Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:29].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:22]3[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:20][C:21]3=[O:29])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4ccccc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 3H-benzooxazol-2-one (94 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (15): HPLC retention time, 2.29 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 401.9, found, 402.5.
Reaction SMILES: [N+](C1C=CC(OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:38][C@H:39]([C:47]([OH:49])=[O:48])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:46])[NH2:45]>>[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH:38][C@H:39]([C:47]([OH:49])=[O:48])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:45])[NH2:46])=[O:34])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O

Procedure:
p-Nitrophenyl ether of benzyloxycarbonylproline is reacted with arginine to give benzyloxycarbonyl-prolyl-arginine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.F[P-](F)(F)(F)(F)F.N1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:40]([O:44][C:45](=[O:50])[NH:46][CH2:47][CH2:48][NH2:49])([CH3:43])([CH3:42])[CH3:41].C(N(C(C)C)C(C)C)C>ClCCl>[C:40]([O:44][C:45](=[O:50])[NH:46][CH2:47][CH2:48][NH:49][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15])([CH3:43])([CH3:41])[CH3:42]
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nc(Cl)c2ccccc2c1O
Reaction time: 120 h
Yield: 10.9 %

Procedure:
To a mixture of 45 mg (0.2 mmol) of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 76 mg (0.2 mmol) of benzotriazol-1-yl-(bis-dimethylamino-methylene)-oxonium hexafluoro phosphate (HBTU), 32 μl (2-amino-ethyl)-carbamic acid tert-butyl ester (0.2 mmol), and 1 ml of dichloromethane was added 96 μl (0.55 mmol) of ethyl-diisopropyl-amine with stirring. Stirring was continued at ambient temperature for 5 days. The product was isolated from the reaction mixture by flash column chromatography on silica gel using hexanes:ethyl acetate (8:2) as the eluent to give a tan gum. 8 mg of the title compound were obtained; MS-(−)-ion: M−1=364.0.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH:7]=O)=[C:5](Br)[N:4]([CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[SH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:21][C:5]=2[N:4]([CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[N:3]=1
Reactant: CCOC(C)n1nc(Br)c(C=O)c1Br
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(Br)nn(C(C)OCC)c2s1
Yield: 88.4 %

Procedure:
1.19 g (3.81 mmol) of 3,5-dibromo-1-(1-ethoxyethyl)-1H-pyrazole-4-carboxaldehyde are introduced with stirring into 50 mL of ethanol under an argon atmosphere at a temperature in the region of 20° C., followed by addition of 0.4 g (3.81 mmol) of sodium carbonate and 0.42 mL (3.81 mmol) of ethyl 2-mercaptoacetate. The reaction mixture is then refluxed for 2 hours, and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 60 mL of water and 60 mL of dichloromethane, and the phases are separated by settling. The organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). 1.17 g of ethyl 3-bromo-1-(1-ethoxyethyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate are thus obtained in the form of a pale yellow oil that crystallizes to give cream-colored crystals melting at 69° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:25])=[CH:9][C:10]([O:23]C)=[CH:11][C:12]=3[C:13]32[CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]3)=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:22][C:20]1=[N:21][C:13]2([CH2:16][O:17][CH2:18][CH2:19]1)[C:12]1[CH:11]=[C:10]([OH:23])[CH:9]=[C:8]([F:25])[C:7]=1[O:6][C:5]1[C:14]2=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COc1cc(F)c2c(c1)C1(COCCC(N)=N1)c1cc(Br)ccc1O2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC1=NC2(COCC1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (E)-7′-bromo-4′-fluoro-2′-methoxy-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine (0.990 g, 2.431 mmol) in DCM (24.31 mL) was cooled in an ice-bath for 5 min. Boron tribromide (0.919 mL, 9.72 mmol) was added dropwise to give a resulting brown mixture. The mixture was stirred for 1 h, at which time a saturated aq. sodium bicarbonate solution (25 mL) was added. The mixture was stirred for 5 min. and concentrated on a rotary evaporator to remove the DCM. The mixture was heated with a heat gun for 5 min, and at this point the solid was scraped from the sides of the flask. The flask was sonicated for 1 min, then reheated for 2 min. The flask was again sonicated for 1 min, then cooled to RT. The solid was filtered. The filter cake was washed twice with water, then air-dried under a stream of N2 (g) for 1.5 h to give (E)-5-amino-7′-bromo-4′-fluoro-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-2′-ol as a light-yellow solid. The solid was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][CH:7]1O)=[O:5])[CH3:2].C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][CH:7]1[N:28]=[N+:29]=[N-:30])=[O:5])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCC(C)CC1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(C)CC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
2-Hydroxy-4-methyl-cyclohexanecarboxylic acid ethyl ester (495 mg, 2.66 mmol) was dissolved in THF (13 ml) and then diphenylphosphoryl azide (680 ul, 3.19 mmol) and triphenylphosphine (837 mg, 3.19 mmol) were added. The resulting solution was cooled in an ice bath and diethyl azodicarboxylate (502 ul, 3.19 mmol) was added. After stirring at room temperature for 20 hours, the solvents were removed and the residue was purified by flash chromatography (0% to 3% EtOAc/Hexane) to obtain 365 mg (65%) of 2-Azido-4-methyl-cyclohexanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]2[O:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[C:9](=[C:16]=[CH2:17])[CH2:8]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(I)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([CH:7]2[O:11][CH:10]3[C:9]([C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH2:17])([O:14][C:13](=[O:15])[CH2:12]3)[CH2:8]2)=[CH:5][CH:6]=1
Reactant: Ic1ccccc1
Reactant: C=C=C1CC(c2ccc(C)cc2)OC1CC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(c1ccccc1)C12CC(c3ccc(C)cc3)OC1CC(=O)O2
Temperature: 85 °C
Reaction time: 4 h

Procedure:
(5-p-tolyl-3-vinylidene-tetrahydro-furan-2-yl)acetic acid (35 mg, 0.14 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol) and K2CO3 (84 mg, 0.61 mmol) were dissolved in 3 mL of dimethylformamide, followed by addition of PhI (68 μL, 0.61 mmol). The solution was stirred for 4 hours at 85° C. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:15, v/v), thus providing products (27 mg, 58%).
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=2[C:28]([NH:30][CH2:31][CH3:32])=[O:29])[C:22]([Cl:38])=[CH:21][N:20]=1>>[C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=4[C:28]([NH:30][CH2:31][CH3:32])=[O:29])[C:22]([Cl:38])=[CH:21][N:20]=3)[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(C)=O)ncc1Cl

Procedure:
Title compound was prepared from 1-Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 1221d (120° C., 80 min) Isolated 68 mg (34%) as a pale yellow foam. 98% HPLC purity, LCMS 526.16 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 7.48-7.46 (m, 1H), 7.41 (s, 1H), 7.35-7.33 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.69 (bt 1H), 6.38 (bs, 1H), 4.77-4.74 (m, 1H), 4.26-4.20 (m, 1H), 3.69-3.64 (m, 1H), 3.47-3.36 (m, 2H), 2.99-2.93 (m, 1H), 2.66-2.60 (m, 1H), 2.55-2.50 (m, 1H), 1.77 (s, 3H), 1.14 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C>C([O-])(O)=O.[Na+].O>[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
A mixture of uridine (14; 13.25 g, 54.5 mmol), diphenyl carbonate (15.48 g, 72.5 mmol), anhydrous NaHCO3 (349 mg, 4.15 mmol), and hexamethylphosphoric triamide (50 mL) was heated with stirring at 150° C. under nitrogen for 20 min, and then cooled to room temperature. The mixture was poured into cold water (400 mL), and washed with CHCl3. Et3N (25 mL) was added, and the aqueous solution was heated at 70° C. for 5 h. The solvent was evaporated in vacuo, and the residue was crystallized from MeOH/water to give the title compound 15 as a white solid (11.13 g, 84%). 1H NMR (DMSO-d6) δ 11.2 (s, 1H, NH), 7.60 (d, J=7.5 Hz, 1H, H-6), 5.95 (d, 1H, H-1′), 5.51 (d, J=7.5 Hz, 1H, H-5), 6.30–5.30 (br, 2H, 2 OH), 4.10–3.50 (m, 6H, H-2′, H-3′, H-4′, H-5′, OH).
Reaction SMILES: [ClH:1].[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>C(O)C>[ClH:1].[C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:9]=1)([CH3:18])([CH3:17])[CH3:10]
Reactant: NNC1CCCCC1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C2CCCCC2)n1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A stirred solution of cyclohexylhydrazine hydrochloride (1.5 g, 9.96 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.5 g, 11.98 mmol) in ethanol (5 mL) was refluxed for 15 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure and the obtained crude product was recrystallized from a mixture of diethyl ether and petroleum ether to afford 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (1.0 g, 39%) as colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 13.24 (brs, 1H), 7.02 (brs, 2H), 5.52 (s, 1H), 4.30 (m, 1H), 1.63-1.98 (m, 7H), 1.10-1.40 (m, 12H); LC-MS (ESI) m/z 222 (M+H)+.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.CI.[CH2:22]=[CH:23][CH:24]=[CH2:25]>C(OCC)(=O)C>[C:16]([C:7]1[C:8](=[O:15])[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]2([CH2:25][CH2:24][CH:23]=[CH:22][CH2:4]2)[CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC=C
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(C)(C)C1=CC2(C=C(C(C)(C)C)C1=O)CC=CCC2
Temperature: 100 °C
Yield: 98.4 %

Procedure:
To a 250 mL glass reaction vessel containing an ethyl acetate (50 mLs) solution of N,N-dimethyl,2,6-di-t-butyl-4-aminomethylphenol (1.32 g; 5 mmols), there was added methyl iodide (0.31 mLs; 5 mmols) to give a colorless slurry. The vessel was sealed and 1,3-butadiene (20 mmols) was introduced into the system. The reaction mixture was heated to 100° C. and the pressure was increased from atmospheric to 45 psig. The reaction mixture was maintained at these conditions for approximately 30 hours. The reaction vessel was then allowed to cool to room temperature. After cooling, the black reaction mixture was filtered to remove ammonium iodide salt by-product. The filtrate was concentrated to afford a viscous oil which was crystallized from ethanol:water (80:20) to give 1.34 g of 2,4-di-t-butylspiro[5.5]undeca-1,4,8-trien-3-one (49% yield based on the N,N-dimethyl,2,6-di-t-butyl-4-aminomethylphenol starting reactant) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:21]([C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][C:28]([NH2:30])=O)#[N:22].C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]2[C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[N:30]=[C:28]2[CH2:27][O:26][C:25]2[CH:24]=[C:23]([CH:33]=[CH:32][CH:31]=2)[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: N#Cc1cccc(OCC(N)=O)c1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(Cl)c2)c(COc2cccc(C#N)c2)n1
Temperature: 165 °C
Reaction time: 24 h
Yield: 58.4 %

Procedure:
A mixture of N-(3-chloro-4-morpholinophenyl)-3-oxobutanamide (0.59 g, 2.00 mmol), 2-(3-cyanophenoxy)acetamide (0.71 g, 4.03 mmol) and titanium tetraisopropanolate (4.8 mL) in xylene (20 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 30 mL of toluene and 40 mL of saturated NH4Cl aqueous solution were added. The resulting mixture was stirred at rt overnight and filtered and the filtrate was extracted with DCM (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.51 g, 59%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1cc(Br)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.8 %

Procedure:
A mixture of 4-bromo-2-chloro-phenylamine (4 g, 19.37 mmol), tetrahydro-4H-pyran-4-one (2.69 ml, 29.05 mmol), oven dried molecular sieves 4 Å (2 g) and sodium triacetoxyborohydride (6.12 g, 29.05 mmol) in 1,2-dichloroethane (100 ml) was stirred at room temperature for 72 hours. The mixture was filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with dichloromethane. The combined filtrates were washed with NaHCO3 (aqueous saturated solution), dried over Na2SO4 and evaporated till dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 5%). The desired fractions were collected and evaporated in vacuo to yield intermediate 12 as a brown oil (4.83 g, 86%).
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[N+:12]([C:15]1[CH:21]=[CH:20][C:18](N)=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1)([O-:14])=[O:13].NC1C=CC=CC=1>CC#N>[CH2:3]([C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][C:17]=1[C:22]([F:25])([F:24])[F:23])[CH:1]=[CH2:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 18.5 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-nitro-2-trifluoromethylaniline (618 mg, 3.0 mmol) was added during 20 minutes while maintaining the temperature of the reaction mixture at 18-19° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 25° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 49:1) gave 587 mg (85%) of allyl-4-nitro-2-trifluoromethylbenzene as a light yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.53, (d, 1H, J=2.4 Hz), 8.35, (dd, 1H, J=8.5, 2.4 Hz), 7.59, (d, 1H, J=8.5 Hz), 6.00-5.88, (m, 1H), 5.24-5.12, (m, 2H), 3.68, (d, 2H, J=6.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 146.8, 146.6, 134.9, 133.0, 130.3, (q, J=32.2 Hz), 127.7, 126.9, 124.9, 122.2, 122.1, (q, J=6.0 Hz), 118.7, 37.0, (m); Anal HRMS Calcd. for C10H8F3NO2 (M): 231.0507. Found: 208.0515.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]=[C:12]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:13]4[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:14]=4[N:15]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.O1CCOC[CH2:35]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]=[C:12]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]4[CH3:35])[C:13]4[CH2:19][CH2:18][NH:17][CH2:16][C:14]=4[N:15]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(-c3ccc4[nH]ccc4c3)nc2N2CCOCC2)C1
Reactant: C1COCCO1
Agent: Cl
Product: C[C@H]1COCCN1c1nc(-c2ccc3[nH]ccc3c2)nc2c1CCNC2
Reaction time: 2 h

Procedure:
Tert-butyl 2-(1H-indol-5-yl)-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.199 g, 0.000443 mol) and 4.0 M of Hydrogen chloride in 1,4-Dioxane (3.4 mL) were combined and shaken for 2 hours then concentrated, diluted 10% MeOH in dichloromethane and sat NaHCO3, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, and vacuum pump dried overnight, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 8.56 (s, 1H), 8.12 (dd, J=8.6, 1.4, 1H), 7.42 (d, J=8.6, 1H), 7.36 (t, J=2.7, 1H), 6.53 (s, 1H), 4.10 (d, J=6.7, 1H), 3.95-3.78 (m, 3H), 3.74 (dd, J=11.3, 2.8, 1H), 3.68-3.50 (m, 3H), 3.50-3.39 (m, 1H), 3.02-2.90 (m, 1H), 2.87-2.76 (m, 1H), 2.55 (d, J=11.2, 2H), 1.25 (t, J=10.2, 3H). LC/MS-m/z+350.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(#N)C.C(Cl)Cl.O>[C:23]([O:22][C:20]([CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Reaction time: 12 h
Yield: 92.3 %

Procedure:
A solution of 4-hydroxybenzaldehyde (2.44 g, 20.0 mmol) in dry acetonitrile (8.0 mL) was treated with powdered, dried K2CO3 (3.04 g, 22.0 mmol) and NaI (304 mg, 2.00 mmol). The mixture was refluxed under argon for 30 min. tert-Butyl bromoacetate (1.48 mL, 1.95 g, 10.0 mmol) was added dropwise, and the reflux was continued for 12 h. Water and CH2Cl2 were added and the phases were separated. The aqueous layer was extracted with CH2Cl2. The combined organic phase was washed with water. The organic layer was dried (Na2SO4). Evaporation of the solvent and chromatography of the oily residue [silica, ethyl acetate/hexanes (3:7)] afforded a white, crystalline solid (2.18 g, 92%): mp 56-57° C.; IR (film, νmax cm−1) 1762, 1752, 1685, 1600; 1H NMR δ 1.48 (s, 9H), 4.60 (s, 2H), 6.99 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.7 Hz, 2H), 9.89 (s, 1H); 13C NMR δ 28.25, 65.76, 83.17, 115.08, 130.82, 132.18, 163.00, 167.37, 190.98; EI-MS 105/107, 135, 193/194, 236/237; FAB-MS obsd 237.1120, calcd 237.1127 [(M+H)+, M=C13H16O4]; Anal. Calcd C, 66.09; H, 6.83. Found C, 66.06; H, 6.82.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:14]([F:16])[F:15])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][C:19]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCCC.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH:14]([F:15])[F:16])([CH3:13])[CH2:11][O:12][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[C:19]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:20]=2)=[CH:8][CH:9]=1
Reactant: CC(CO)(c1ccc(Cl)cc1)C(F)F
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(COCc1ccc(F)c(Oc2ccccc2)c1)(c1ccc(Cl)cc1)C(F)F

Procedure:
0.44 g (10 mmol) Sodium hydride dispersion (55%) was freed from oil by washing three times with dry toluene. It was suspended in 10 ml dry dimethoxyethane and then, with stirring, 1.77 g (8.0 mmol) 2-(4-chlorophenyl)-2-difluoromethylpropanol and 2.24 g (8.0 mmol) 4-fluoro-3-phenoxybenzyl bromide added. After stirring for five hours at room temperature a thin layer chromatogram (Merck DC silica gel 60F254 plate, using hexane/ethyl acetate 1:1 as eluant, Rf : 0.57) showed that no starting material was present.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH3:20])=[O:12]>C(N(CC)CC)C.C(O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])=[O:12])[CH:7]=1
Reactant: Cc1ccc(C(=O)CBr)c(C)c1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)Cn2cc(Cl)cnc2=O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloropyrimidin-2-one (425 mg) and 2-bromo-2',4'-dimethylacetophenone (682 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and the solid filtered off.