Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:19])[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].[H-].[Na+].Br[C:23]([CH3:33])([CH3:32])[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25]>C1C=CC=CC=1>[CH2:1]([S:19][C:23]([CH3:32])([CH3:33])[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[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]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: CCOC(=O)CC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCSC(C)(C)C(=O)CC(=O)OCC
Yield: 73.3 %

Procedure:
A mixture of 14.3 g of stearylmercaptan and 200 ml of anhydrous benzene was heated with stirring, to which 1.2 g of sodium hydride was gradually added. To the reaction slurry in an ice bath, a solution containing 13.2 g of ethyl (2-bromo-2-methylpropionyl)acetate and 20 ml of anhydrous benzene was gradually added with stirring. After the completion of the addition, the reaction mixture was removed from the ice bath and stirred for three hours. The reaction mixture was then poured into ice water and neutralized by addition of glacial acetic acid. The mixture was extracted with 300 ml of ethyl acetate, the extract was washed twice with a saturated aqueous sodium chloride solution. The ethyl acetate phase was dried with anhydrous sodium carbonate. After distilling off the ethyl acetate, the residue was purified using silica gel chromatography (eluting solvent: chloroform) to obtain 16.2 g (yield 62%) of the intended compound having a melting point of 34° to 37° C.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[O:2][CH2:3][CH3:4].[CH:7]1([N:14]([C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[C:15](=[O:30])[NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]=2[OH:29])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>ClCCl>[ClH:6].[CH2:3]([O:2][C:1]([O:29][C:18]1[C:19]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[NH:16][C:15]([N:14]([CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=[O:30])=[O:5])[CH3:4]
Reactant: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(O)c(C(C)(C)C)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1c(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)cc(OC)cc1C(C)(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
Under ice-cooling, 1.03 ml of ethyl chlorocarbonate was added dropwise to a mixed solution of 2.45 g of 2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tertbutylphenol, 1.51 ml of triethylamine and 50 ml of dichloromethane, and the mixture was stirred at room temperature for 2 hours. After washing and drying, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=20:1), and precipitated crystals were recrystallized from a mixed solution of isopropyl ether and ethyl acetate. The resulting crystals were dissolved in 50 ml of dichloromethane, and 2 ml of a 4N hydrogen chloride-dioxane solution was added thereto. The mixture was evaporated to dryness under reduced pressure. The residue was crystallized from an isopropyl ether solution to give 1.34 g of O-ethoxycarbonyl-2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol hydrochloride (yield: 44%, melting point: 163°-167° C. (decomposed)).
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([CH2:10][C:11](O)=O)#[N:9].C=O.[C:16](=O)=O.C(=O)(O)[O-].[Na+]>O.O1CCOCC1>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:16][C:10](=[CH2:11])[C:8]#[N:9])[CH2:4][CH2:3]1
Reactant: O=C=O
Reactant: FC1CCNCC1
Reactant: N#CCC(=O)O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C#N)CN1CCC(F)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
4-Fluoropiperidine (0.7 g., 0.005 mole) was dissolved in a mixture of 3 ml. of dioxane and 2 ml. of water containing cyanoacetic acid (0.43 g., 0.005 mole). Then, 0.85 g. (0.01 mole) of 37% aqueous formaldehyde was added to the solution. The solution was heated to 65° C. and carbon dioxide evolution began. It was maintained at 60°-65° C. for 21/2 hours and allowed to stand overnight. A solid gummy residue, 1 gm., was obtained upon stripping in a bath at 55° C. and at 1 mm. It was taken up in a small amount of water, made alkaline with sodium bicarbonate and extracted with ether. The organic layer was water washed and dried over anhydrous sodium sulfate. After solvent stripping, the product was obtained as a colorless oil, 0.7 g., of analytical purity.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](OC(C)(C)C)=O)[CH:12]=[N:13][C:14]=1[Cl:15])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C=O.C([O-])(O)=O.[Na+]>C(O)=O>[ClH:15].[ClH:15].[C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])[CH:12]=[N:13][C:14]=1[Cl:15])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CCCCCCC#Cc1cc(OC[C@H]2CCCN2C)cnc1Cl
Product: Cl
Temperature: 70 °C
Yield: 64 %

Procedure:
To 5-(1-octynyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 79a (330 mg, 0.78 mmol) was added formalin (37%, 9 mL) and formic acid (4.5 mL), and the mixture was heated at 70° C. for 2 hours. The solvent was concentrated,and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with methylene chloride, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:1-100:3 to afford to give the free base of the title compound (166.5 mg (64% yield). MS (DCI/NH3) m/z 321 (M+)+. 1H NMR (CDCl3, 300 MHz) δ0.92 (m, 3H), 1.32 (m, 4H), 1.48 (m, 2H), 1.62 (m, 2H), 1.80 (m, 4H), 2.02 (m, 1H), 2.30 (m, 1H), 2.45 (m, 1H), 2.47 (s, 3H), 2.66 (m, 1H), 3.12 (m, 1H), 3.93 (m, 2H), 7.27 (m, 1H), 7.98 (m, 1H). The base was converted to the salt by treatment with HCl in ether to give the title compound. mp 114°-116° C. (dec). MS (DCI/NH3) m/z 335 (M+H)+. 1 H NMR (D2O, 300 MHz) δ: 1.02 (t, J=6.7 Hz, 3H), 1.43 (m, 4H), 1.58 (m, 2H), 1.71 (m, 2H), 2.06 (m, 1H), 2.21 (m, 2H), 2.42 (m, 1H, 2.56 (t, J=6.7 Hz, 2H), 3.06 (s, 3H), 3.28 (m, 1H), 3.77 (m, 1H), 3.87 (m, 1H), 4.41 (m, 2H), 7.50 (m, 1H), 8.12 (d, J=2.4 Hz, 1H). Anal. Calcd for C19H27N2OCl·1.5 HCl: C, 58.58; H, 7.37; N, 7.19. Found: C, 58.64; H, 7.39; N, 7.20. [α]25D =+8.99° (c 0.64, MeOH).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>CN(C)C=O.ClCCl>[CH:7]1([C:12]([N:16]([CH3:15])[O:17][CH3:18])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)C1CCCC1
Reactant: CNOC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCCC1
Reaction time: 2 h

Procedure:
Oxalyl chloride (7.5 ml, 85 mmol) was added dropwise to a stirred solution of cyclopentanecarboxylic acid (4.56 g, 40 mmol) and dimethylformamide (2 drops) in dichloromethane (20 ml) under nitrogen at room temperature. After 2 hours, the reaction mixture was evaporated under reduced pressure and the residual oxalyl chloride removed azeotropically using dichloromethane. The resulting oil was dissolved in dichloromethane (50 ml) and N,O-dimethylhydroxylamine (4.3 g, 44 mmol) added portionwise to the stirred solution. The resulting mixture was cooled using an ice bath, pyridine (7.1 ml, 88 mmol) added, the cooling bath removed and stirring continued for 18 hours. The reaction mixture was then diluted with dichloromethane (50 ml), washed with 5% aqueous citric acid solution (×2) and saturated brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a solvent gradient of methanol:dichloromethane (0:100 to 2:98), to furnish the required amide as an oil. Rf 0.50 (SS 18). Found: C,59.28; H,9.74; N,8.81. C8H15NO2 ; 0.25 H2O requires C,59.41; H,9.66; N,8.66%.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([O:38][CH3:37])[CH3:49])=[O:48])[CH2:47][CH2:46]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-methoxy-N-methyl-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 16b) in an analogous manner as described in example 25. LR-MS: 716.4 [(M+H)+]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]OC.COCC(=O)C>COCOC1C=C([Mg]Br)C=CC=1>[CH3:9][O:10][CH2:11][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: COCOC
Agent: COCC(C)=O
Agent: COCOc1cccc([Mg]Br)c1
Product: COCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Methoxymethoxyphenyl bromide was prepared by the reaction of 3-bromophenol and dimethoxymethane using the general procedure described in Synthesis, 1976, 244. Methoxyacetone (4.41 g) was added to a solution of 3-methoxymethoxyphenylmagnesium bromide [prepared from 3-methoxymethoxyphenyl bromide (10.85 g) and magnesium (1.2 g) in tetrahydrofuran (100 ml)]. The mixture was stirred at ambient temperature for 15 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 20:3 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained 2-hydroxy-2-(3-methoxymethoxyphenyl)-prop-1-yl methyl ether (7.87 g, 69%), as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[O:29]=[C:27]1[N:14]2[CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]3[C:15]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:28]1
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Nc1cccc2c1NC1CCN(C(=O)OCC)CC21
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)CN3C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
To a solution of ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (2.2 g, 6.6 mmol) in DMF (20 mL) at 0° C. was added NaH (660 mg, 16.5 mmol), DMAP (878 mg, 7.2 mmol), acetyl chloride (0.6 mL, 7.2 mmol) and stirred at rt for 16 hours. The solution was diluted with water (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (1.1 g, 57%) as a clear oil. MS [M+H]+ 374. 1H NMR (CDCl3, 300 MHz): δ 6.75 (t, 1H, J=7.7 Hz), 6.59 (m, 1H), 6.45 (m, 1H), 4.05 (m, 1H), 3.60–4.00 (m, 7H), 3.40 (m, 1H), 3.00 (m, 3H), 1.92 (m, 2H), 0.91 (m, 1H), 0.85 (m, 6H) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.[C:17]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH:17]1([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10](=[O:12])[NH:9][C:8]4[CH:13]=[CH:14][CH:15]=[CH:16][C:7]3=4)[CH2:5][CH2:6]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCCCC1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C2(CCN(C3CCCCCC3)CC2)O1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (A4) (353 mg, 1.62 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL) and treated with cycloheptanone (iiia) (273 mg, 2.43 mmol), followed by glacial acetic acid (195 mg, 3.24 mmol) and sodium triacetoxyborohydride (687 mg, 3.24 mmol). The reaction was stirred at room temperature under nitrogen for 90 hours. The reaction was diluted with dichloromethane (50 mL), quenched with 1.0 N NaOH (20 mL), and stirred vigorously at room temperature for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The pooled organic layers were washed with (20 mL each) water and saturated brine; and dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford crude 1′-cycloheptylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one as an off-white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].[NH2:25]/[C:26](/[CH3:32])=[CH:27]\[C:28]([O:30][CH3:31])=[O:29]>C(O)(C)C>[CH3:32][C:26]1[NH:25][C:4]([CH3:5])=[C:3]([C:2]([O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:9][CH:10]=2)=[O:1])[CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)[C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: c1ccc(OC2CCCCO2)cc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(OC3CCCCO3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
3.36 Grams of 1-[2(E)-acetoacetocymethylvinyl]-(4-(2-tetrahydropyranyloxy)benzene, 1.5 g of 3-nitrobenzaldehyde and 1.2 g of methyl 3-aminocrotonate were added to 20 ml of isopropanol, and the mixture was refluxed for 8 hours. The reaction mixture was concentrated and the residue was purified by means of a silica gel column chromatography (eluent: chloroform) to yield 1.2 g of methyl 3-(4-tetrahydropyranyloxyphenyl)-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate.
Reaction SMILES: C(=N/[OH:9])\C1C=CC=CC=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=O)[C:14]=1[C:27]#[C:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C.O1CCOCC1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:14]=1[C:27]([OH:9])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20](=[O:22])[C:19]2([CH3:25])[CH3:26]
Reactant: CCOC(=O)C#Cc1c(Cl)cccc1C(C)(C)C(=O)OCC
Reactant: O/N=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2c(Cl)cccc2C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A solution of (E)-benzaldehyde oxime (234 mg, 1.93 mmol) in dry DMF (9 mL) was added to a suspension of NaH (46 mg, 1.93 mmol) in dioxane (9 mL) at room temperature. The mixture was stirred for 30 minutes and then cooled to 0° C. A solution of ethyl 3-(2-chloro-6-(1-ethoxy-2-methyl-1-oxopropan-2-yl)phenyl)propiolate (520 mg, 1.61 mmol) in dry DMF (9 mL) was added, and the mixture was stirred at 0° C. for 3 hours and then at room temperature for 1 hour. The mixture was quenched with water and then washed with EtOAc (2×). The aqueous layer was made acidic with 10% HCl and then extracted with EtOAc (2×). The extracts were dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography to give 210 mg of ethyl 5-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate as a colorless oil. MS m/e=295 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40](O)=[O:41])[C:35]2=[O:43])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([N:4]3[C:5]4[CH:10]=[CH:9][C:8]([O:11][C:12]5[CH:21]=[CH:20][N:19]=[C:18]6[C:13]=5[C:14]5[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=5[C:16](=[O:22])[NH:17]6)=[CH:7][C:6]=4[O:1][CH2:2][CH2:3]3)=[O:41])[C:35]2=[O:43])=[CH:30][CH:29]=1
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Product: O=C(c1cccn(-c2ccc(F)cc2)c1=O)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Yield: 80.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 181 using 218 (40 mg, 0.12 mmol) and 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (41 mg, 0.17 mmol) to provide 228 (54 mg, 83% yield) as a tan solid. LC-MS (M+H=561, obsd.=561).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.II.[O:15]1CC[CH2:17][CH2:16]1>BrCCBr>[CH3:17][CH:16]([C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[OH:15]
Reactant: Brc1ccc2c(c1)OCCCC2
Reactant: C1CCOC1
Agent: II
Solvent: BrCCBr
Product: CC(O)c1ccc2c(c1)OCCCC2
Temperature: -10 °C
Reaction time: 2 h

Procedure:
7.3 g of 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine in 30 ml of absolute tetrahydrofuran were added under argon to 930 mg of Mg shavings and a granule of iodine. The reaction was initiated by the addition of a few drops of 1,2-dibromoethane and had finished after 2 hours. Thereafter, the reaction mixture was cooled to -10° C. and excess acetaldehyde was distilled into the reaction vessel. After 10 minutes, the mixture was hydrolyzed with saturated sodium bicarbonate (NaHCO3) solution, extracted with ether, washed with water, dried and evaporated to dryness. Chromatography on silica gel (petroleum ether/ethyl acetate 3:1) yielded 4.93 g of 2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-8-methanol as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4]C=[CH:6][CH:7]=1.[CH2:8]([N:12]1[CH:16]=[C:15]([C:17]2[S:21][C:20]([C:22]([NH:24][C@H:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)=[O:23])=[CH:19][CH:18]=2)[CH:14]=[N:13]1)[CH:9]([CH3:11])[CH3:10].[NH:30]1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)C1>>[CH3:10][CH:9]([CH3:11])[CH2:8][N:12]1[CH:16]=[C:15]([C:17]2[S:21][C:20]([C:22]([NH:24][C@H:25]3[CH2:29][CH2:28][N:27]([C:7]4[CH:2]=[CH:3][N:4]=[N:30][CH:6]=4)[CH2:26]3)=[O:23])=[CH:19][CH:18]=2)[CH:14]=[N:13]1
Reactant: Brc1cccnc1
Reactant: CC(C)Cn1cc(-c2ccc(C(=O)N[C@H]3CCNC3)s2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Product: CC(C)Cn1cc(-c2ccc(C(=O)N[C@H]3CCN(c4ccnnc4)C3)s2)cn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 4-bromopyridazine for 3-bromopyridine and (S)-5-(1-isobutyl-1H-pyrazol-4-yl)-N-(pyrrolidin-3-yl)thiophene-2-carboxamide for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.75-0.98 (m, 6 H) 1.98-2.44 (m, 3 H) 3.67-4.18 (m, 6 H) 4.66 (s, 1 H) 7.15 (dd, J=7.12, 3.05 Hz, 1 H) 7.21 (d, J=3.73 Hz, 1 H) 7.54-7.91 (m, 2 H) 8.14 (s, 1 H) 8.56-8.95 (m, 3 H); MS (ESI(+)) m/e 397 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:25][CH:21]3[CH2:22][NH:23][CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)=[N:6][CH:7]=1.[C:26]([CH2:28][C:29](O)=[O:30])#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:25][CH:21]3[CH2:22][N:23]([C:29](=[O:30])[CH2:28][C:26]#[N:27])[CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: OCCn1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CC2CC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 2-(4-((5-chloro-4-((octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)ethanol (0.29 g, 0.80 mmol) and 2-cyanoacetic acid (87.2 mg, 1.03 mmol) in a mixture of DCM (20 mL) and DMF (5 mL) were added HATU (462.4 mg, 1.22 mmol) and Et3N (0.17 g, 1.68 mmol). After addition, the reaction mixture was stirred at rt for 1 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as a beige solid (300.1 mg, 87%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:5]=[C:6]([CH3:8])[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)pyrimidine (example A.12) (0.5 g, 1.83 mmol) and commercially available 3-bromo-benzeneboronic acid (0.48 g, 2.39 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.11 g, 15%). MS (ISP) 395.0 [(M+H)+]; mp 102.5° C.