Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=[O:13])[CH:4]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[O:13]=[C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:11]=2)[NH:6]1
Reactant: O=S(=O)(O)Cl
Reactant: O=c1cc(C(F)(F)F)c2ccccc2[nH]1
Product: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc2[nH]1
Temperature: 140 °C
Reaction time: 7 h
Yield: 40 %

Procedure:
4-Trifluoromethyl-1H-quinolin-2-one (5.00 g, 23.5 mmol) was treated with ClSO3H (3.1 mL, 47.0 mmol) at 0° C. The mixture was then heated with stirring to 140° C. for 7 hours. On cooling, ice-cold H2O (50 mL) was added. The solid produced was collected and dried to give the title compound (2.93 g, 41%): δH (CDCl3)=7.20 (s, 1H), 7.60 (d, 1H), 8.20 (dd, 1H), 8.50 (d, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C[O:6][C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][C:20](=O)[CH2:21][C:22](OCC)=[O:23])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:8].[Li+].[OH-]>C(O)(C)(C)C.[OH-].[Na+].CCOC(C)=O>[O:23]=[C:22]1[NH:4][C:2](=[S:3])[NH:1][C:20]([CH2:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[C:9]([C:7]([OH:8])=[O:6])=[CH:10][CH:11]=[CH:12]3)=[CH:21]1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)Cc1ccc2c(C(=O)OC)cccc2c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: O=C(O)c1cccc2cc(Cc3cc(=O)[nH]c(=S)[nH]3)ccc12
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
3.46 g (45.4 mMol) thiourea are added to a solution of 29.7 mMol 6-(3-ethoxycarbonyl-2-oxo-propyl)-naphthalene-1-carboxylic acid methyl ester in 25 ml tert-butanol. Then 13.3 g (119 mMol) potassium tert-butyrate are added (exothermic). After 50 min, the mixture is heated for 4.5 h in an oil bath of 100° C. Cooling to rt gives an almost solid mixture, which is redissolved by addition of 59 ml of a 1 M aq. solution of LiOH and stirring during 40 min. This solution is diluted with 500 ml of a 0.33 M solution of NaOH and EtOAc. The organic phase is separated off, washed with 300 ml of a 0.33 M solution of NaOH and discarded. The aq. phases are acidified by addition of 2 N HCl (pH=3), the precipitated product filtered off, washed with 0.001 N HCl and dried in vacuo at 80° C. The crude material is stirred in a boiling mixture of 0.6 l CH3CN, 60 ml EtOAc, 120 ml MeOH and 120 ml THF. Filtration of the hot suspension then leads to the title compound: m.p.: 334-337° C.
Reaction SMILES: [O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([O:29]C)=[O:28])[CH2:20][CH2:19]3)=[N:6][C:5]=2[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO>[O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([OH:29])=[O:28])[CH2:22][CH2:23]3)=[N:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(C2CCN(c3nc4c(c(NC5CCOCC5)n3)S(=O)CC4)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(C2CCN(c3nc4c(c(NC5CCOCC5)n3)S(=O)CC4)CC2)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
1.3 g methyl 3-{1-[5-oxo-4-(tetrahydropyran-4-ylamino)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-piperidin-4-yl}-benzoate are placed in 24.6 ml of methanol, then 9.2 ml of a 1 N NaOH solution are added. The reaction mixture is stirred at ambient temperature until there is no further reaction, then combined with a 1 N HCl solution. The methanol is spun off and the precipitated solid is suction filtered. The product is purified by preparative HPLC (method B). 760 mg product are obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:30]N1C(=O)CCC1=O.CCOC(C)=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[C:9]=2[Cl:30])=[CH:6][CH:7]=1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(Br)cc4)nc32)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccc(Br)cc2)c3Cl)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromophenyl)-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 81A) (140 mg, 0.31 mmole) in CH2Cl2 (7 mL) cooled at 0° C. is added N-chlorosuccinimide (41 mg, 0.31 mmole). The reaction mixture is stirred at 0° C. for 1 h then is allowed to reach room temperature. Another portion of N-chlorosuccinimide (60 mg) is added. After 1 hour at room temperature, AcOEt is added and the reaction mixture is basified to pH 10 with 1N NaOH solution. The organic phase is washed with water, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) with a gradient from (100:0) to (90:10) to give 2-(4-bromophenyl)-1-chloro-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 169° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:17])[CH3:3].[CH3:18][O:19][C:20](=[O:24])/[CH:21]=[CH:22]\Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:19][C:20](=[O:24])/[CH:21]=[CH:22]/[N:8]1[C:7](=[O:17])[C:6]2[C:11](=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)[N:10]=[CH:9]1
Reactant: CC(C)c1cc(C(C)C)c2nc[nH]c(=O)c2c1
Reactant: COC(=O)/C=C\Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C/n1cnc2c(C(C)C)cc(C(C)C)cc2c1=O
Yield: 74 %

Procedure:
A mixture of 3.10 g (0.013)mol) of 6,8-bis-(1-methylethyl)-quinazolin-4(3H)-one, 1.78 g (0.0148 mol) of (Z)-3-chloro-2-propenoic acid methyl ester and 3.72 g (0.027 mol) of anhydrous potassium carbonate in 100 ml. of anhydrous acetone was stirred at reflux for 17 hr. The reaction mixture was filtered, the solid was washed with acetone and the filtrate was concentrated in vacuo to an oil which soon crystallized. Recrystallization from methanol gave 3.11 g, m.p. 102°-103°, (74% yield) of (E)-3-[6,8-bis-(1-methylethyl)-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:19]([CH2:25][CH3:26])=[N:20][CH:21]=[CH:22][C:23]=1[Cl:24]>CN(C=O)C>[Cl:24][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:25][CH3:26])[C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CCc1nccc(Cl)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nccc(Cl)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 12.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (382 mg, 2.7 mmol) was dissolved in anhydrous DMF (15 mL), and then potassium carbonate (1.12 g, 8.1 mmol) and 3-(bromomethyl)-4-chloro-2-ethylpyridine (3.5 mmol) in DMF (10 mL) were added. The mixture was stirred for 2.5 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 5-10% DCM/MeOH to afford 2-{[(4-chloro-2-ethylpyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (100 mg, 13% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.22 (t, J=7.4 Hz, 3H), 2.24 (s, 3H), 2.97 (q, J=7.4 Hz, 2H), 4.62 (s, 2H), 6.07 (bs, 1H), 7.44 (d, J=5.3 Hz, 1H), 8.40 (d, J=5.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:12](I)=[CH:13][C:14](=O)[C:15]2[NH:16][CH:17]=[C:18]([CH3:21])[C:19]=2[CH3:20])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][SH:35])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][S:35][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[C:18]([CH3:21])[C:19]=2[CH3:20])[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Cc1c[nH]c(C(=O)C=C(I)c2c(F)ccc3c2CC(=O)N3)c1C
Agent: [H-]
Agent: [Na+]
Product: Cc1c[nH]c(-c2cc(SCCNC(=O)OC(C)(C)C)c3c(F)ccc4c3c2C(=O)N4)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-fluoro-4-[1-iodo-3-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 48 above) (1.58 g, 4.0 mmol) in tert-butyl-N-(2-mercaptoethyl)-carbamate (Aldrich, 8 mL) was added NaH (Aldrich, 95%, 0.3 g, 11.8 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated to 120° C. for 3 hours. The reaction was quenched by adding brine and ethyl acetate. The organic layer was dried over an hydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, 4:1 hexaneslethyl acetate) afforded [2-[6-fluoro-2-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester as an orange oil. (Yield 66 mg, 31%).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:10][OH:11])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl:19][CH2:20][C:21](OC(=O)CCl)=O>O>[CH2:7]([C:8]1[N:9]=[C:21]([CH2:20][Cl:19])[O:11][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: O=C(CCl)OC(=O)CCl
Solvent: O
Solvent: Cc1ccccc1
Product: ClCc1nc(Cc2ccccc2)no1

Procedure:
A solution of 40 g. (0.27 mole) of crude phenylacetamide oxime in 200 ml. of dry toluene is treated with 45.9 g. (0.27 mole) of chloroacetic anhydride in 100 ml. of toluene. The resultant mixture is then refluxed and the water formed is removed by means of a Dean Stark trap. The mixture is refluxed for 3-4 hours after which it is cooled and extracted once with 150 ml. of water and four times with 100 ml. of a saturated sodium bicarbonate solution. The toluene solution is then dried over magnesium sulfate and the solvent is removed in vacuo. Upon distillation of the residue, 3-benzyl-5-chloromethyl-1,2,4-oxadiazole, 19.8 g. having a b.p. of 100-108 (0.04 mm) is obtained.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(OCC)C>O>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:22][CH2:21][CH:20]([CH2:23][O:24][C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Yield: 83.1 %

Procedure:
A solution of 2-O-Octadecyl-3-O-trityl-glycerol (10 g, 17.04 mmol) in 52 ml water-free pyridine is added dropwise during 30 min. to a solution of p-toluenesulfonyl chloride (5.1 g, 26.75 mmol) in 39 ml water-free pyridine under stirring. After 2 days at room temperature 162 ml diethyl ether are added and the precipitate formed is removed by filtration. The organic phase is washed successively with water (6×50 ml), 0.5N HCl (2×29 ml), 0.5N sodium carbonate (2×29 ml), and water (4×50 ml). Evaporation of the solvent under vacuum gives an oily product which becomes solid after drying in vacuo. The product, 1-p-toluenesulfonyl-2-O-Octadecyl-3-O-trityl-glycerol (10.5 g, 85% yield), is used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)=[C:20]=[O:21]>C1COCC1>[N+:28]([C:24]1[CH:23]=[C:22]([NH:19][C:20]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)=[O:21])[CH:27]=[CH:26][CH:25]=1)([O-:30])=[O:29]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc2c(c1)NC(=O)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1Cc2ccc(NC(=O)Nc3cccc([N+](=O)[O-])c3)cc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-amino-1,3-dihydro-indol-2-one (0.15 g, 1.0 mmol) and triethylamine (0.30 g, 3.0 mmol) in THF (10 ml) is added 1-isocyanato-3-nitro-benzene (0.16 g, 1.0 mmol). The reaction is stirred at room temperature for 1 hour and the precipitate is collected by vacuum filtration and washed with ethanol to give the desired compound as a light yellow solid. LC-MS: 313.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:21]1[CH2:24][CH:23]([CH2:25]O)[CH2:22]1.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)[CH2:25][CH:23]2[CH2:24][O:21][CH2:22]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: OCC1COC1
Reactant: CC(C)c1ccc(NS(=O)(=O)c2ccc(F)cc2)nc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(N(CC2COC2)S(=O)(=O)c2ccc(F)cc2)nc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a solution of 4-fluoro-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (100 mg, 0.340 mmol) and oxetan-3-ylmethanol (20.95 mg, 0.238 mmol) in toluene (1.5 mL) stirred in air at room temperature was added a solution of 2-(tributylphosphoranylidene)acetonitrile (82 mg, 0.340 mmol) in toluene (0.5 mL). The reaction mixture was stirred at 20° C. for 16 hours. Additional 2-(tributylphosphoranylidene)acetonitrile (82 mg, 0.340 mmol) and oxetan-3-ylmethanol (20.95 mg, 0.238 mmol) were added and the solution stirred for a further 24 hours. The reaction solution was then purified on an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with a 0-50% ethyl acetate-cyclohexane gradient, to give the title product (63 mg) as a colourless gum. LCMS (2 min, formic) Rt 1.12 min, m/z (ES+) 365 (M+H).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].[OH-].[Na+]>>[NH2:2][C:1]1[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[N:28]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-c2nn(-c3cccc([N+](=O)[O-])c3)c(N)c2C(N)=O)cc1
Yield: 7.4 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (464 mg, 2.0 mmol), 3-nitrophenylhydrazine hydrochloride (417 mg, 2.2 mmol) and sodium hydroxide (88 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was purified by column chromatography (SiO2, 50% ethyl acetate in hexane) and recrystallisation from ethyl acetate to give the title compound as white crystals (50 mg) m.p. 237-238°. δH (d6DMSO) 8.42 (1H, s), 8.21 (1H, d, J 7.8 Hz), 8.11 (1H, d, J 7.8 Hz), 7.79 (1H, t, J 8.2 Hz), 7.50 (2H, d, J 8.0 Hz), 7.30 (2H, d, J 8.1 Hz), 6.70 (2H, s), 5.50 (2H, br s) and 2.37 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:12]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc2cccnc12
Solvent: CC#N
Product: Nc1ccc(Br)c2cccnc12
Reaction time: 0.25 h

Procedure:
To a solution of 8-aminoquinoline (4.0 g, 28 mmol) in CH3CN (185 mL) was added N-bromosuccinimide (2.47 g, 13.9 mmol). After stirring for 15 minutes, a second portion of N-bromosuccinimide (2.71 g, 15.2 mmol) was added. After stirring for an additional 30 minutes, the mixture was concentrated. The residue was dissolved in EtOAc, then washed with water (2×100 mL) and saturated NaCl (aq) (100 mL). The organics were dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 10-15% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.79 (dd, J=1.5, 4.1 Hz, 1H), 8.46 (dd, J=1.5, 8.5 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.52 (dd, J=4.1, 8.5 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H); LC7: 2.48 min. (M+H) 225.
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:9]([OH:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCCl>[C:1]([NH:6][C:7](=[O:8])[O:18][CH2:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)N=C=O
Reactant: OCC=Cc1ccccc1
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OCC=Cc1ccccc1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
Into a three-necked flask purged with nitrogen gas, methacryloyl isocyanate (1.11 g; 10 mmol) was charged, and 1,2-dichloroethane (20 ml) was added thereto. A solution of cinnamyl alcohol (1.34 g) in 1,2-dichloroethane (20 ml) was dropwise added thereto under nitrogen stream in 10 minutes while stirring. 1,2-Dichloroethane was removed by evaporation under reduced pressure to give cinnamyl N-methacryloylcarbamate (2.4 g), which was washed with hexane and purified by silica gel column chromatography to give colorless needles. M.P., 66°-67° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:40]([O:41][CH3:42])=[CH:39][C:27]2[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:31][CH2:32][C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[C:40]([O:41][CH3:42])=[CH:39][C:27]3[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:31][CH2:32][C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: COc1ccc(Nc2nc(Nc3cc4c(cc3OC)CCN(CC(=O)N(C)C)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide, in a similar manner as Example 601b, to yield desired product {7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N,N-dimethyl-acetamide as a lyophylate (38%); 1H NMR (400 MHz, DMSO-d6) δ 9.80 (bm, 2H), 8.20 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=9.07 Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.23 (d, J=2.06 Hz, 1H), 6.98 (d, J=8.92 Hz, 1H), 6.90 (s, 1H), 6.52 (s, 1H), 4.32 (s, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.63 (bs, water+H), 3.4-2.95 (m, 6H), 2.95 (s, 6H); MS (m/e) 577.42 (M+H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH2:10]([NH:17][C:18]([NH2:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC(=O)C)(=O)C>>[CH2:10]([N:17]1[C:4](=[O:5])[CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:20][C:18]1=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1Cc1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (350 mg; 2.5 mmoles), benzylurea (389 mg; 2.6 mmoles) and acetic anhydride (2 ml) was heated with stirring at 100° C. for 1 hour. The solvent was evaporated under reduced pressure, and the residue was recrystallized from chloroform/hexane to give 500 mg (yield: 72%) of 3-benzyl-5-trifluoromethyldihydrouracil. The physical and spectral properties of this product completely agreed with those of the product obtained in Example 6.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O-:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].[K+].S(=O)(=O)(O)O>C(OCC)(=O)C>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]
Reactant: O=C([O-])[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Temperature: 0 °C

Procedure:
A solution of potassium clavulanate in ice cold water was stirred with ethyl acetate under cooling with ice-water. With a solution of about 10% (w/w) sulphuric acid the pH was brought at about 2, the water layer separated and two times extracted with ethyl acetate. The collected extracts were dried with magnesium sulphate, filtered and washed with ethyl acetate, yielding a solution of clavulanic acid of about 2% (w/w).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH2:10])[C:4]=1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.[C:52]([O:56][C:57]([NH:59][C@@H:60]([CH3:64])[C:61](O)=[O:62])=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[NH2:10][C:5]1[C:4]([CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:61](=[O:62])[C@@H:60]([NH:59][C:57](=[O:58])[O:56][C:52]([CH3:54])([CH3:53])[CH3:55])[CH3:64])[CH2:15][CH2:14]2)=[C:3]([Cl:2])[N:8]=[C:7]([CH3:9])[N:6]=1
Reactant: Cc1nc(N)c(CCC2CCNCC2)c(Cl)n1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(Cl)n1
Reaction time: 0.08 h
Yield: 153.2 %

Procedure:
Into each of two round bottom flasks add 6-chloro-2-methyl-5-[2-(4-piperidyl)ethyl]pyrimidin-4-amine hydrochloride (12.50 g, 42.92 mmol), diisopropylethylamine (22.46 mL, 128.7 mmol) and DMF (100 mL). Cool the two mixtures in a cold water bath and stir for 5 min. Add to each of the mixtures [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (17.95 g, 47.21 mmol) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (8.93 g, 47.21 mmol) in one portion. Stir the mixtures at RT for 90 min Pour the mixtures into separate separatory funnels along with water (300 mL) and EtOAc (400 mL), shake and partition. Extract the aqueous layers with EtOAc (3×300 mL), wash the respective organic layers with water (4×250 mL), saturated aqueous NaCl (200 mL) and dry over MgSO4, filter and concentrate under reduced pressure. Purify the combined materials via silica gel chromatography eluting with 70% to 100% EtOAc in hexanes. Combine and concentrate the purified fractions under reduced pressure. Dilute the residue with EtOAc (500 mL) and wash with saturated aqueous NH4Cl (100 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL) and saturated aqueous NaCl (100 mL). Dry the organics over MgSO4, filter, and concentrate under reduced pressure to give the title compound as a white solid (28.00 g, 76%). LC-ES/MS m/z (35Cl/37Cl) 426.2/428.2 (M+1).