Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.CC(C)([O-])C.[K+].P(Cl)(OCC)(OCC)=O.[N+:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])#[C-:36]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:36]=[N:35][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccn1)c1cc(Br)ccc1-2
Reaction time: 0.17 h

Procedure:
A solution of 15.8 g (0.05 mol) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one in 300 ml of dry tetrahydrofuran was cooled to 10° with stirring under argon. Potassium tert. butoxide 6.3 g (0.056 mol) was added and stirring was continued for 10 min. Following the addition of 14 ml of diethyl chlorophosphate the mixture was stirred for additional 20 min. A previously prepared mixture of 11.3 g ethyl isocyanoacetate, 11.3 g of potassium tert. butoxide and 300 ml of tetrahydrofuran was then poured into the reaction mixture.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:15]>CC(N(C)C)=O>[Cl:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([NH2:12])=[N:11][C:2]([NH:27][CH:24]3[CH2:25][CH2:26][N:21]([CH2:20][C:19]4[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:17]([O:16][CH2:14][CH3:15])[CH:18]=4)[CH2:22][CH2:23]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Nc1nc(Cl)nc2cc(Cl)ccc12
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nc(N)c4ccc(Cl)cc4n3)CC2)ccc1OC
Yield: 28 %

Procedure:
A solution of 2,7-dichloro-quinazolin-4-ylamine (32.1 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 200° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 22.0 mg (28%) of the title compound. MS (ISP): 442.4 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:43][C:44]1[C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:49][C:47]([NH2:48])=[CH:46][C:45]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:48][C:47]2[CH:46]=[C:45]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:44]([O:43][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:50]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:49]=2)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Reactant: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N)cc1-c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N=C(C)c2cccc(C(C)=Nc3ccccc3C(C)(C)C)n2)cc1-c1ccccc1
Reaction time: 24 h

Procedure:
2-[1-(2-tert-butylphenylimino)ethyl]-6-acetylpyridine (487 mg, 1.65 mmol), prepared according to the method described in WO 02/28805, and 4-eicosanoxy-3,5-diphenylaniline (900 mg, 1.65 mmol) were dissolved in 50 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 1 day the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. The product N was isolated as an yellow solid (600 mg, 0.73 mmol, 44%).
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([NH:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(N)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)NC(C(=O)O)C(C)C
Reaction time: 0.17 h

Procedure:
11.7 g (0.10 mol) D,L-Valine were dissolved in 100 ml of acetic acid and treated with 11.2 g (0.11 mol) acetic anhydride at 90° C. Concentration was carried out after 10 minutes at 15 mbar and 100° C. After HPCL analysis the crystalline residue was shown to contain 95.6% Acetyl-D,L-valine and 2.8% N-Acetyl-D,L-valyl-D,L-valine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15]>C(Cl)Cl>[CH3:1][N:2]([CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:3]
Reactant: CNC
Reactant: COC(=O)c1cc(F)cc(CBr)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)cc(CN(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of 2.0M dimethylamine in THF (3.24 mL, 6.48 mmol) was added methylene chloride (2 mL) and methyl 3-(bromomethyl)-5-fluorobenzoate (0.200 g, 0.810 mmol from Step 2). The reaction was heated in a sealed reaction vessel in an oil bath held at 60° C. for 2 hours. Solvent and excess reagent were removed in vacuo and the residue was subjected to flash chromatography, eluting with a gradient from 0-20% MeOH in DCM containing some NH4OH (50 mg, 29%). 1H NMR (300 MHz, CDCl3): δ 7.80-7.77 (m, 1H), 7.62 (ddd, 1H), 7.29 (ddd, 1H), 3.90 (s, 3H), 3.53 (s, 2H), 2.29 (s, 6H); 19F NMR (282 MHz, CDCl3): δ−113.10 (t, 1F); LCMS (M+H)+: 212.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][N:17]=1
Reactant: Cc1cc(S(C)(=O)=O)ccc1-c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(C)(=O)=O)ccc1-c1ccc(OCC2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 136 %

Procedure:
A mixture of 1,1-dimethylethyl 4-[({6-[2-methyl-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (Example 185, 57 mg, 0.124 mmol), TFA (0.095 mL, 1.24 mmol) in CH2Cl2 (3 mL) was stirred at ambient temperature for 3 h. The mixture was concentrated to give (80 mg, quantitative yield) of 2-[2-methyl-4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine trifluoroacetate as a clear oil. 1H NMR (400 MHz, CDCl3): δ 8.78 (d, 1H, J=2.0 Hz), 7.97-7.83 (m, 3H), 7.69 (d, 1H, J=8.7 Hz), 7.58-7.48 (m, 1H), 4.17 (d, 2H, J=5.5 Hz), 3.70-3.55 (m, 2H), 3.14-3.01 (m, 5H), 2.39 (s, 3H), 2.34-2.21 (m, 2H), 2.25-2.10 (m, 2H), 1.97-1.83 (m, 2H); LRMS (ESI), m/z 361 (M+H).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8](Br)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:38][C:37]=1B1OC(C)(C)C(C)(C)O1.C1COCC1.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:41]3[CH:40]=[C:39]([CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH:38]=[CH:37][C:36]=3[O:35][CH3:34])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CCC2)ccc1Br
Reactant: COC(=O)CCc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC)c(-c2ccc(N3CCC3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A flask was charged with (4S,5R)-3-[(6-azetidin-1-yl-3-bromopyridin-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (134 mg, 0.249 mmol), methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (100 mg, 0.312 mmol), 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (8.11 mg, 0.012 mmol), and THF (3 mL). The reaction was degassed with N2 then 1M K2CO3 (3 mL, 3.00 mmol) was added. The reaction was stirred at room temperature for 45 min. The reaction was then diluted with ethyl acetate (20 mL), washed with water (2×15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0 to 100% ethyl acetate/hexanes) to afford methyl 3-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}propanoate. LCMS=652.2 (M+H)+. 1H NMR (CDCl3, 500 MHz) δ 7.84 (s, 1H), 7.72 (s, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8.3, 2.2 Hz, 1H), 6.97 (bs, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.26 (d, J=8.4 Hz, 1H), 5.57 (bs, 1H), 4.75 (m, 1H), 4.33-3.95 (m, 6H), 3.75 (s, 3H), 3.64 (s, 3H), 2.91 (m, 2H), 2.62 (m, 2H), 2.40 (m, 2H), 0.66-0.59 (m, 3H).
Reaction SMILES: C(O)C.[CH2:4]([C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[C:12]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]3)=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:5].[Cl:27]C1C(OC2C=CC(CC)=CC=2)=CN=CN=1>C(OCC)(=O)C>[ClH:27].[CH2:4]([C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[C:12]([NH:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([OH:24])[CH2:22][CH2:23]3)=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:5]
Reactant: CCc1ccc(Oc2cncnc2Cl)cc1
Agent: CCc1ccc(Oc2cncnc2N[C@H]2CC[C@H](O)CC2)cc1
Agent: CCc1ccc(Oc2cncnc2N[C@H]2CC[C@H](O)CC2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cl

Procedure:
Science, 230-440 mesh) (13×4 cm column bed) using ethyl acetate as the eluent for the first 1.2 L and then with 5% ethanol in ethyl acetate. The fractions that contained homogeneous product were spin evaporated in vacuo to give a syrup. The pure 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine was converted to the hydrochloride by the same procedure described in Example 4. The residue was triturated under ethyl acetate to give a white solid which was collected, washed with ethyl acetate and dried in vacuo to give 1.25 g (77% yield) of 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine hydrochloride as a white solid, mp 245-243° C.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])[N:26]=1>>[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:30])[N:26]=1
Reactant: Nc1nc(-c2ccccc2C(=O)O)cs1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: Nc1nc(-c2ccccc2C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)cs1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-(2-amino-thiazol-4-yl)-benzoic acid. LC-MS (basic): tR=1.24 min; [M+H]+=477.1.
Reaction SMILES: C([Li])CCC.[I-].[CH:7]([P+:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])[CH3:8]>CCCCCC.O1CCCC1>[C:23]1([P:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([CH3:9])[CH3:8])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of n-butyllithium in hexane was added to a suspension of isopropyltriphenylphosphonium iodide in tetrahydrofuran to obtain a solution of 12.5×10-3M of triphenylisopropylidene phosphorane in tetrahydrofuran and 20 ml of the solution were added to a solution of 1.35 g of the product of Step B in 25 ml of tetrahydrofuran. After stirring at 0° C. for one hour and then at room temperature for one hour, the mixture was diluted with 10 ml of water and was extracted with ether. The extract was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica to obtain the expected product in a 50 to 60% yield which after crystallization from cyclohexane had a specific rotation of [α]D =-55.5° (c=20.25 in CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][C:12]1([CH3:22])[C:20]2[C:15](=[C:16]([NH2:21])[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]1([CH3:22])[C:20]2[C:15](=[C:16]([NH:21][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC1(C)CCc2c(N)cccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1C(=O)Nc1cccc2c1CCC2(C)C
Temperature: 0 °C
Yield: 93.3 %

Procedure:
A solution of 0.81 g of o-methylbenzoyl chloride (5.25 m mol) in 3 ml of tetrahydrofuran is added dropwise to a solution of 0.81 g of 1,1-dimethyl-4-aminoindan (5.00 m mol) and 0.61 g of triethylamine (6.00 m mol) in 10 ml of tetrahydrofuran, while maintaining the reaction mixture at 0° C. by ice-cooling. Then, reaction mixture is stirred over night at room temperature, and water and ethyl acetate are added to the mixture. The organic layer is washed with 5% hydrochloric acid and water and dried over anhydrous sodium sulfate. After the solvent is removed by distillation, the residue is dried to give 1.31 g of N-(1,1-dimethyl-4-indanyl)-o-methylbenzamide (yield: 93.9%).
Reaction SMILES: [CH2:1]1[CH:12]2[C:13]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[CH2:9][CH2:10][CH2:11]2)[CH2:3][C:2]1=O.[NH2:15][OH:16].Cl>N1C=CC=CC=1.C(O)C.O>[CH2:1]1[CH:12]2[C:13]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[CH2:9][CH2:10][CH2:11]2)[CH2:3][C:2]1=[N:15][OH:16]
Reactant: NO
Reactant: O=C1Cc2cccc3c2C(CCC3)C1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1Cc2cccc3c2C(CCC3)C1
Reaction time: 1 h

Procedure:
9.86 g Of 2,3,7,8,9,9a-hexahydro-1H-phenalen-2-on was dissolved in 15 ml pyridine. A solution of 3.8 g hydroxylamine.HCl in 12 ml ethanol/H2O (1:1) was added to this solution and the mixture was stirred for one hour. The resultant deposit was filtered off, washed off H2O and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19](OC)=[O:20])=[CH:15][CH:14]=2)=[N:3]1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:3]1
Reactant: COC(=O)c1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Yield: 93 %

Procedure:
2.0 g (6.46 mmol) of 4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2-yl)oxazoline was dissolved in tetrahydrofuran (20 ml). 0.49 g (12.9 mmol) of aluminum lithium hydride was gradually added thereto under cooling with ice, followed by the stirring for 2 hours as such. Water (50 ml) was added thereto to conduct hydrolysis, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.69 g of the title compound (yield 93%).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12](#[N:15])[CH:13]=C>>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]#[N:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: C=CC#N
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Product: N#CC=Cc1ccc(C=O)cc1
Yield: 44.6 %

Procedure:
The procedure described in Example 28 is repeated, except that 8.23 g (0.05 mol) of 4-formylbenzoyl chloride and 3.32 g (0.0625 mol) of acrylonitrile are used. After a reaction time of 3 hours at 120° C., 3.5 g (0.0223 mol) of 4-formylcinnamonitrile are obtained, corresponding to a yield of 44.6% of theory; melting point 122° C. Analysis for C10H7NO (molecular weight 157): calculated C 76.22%, H 4.49%, N 8.91%, found C 76.30%, H 4.55%, N 8.96%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C@@H:16]([CH2:19][OH:20])[CH2:17][CH3:18])[C:12]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[S:26]([CH3:34])(=[N:28]C(OCC)=O)=[O:27].CC[O-].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C@@H:16]([CH2:19][OH:20])[CH2:17][CH3:18])[C:12]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[S:26]([CH3:34])(=[NH:28])=[O:27]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1Br
Agent: CC[O-]
Agent: [Na+]
Product: CC[C@H](CO)Nc1nc(Nc2ccc(S(C)(=N)=O)c(Br)c2)ncc1-c1cccs1
Yield: 64 %

Procedure:
In the reaction of (RS)—S-{2-bromo-4-[(4-{[(R)-1-(hydroxymethyl)propyl]amino}-5-(2-thienyl)pyrimidine-2-yl)amino]phenyl}-N-(ethoxycarbonyl)-S-methyl-sulfoximide (130 mg, 0.23 mmol) with sodium ethylate (22 mg, 0.31 mmol) according to procedure 14, the desired product is obtained in 64% yield (73 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (9/1)).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[Cl:24][C:25]1[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:24][C:25]1[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:27][N:26]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 223.1.1) to give the title compound as a white solid. (HPLC: tR 2.31 min (Method A); M+H=498 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.87 (s, 1H), 9.01 (s, 1H), 8.41-8.38 (m, 1H), 8.18-8.11 (m, 2H), 7.98-7.93 (m, 1H), 7.91-7.88 (m, 1H), 7.62-7.59 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 3.18 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.OS(O)(=O)=O.[CH3:19][C:20](=[CH2:22])[CH3:21]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([O:12][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: C=C(C)C
Reactant: O=C(O)c1cc2cc(Br)ccc2s1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc2cc(Br)ccc2s1

Procedure:
A mixture of Example 274B and concentrated H2SO4 (0.5 mL) in dichloromethane (100 mL) saturated with isobutylene at room temperature was stirred for 4 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclobutanecarbonyl chloride (3.7 ml) and triethylamine (14 ml) were added to a solution of [1,4]diazepane-1-carboxylic acid tert-butyl ester (4.9 ml) in dichloromethane (175 ml). After stirring for 1 h at room temperature, the reaction mixture was washed with water, an aqueous HCl solution (1 N), water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH:1]12[CH2:7][NH:6][CH:5]1[CH2:4][N:3](C1C=NC3C(=CC=CC=3)N=1)[CH2:2]2.Cl[C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][N:20]=1>>[C:25]1([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([N:3]3[CH2:4][CH:5]4[CH:1]([CH2:7][NH:6]4)[CH2:2]3)[N:24]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Clc1nccc(-c2ccccc2)n1
Reactant: c1ccc2nc(N3CC4CNC4C3)cnc2c1
Product: c1ccc(-c2ccnc(N3CC4CNC4C3)n2)cc1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 8, using 2-chloro-4-phenyl pyrimidine. MS (ESI) mass calcd. for C15H16N4, 252.31; m/z found 253.2 [M+H]+.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].C(N(CC)CC)C.[C:20](Cl)(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[CH2:21]([C:20]1[NH:9][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N:10]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC(=O)Cl
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1nc2ccccc2[nH]1
Yield: 46.6 %

Procedure:
To a solution of O-phenylenediamine (2.2 g) and triethylamine (2.0 g) in methylene chloride (20 ml) was added dropwise caproyl chloride (2.3 g) with stirring under ice-cooling. The mixture was stirred for 3 hours at room temperature, washed with a saturated aqueous sodium bicarbonate and water, then dried. The solvent was evaporated. To the residue was added 3N-HCl, and the mixture was heated for 1.5 hour under reflux. The reaction mixture was made basic with 6N NaOH. Then precipitating crystals were recrystallized from ethyl acetate-hexane to give colorless needles (1.5 g, 47%), m.p. 161-162° C.