N(C)C)cc1N
Solvent: CCO
Product: Cc1cc2ccc(N(C)C)cc2[nH]c1=O
Yield: 98 %

Procedure:
In a 30-ml Erlenmeyer flask made of quartz, 200 mg of (E) ethyl 3-(2-amino-4-dimethylaminophenyl)-2-methyl-2-propenate were dissolved in ethanol; and, while being stirred, the mixture was irradiated with ultraviolet rays at 365 nm for 48 hours. The reaction liquid was concentrated under a reduced pressure, and the resulting crude crystal was recrystallized from ethanol, whereby the aimed compound was obtained (yield: 98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH2:16][N:17]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20](=[O:27])OC2=O)[CH:13]=[CH:12][N:11]=1)=[O:8])[CH3:2].Cl.[C:31]([C:33]1[CH:41]=[CH:40][C:36]([CH2:37][O:38][NH2:39])=[CH:35][CH:34]=1)#[N:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH2:16][NH:17][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20](=[O:27])[NH:39][O:38][CH2:37][C:36]2[CH:40]=[CH:41][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)[CH:13]=[CH:12][N:11]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Reactant: N#Cc1ccc(CON)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)Nc1cc(CNc2ccccc2C(=O)NOCc2ccc(C#N)cc2)ccn1

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (600 mg, see preparation 7b) in pyridine (7 ml) was added isocyanato-acetic acid ethyl ester (0.4 ml). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The resulting oil was treated with EtOAc (3 ml) and gave a precipitate that was isolated by filtration and dried in vacuo, affording {3-[4-(2,4-Dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-ureido}-acetic acid ethyl ester (0.53 g). Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 170.3, 167.4, 154.8, 153.5, 151.4, 148.5, 146.7, 141.8, 132.7, 132.2, 129.1, 128.0, 118.6, 115.4, 114.8, 112.9, 111.5, 110.7, 109.3, 76.0, 60.3, 45.2, 41.2, 14.0.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:38][CH2:37][CH:36]2[C:39]([O-])=[O:40])[CH2:31][CH2:30]1)=[O:28])[CH3:25].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=3)(=[O:16])=[O:15])[CH2:11][N:10]2[C:39]([CH:36]2[CH2:37][CH2:38][N:35]2[CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:33]2)=[O:40])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: Cc1ccc(S(=O)(=O)[C@H]2CN[C@H](C(=O)NC3(C#N)CC3)C2)cc1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccc(C)cc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-tosylpyrrolidine-2-carboxamide 7G and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-tosylpyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (70%). MS ISP (m/e): 572.2 (100) [(M+H)]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)[CH3:2].[CH:14]([S:16]([F:19])(=[O:18])=[O:17])=[CH2:15]>C(O)(C)C>[F:19][S:16]([CH2:14][CH2:15][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)(=[O:18])=[O:17]
Reactant: C=CS(=O)(=O)F
Reactant: CCNc1cccc(NC(C)=O)c1
Solvent: CC(C)O
Product: CCN(CCS(=O)(=O)F)c1cccc(NC(C)=O)c1
Reaction time: 2.5 h

Procedure:
N-ethyl-m-acetamidoaniline (178.0 g, 1.0 m is dissolved in isopropyl alcohol (450 ml) and vinylsulfonylfluoride (110 g, 1.0 m) is added dropwise allowing temperature to rise to 40° C. The reaction is stirred for 2.5 hrs., the product collected by filtration, washed with cold ethanol and air dried.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([NH:12][NH2:13])=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:14]([C:16]1[O:20][C:19]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)=[CH:18][CH:17]=1)=O.C(O)C>>[C:1]([C:5]1[CH:9]=[C:8]([C:10](/[N:12]=[N:13]/[CH2:14][C:16]2[O:20][C:19]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:22]=3)=[CH:18][CH:17]=2)=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(-c2ccc(C=O)o2)cc1C(F)(F)F
Reactant: CC(C)(C)c1cc(C(=O)NN)[nH]n1
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)/N=N/Cc2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)o2)[nH]n1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To the solution of 3-tert-butyl-1H-pyrazole-5-carbohydrazide (0.076 g, 0.41 mmol) in 10 ml of ethanol 4-(5-formylfuran-2-yl)-2-(trifluoromethyl)benzonitrile (0.10 g, 0.37 mmol) was added and the mixture was stirred at RT for 36 h. The solvent was evaporated and the residue purified with Combiflash using DCM/-methanol as eluent system affording fractions containing the title compound. After treatment of these fractions with DCM the product precipitated out producing 0.048 g of title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.31 (s, 9H), 6.55 (m, 1H), 7.12 (d, 1H), 7.65 (d, 1H), 8.24 (m, 2H), 8.28 (m, 1H), 8.48 (m, 1H), 11.82 (m, 1H), 13.07 (m, 1H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7](Cl)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][OH:14])=[CH:17][CH:18]=2)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Reactant: OCc1ccc(B(O)O)cc1
Product: CC(C)(C)N1C(=O)C=C(c2ccc(CO)cc2)S1(=O)=O

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 4, using 9-A and 4-(hydroxymethyl)phenylboronic acid as the starting materials. 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 6.64 (s, 1H), 4.79 (d, J=5.9 Hz, 2H), 1.86–1.84 (m, 1H), 1.73 (s, 9H); LCMS found for C14H17NO4SNa (M+Na)+: m/z=318.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:27]([O:29][NH2:30])[CH3:28]>C(Cl)Cl>[CH2:27]([O:29]/[N:30]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:13][CH2:12]3)=[N:15][N:16]=2)[N:19]=1)\[CH3:24])[CH3:28]
Reactant: CCON
Reactant: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Agent: Cl
Solvent: ClCCl
Product: CCO/N=C(\C)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1

Procedure:
A solution of 1-(3-(1-(quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (30 mg, 0.09 mmol) and O-ethyl-hydroxylamine hydrochloride (18 mg, 0.18 mmol) in 2 mL of DCM was stirred at 40° C. overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, CDCl3) 3 ppm 8.84 (d, 1H), 8.29 (d, 1H), 8.25 (d, 1H), 7.92-7.91 (m, 2H), 7.72-7.68 (m, 2H), 7.49 (dd, 1H), 4.26 (q, 2H), 2.01 (s, 3H), 1.76 (s, 2H), 1.66 (s, 2H), 1.27 (t, 3H). LCMS (method A): [MH]+=373, tR=5.56 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH3:22])=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[C:14]([CH3:22])=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1c(N)cccc1C(=O)O
Solvent: c1ccncc1
Product: Cc1c(NS(=O)(=O)c2ccc(Br)cc2)cccc1C(=O)O

Procedure:
The title compound was prepared using a method analogous to Method A, using 4-bromobenzene sulfonyl chloride, 3-amino-2-methylbenzoic acid, and a large excess of pyridine. The title compound was precipitated on partition of the reaction mixture between dilute HCl and DCM. The precipitate was collected by filtration, dissolved in ethyl acetate and dried. Evaporation of the solvent gave the title compound as a pale brown solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[N:13]=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[C:20]([C:21]=1[C:22]#N)=[CH:19][CH:18]=[CH:17][CH:16]=2.C(O)(=[O:32])C.O>C1(C)C=CC=CC=1>[Cl:11][C:12]1[N:13]=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[C:20]([C:21]=1[CH:22]=[O:32])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC(=O)O
Reactant: N#Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In an atmosphere of argon and at -5° C. 10.7 ml of a 20% diisobutylaluminum hydride solution in toluene are slowly added dropwise to 2.64 g of 3-chloro-4-cyano-1-phenyl-isoquinoline in 150 ml of absolute toluene. The mixture is stirred for 10 minutes at 0° C. and then hydrolized with a small amount of glacial acetic acid until the reaction is weakly acid. Next, water is added and the toluene phase is separated. The organic phase is washed successively with saturated sodium bicarbonate solution and with water, dried and the solvent is removed under reduced pressure. The residue is rubbed with ether and recrystallized from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)[N:9]=[C:10]([I:11])[C:3]=12.[ClH:24]>CC(C)=O>[ClH:24].[I:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(I)nn2C1CCNC1
Temperature: 40 °C
Reaction time: 15 h
Yield: 31 %

Procedure:
A suspension of the crude tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate in acetone (100 mL) was treated with 6 N hydrochloric acid (50 mL). The reaction mixture was stirred at 40° C. for 15 hours. The initial precipitate was filtered and confirmed by LCMS to be impurities. The reaction mixture was allowed to sit at room temperature and a precipitate formed over night. The precipitate was filtered and washed with diethyl ether. The filtration afforded 2.186 g (31%) of pure 3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride. 1H NMR (DMSO-d6, 400 MHz) δ 9.8815 (s, 1H), 8.9923 (br.s, 1H), 8.4803 (s, 1H), 7.82 (br.s, 1H), 5.5908-5.5295 (m, 1H), 3.7131-3.6706 (m, 1H), 3.5590-3.5003 (m, 1H), 3.4466-3.4174 (m, 2H), 2.4592-2.4255 (m, 1H), 2.4064-2.3146 (m, 1H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 1.09 min (100%), MH+ 331.0.
Reaction SMILES: [Cl:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3](Cl)=[O:4].N1C=CC=CC=1.[CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH2:18]>ClCCl>[CH2:20]([O:19][CH:17]=[CH:18][C:3](=[O:4])[C:2]([Cl:1])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(Cl)C(F)(Cl)C(F)(F)F
Reactant: C=COCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOC=CC(=O)C(F)(Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 15 h

Procedure:
With stirring and at 0° C., 9.59 g (48.2 mmol) of 2-chlorotetrafluoropropionyl chloride were added dropwise to a mixture of 4.19 g (50.0 mmol) of pyridine and 4.83 g (48.2 mmol) of butyl vinyl ether in 75 ml of dichloromethane. After the addition, stirring was continued at room temperature for another 15 h. The mixture was then washed with 1N hydrochloric acid and 2×100 ml of water, and the organic phase was separated off, dried and concentrated. This gave 6.33 g (50% of theory) of a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]2.[N:15]1([C:20]([C:22]2[CH:23]=[N:24][CH:25]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[N:15]1([C:20]([C:22]2[CH:27]=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[N:10][CH:11]=3)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]4)[CH:25]=[N:24][CH:23]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2cncc(C(=O)N3CCCC3)c2)OC1(C)C
Reactant: NC(=O)N1CCCc2cc(Br)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)N1CCCc2cc(-c3cncc(C(=O)N4CCCC4)c3)cnc21
Temperature: 90 °C
Yield: 46.6 %

Procedure:
To a mixture of 6-bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (55 mg, 0.22 mmol) and pyrrolidin-1-yl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanone (78 mg, 0.26 mmol) in 1,4-dioxane (2 mL) is added 2.0 N aqueous sodium carbonate solution (0.23 mL, 0.46 mmol). Argon gas is bubbled through the solution for 5 min. To the mixture is added PdCl2(dppf) catalyst (12 mg, 0.02 mmmol) in one portion. The mixture is heated at 90° C. for 2 hrs. The mixture is filtered through short pad of diatomaceous earth, rinsing with EtOAC (3×1 mL). The filtrate is dried under reduced pressure. The reaction mixture is purified by Mass-triggered reverse phase HPLC to give 36 mg of the titled product.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[CH:14]([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[F:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:13]([CH:14]([F:16])[F:15])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CC(=O)C(F)F)c1nc2cccc(F)c2s1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3cccc(F)c3s2)cc1
Yield: 49 %

Procedure:
The procedure of Example 9 was repeated using 1-(7-fluorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(7-fluorobenzothiazol-2-yl)-3-difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (yield, 49%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)O1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH:28]=[C:27](OS(C(F)(F)F)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]=[C:27]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2)CC1

Procedure:
The title compound was prepared by Suzuki coupling of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Synthesis, 993, (1991)) according to the procedure in Example 35, step (b). Mass spectrum (ESI, m/z): Calcd. for C16H22N2O2, 275.2 (M+H), found 275.1.
Reaction SMILES: [Cl:1][C:2]1[CH:59]=[CH:58][C:5]([CH2:6][CH:7]2[N:12]3[C:13](=[O:53])[CH:14]([NH:28][C:29]([CH:31]4[CH2:35][CH2:34][CH2:33][N:32]4C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)=[O:30])[CH2:15][N:16]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])(=[O:19])=[O:18])[CH:11]3[CH2:10][N:9]([CH:54]([CH3:56])[CH3:55])[C:8]2=[O:57])=[CH:4][CH:3]=1.C(NCC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[N:12]3[C:13](=[O:53])[CH:14]([NH:28][C:29]([CH:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[O:30])[CH2:15][N:16]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])(=[O:19])=[O:18])[CH:11]3[CH2:10][N:9]([CH:54]([CH3:56])[CH3:55])[C:8]2=[O:57])=[CH:58][CH:59]=1
Reactant: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCN3C(=O)OCC3c4ccccc4-c4ccccc43)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCN3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A mixture of 50 mg (0.089 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione, 1 ml of DCM, 23 mg (0.178 mmol) of DIEA and 32 mg (0.090 mmol) of Fmoc-Pro-Cl was stirred at room temperature for 1 hour. The mixture was purified by chromatography on 2 g of SiO2 (elution with EtOAc/DCM, gradient 0-20%). 72 mg of the intermediate 9H-fluoren-9-ylmethyl 2-[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-ylcarbamoyl]pyrrolidine-1-carboxylate were obtained. LC/MS: (calculated, monoisotopic MW=877, measured value (M+H)=878) A mixture of 60 mg (0.068 mmol) of 9H-fluoren-9-ylmethyl 2-[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-ylcarbamoyl]pyrrolidine-1-carboxylate and 2 ml of 15% strength diethylamine in DCM was stirred at room temperature overnight. The mixture was concentrated and subjected to a flash chromatography on 2 g of SiO2 (elution with DCM, EtOAc and then with 10% methanol/EtOAc). The amine was converted into the hydrochloride salt. 30 mg of solid were obtained. This was further purified by preparative reverse phase (RP)HPLC. 17 mg of the desired compound were obtained. LC/MS (calculated, monoisotopic MW=655.12; measured value (M+H)=656)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[CH3:36].[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[CH3:36])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](C)C1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f65) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][CH2:13][CH2:12]1)[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:5]2[OH:27].C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:12][CH2:13][CH2:14]1)[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:5]2[OH:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Yield: 67.3 %

Procedure:
1,1-Dimethylethyl N-((6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclobutane-1,1′-naphthalen]-3′-yl)carbonyl)glycinate (151 mg, 385 μmol) was stirred in TFA (1 mL, 13462 μmol) for 20 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (87 mg). MS (m/e)=336.1 (M+H)+. Calculated for C16H15ClO4 335.06.