Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16]C)=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[CH2:7]2.N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:13][O:12][C:11]1[C:3](=[O:2])[C:4]2[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=3)[CH2:7][C:8]=2[C:9](=[O:16])[C:10]=1[O:14][CH3:15]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCOc1ccc(C(=O)O)cc1)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCOc3ccc(C(=O)O)cc3)C2)C1=O
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a mixture of 4-[3-(4,5,6,7-tetramethoxyindan-2-yl)propoxy]benzoic acid (1.20 g), 2,6-pyridinedicarboxylic acid (1.44 g), THF (24 ml), and water (12 ml) was dropwise added a solution of CAN (6.30 g) in water (12 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) and then with recrystallization from ethyl acetate to yield the entitled compound (868 mg) as crystals.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([CH3:6])[CH3:5].[NH2:8][C:9]([NH2:11])=[S:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:4]([C:3]1[N:8]=[C:9]([NH2:11])[S:10][CH:2]=1)([CH3:6])[CH3:5]
Reactant: NC(N)=S
Reactant: CC(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1csc(N)n1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 69.8 %

Procedure:
2 g of 1-bromo-3-methyl-butan-2-one obtained in step 93-1 was added to 20 ml of ethanol and 920 mg of thiourea was added thereto. The mixture was heated to 60° C., stirred for 3.5 hr and cooled to room temperature. The resulting mixture was added with aqueous sodium carbonate and extracted twice with ethyl acetate. The organic layer was washed with water and saline solution, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting residue thus obtained was purified by column chromatography (ethyl acetate/hexane=1/2) to obtain 1.2 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][CH2:13][N:6]2[C:5](=[O:21])[CH2:4][CH2:3]1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:33](Cl)(=[O:42])[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[Cl-].[Na+].O.O>[C:17]([O:16][C:14]([C@H:10]1[N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:33]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:42])[CH2:3][CH2:4][C:5](=[O:21])[N:6]2[CH2:13][CH2:12][CH2:11]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCc3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
In a 20 mL pear-shaped flask, (1S,9S)-tert-butyl 9-amino-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (0.9 g, 3.03 mmol) was combined with DMF (8 ml) to give a colorless solution and cooled to 0° C. Sodium carbonate (385 mg, 3.63 mmol) and benzyl carbonochloridate (516 mg, 432 μl, 3.03 mmol) were added and stirred at room temperature for 6 hr. It was diluted with brine and H2O, extracted with EtOAc (2×60 ml). The combined organic layer was washed with brine and H2O, dried with MgSO4, filtered and concentrated in vacuo to afford (1S,9S)-tert-butyl-9-(benzyloxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate as an oil (1.3 g, 99.5%). ESI-LRMS m/e calcd for C18H21N3O6 [M+] 431. found 432 [M+H+]. The crude was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][CH3:16])[N:6]=1.[C:23]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35](O)=[O:36])(=[O:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[C:23]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]([NH:1][C:2]1[S:3][C:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][CH3:16])[N:6]=1)=[O:36])(=[O:25])[CH3:24]
Reactant: CCOC(=O)Cc1sc(N)nc1-c1ccc(OC)cc1OC
Reactant: CC(=O)n1c(C(=O)O)cc2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1sc(NC(=O)c2cc3ccccc3n2C(C)=O)nc1-c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g of 2-amino-4-(2,4-dimethoxyphenyl)-5-ethoxycarbonylmethylthiazole, 1 g of 1-acetylindole-2-carboxylic acid, 0.7 ml of triethylamine and 2.39 g of BOP are dissolved in 15 ml of dichloromethane. The reaction mixture is stirred overnight at room temperature and then concentrated under vacuum. The residue is taken up in ethyl acetate and the solution is successively washed with a buffer solution, pH=2, with a 5% solution of NaHCO3 and with water, and then the organic phase is dried over MgSO4 and concentrated under vacuum. The residue is purified by chromatography on a silica gel, eluent:dichloromethane/ethyl acetate 100/2.5 (v/v).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]#[CH:13])[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[NH2:21][C:22]1[C:27](Br)=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]#[C:13][C:27]2[C:22]([NH2:21])=[N:23][CH:24]=[C:25]([N+:29]([O-:31])=[O:30])[CH:26]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Reactant: C#Cc1cccc(OCCOC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOc1cccc(C#Cc2cc([N+](=O)[O-])cnc2N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
3-(2-Methoxy-ethoxy)-phenylacetylene (6.3 g, 36 mmol) was added to a solution of triethylamine (1.92 mL, 14 mmol), 2-amino-3-bromo-5-nitropyridine (4 g, 18 mmol), PdCl2(PPh3)2 (966 mg, 1.38 mmol) and CuI (262 mg, 1.38 mmol) in anhydrous tetrahydrofuran (80 mL) in the dark. The mixture was stirred at room temperature for 48 hours then concentrated in vacuo and dissolved in dichloromethane (150 mL). The organic solution was washed with water (25 mL), dried over MgSO4, filtered and concentrated in vacuo to 20% of its original volume and heptane (20 mL) was then added. The resultant yellow solid was filtered and dried to give 3-[3-(2-methoxy-ethoxy)-phenylethynyl]-5-nitro-pyridin-2-ylamine (4.2 g, 74% yield).
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:4]([C@H:5]2[CH2:6][CH2:7][C@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][CH2:10]2)[CH:1]([CH3:3])[CH3:2])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)N[C@H]1CC[C@H](c2ccccc2)CC1
Product: CC(C)N(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from trans-N-isopropyl-4-phenylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 130°-132° C.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[CH:52][C:53]4[N:58]([CH2:59][CH2:60][CH2:61][CH2:62][C:63]#[N:64])[C:57](=[O:65])[CH2:56][O:55][C:54]=4[N:66]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[C:51]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[CH:52][C:53]4[N:58]([CH2:59][CH2:60][CH2:61][CH2:62][C:63]#[N:64])[C:57](=[O:65])[CH2:56][O:55][C:54]=4[N:66]=3)=[CH:48][CH:49]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCCCC#N)C(=O)CO4)cc2)CCC1
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: N#CCCCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 71.2 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(4-cyanobutyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (25 mg, 0.045 mmol) was reacted to afford the title compound (14.5 mg). 1H NMR (500 MHz, CH3OD) 7.60 (1H, s), 7.42 (2H, d), 7.39 (2H, d), 7.31 (3H, m), 7.25 (2H, m), 4.97 (2H, s), 4.11 (2H, t), 2.73-2.79 (2H, m), 2.54-2.61 (4H, m), 2.22-2.25 (1H, m), 1.95-1.97 (1H, m), 1.84-1.89 (2H, m), 1.74-1.78 (2H, m). LCMS (Method A): RT=4.19 min, M+H+=453.5.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OCC)(=O)C.O>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCC(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-methylpentanol (3.0 ml) in pyridine (20 ml) were added in turn with p-toluenesulfonyl chloride (4.6 g) and 4-N,N-dimethylaminopyridine (1.5 g) at ambient temperature. After stirring at ambient temperature, the reaction mixture was taken up into a mixture of ethyl acetate (100 ml) and water (100 ml). The separated organic layer was washed in turn with hydrochloric acid(1N), water, aqueous sodium hydrogencarbonate, and brine, and dried over magnesium sulfate. Evaporation gave 1-p-Toluenesulfonyloxy-4-methylpentane (5.30 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:19]2([CH2:21][CH2:20]2)[C@H:18]2[C@@H:11]([O:12][Si:13]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:14][Si:15]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:16][CH2:17]2)[C@H:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:41])CC)C>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C:19]2([CH2:21][CH2:20]2)[C@H:18]2[C@@H:11]([O:12][Si:13]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:14][Si:15]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:16][CH2:17]2)[C@@H:10]1[F:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@@H](O)[C@@H](OCc1ccccc1)C21CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@H](F)[C@@H](OCc1ccccc1)C21CC1
Yield: 45.9 %

Procedure:
To a solution of alcohol 25 (5.1 g, 10.7 mmol) in anhydrous CH2Cl2, (diethylamino) sulfur trifluoride (DAST) (9.3 ml, 70.5 mmol) was added slowly at room temperature. The reaction mixture was quenched with iced H2O after 20 min. The organic layer was collected and the aqueous phase was extracted with dichloromethane. The organic layer was then combined, dried over Na2SO4 and the volatiles removed under reduced pressure. The crude residue was purified by flash silica gel column chromatography (1% EtOAc/Hexane) to give 26 (2.5 g, 49%). [α]24D −98.08° (c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.26 (m, 5H), 4.92 (ddd, J=6.0, 7.5 & 5.5 Hz, 1H), 4.78 (d, J=11.5 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.31-4.26 (m, 1H), 4.23-4.16 (m, 1H), 4.01-3.92 (m, 2H), 2.70 (m, 1H) 1.08-0.94 (m, 28H), 0.72 (m, 1H), 0.68-0.43 (m, 2H), 0.28 (m, 1H); 13C NMR (125 MHz, CDCl3) δ142.6 (d, J=9.2 Hz), 141.8, 137.9, 128.4, 112.7, 103.4 (d, J=189.0 Hz), 80.4 (d, J=21.3 Hz), 73.8 (d, J=19.8 Hz), 71.3, 61.6, 48.8 (d, J=5.3 Hz), 29.4, 24.5, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 16.9, 16.8, 13.4, 13.3, 12.7, 12.5, 7.9; HR-MS Calcd. For (C27H45FO4Si2+H)+ 509.2840, found 509.2923.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=O)C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][CH3:21])=[N:17][CH:18]=1>C(Cl)Cl.P(Cl)(Cl)(Cl)=O>[Cl:1][C:18]1[C:13]([Cl:12])=[CH:14][CH:15]=[C:16]([CH2:19][O:20][CH3:21])[N:17]=1
Reactant: COCc1ccc(Cl)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCc1ccc(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
3-chloroperbenzoic acid (80%, 4.83 g, 13.96 mmol) was added portion-wise to a solution of 5-chloro-2-(methoxymethyl)pyridine (Preparation 57, 2 g, 12.69 mmol) in DCM (50 mL) at 0° C. The reaction was stirred for 18 hours at room temperature. The reaction mixture was quenched with 2M aqueous sodium hydroxide (25 mL) and brine (25 mL) and stirred vigorously. The organic layer was collected, washed with 2M aqueous sodium hydroxide (2×10 mL), water (10 mL), dried over sodium sulfate and concentrated in vacuo. A portion of the residue (100 mg, 0.576 mmol) was stirred in phosphoryl chloride (2 mL) at 80° C. for 2 hours. The reaction was concentrated in vacuo and vigorously stirred in DCM (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL) for 5 hours. The organic layer was collected dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM to afford the title compound (38 mg, 34%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.[O:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C(C)(C)C>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:19]1[C:23]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]23)=[CH:22][N:21]=[CH:20]1
Reactant: c1cocn1
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: CC(=O)N(C)C
Product: O=C1C=C2c3cccc(-c4cnco4)c3CCN2C(=O)CN1
Temperature: 120 °C
Yield: 32.3 %

Procedure:
112-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (520 mg, 1.47 mmol), oxazole (0.24 mL, 3.67 mmol), Pd(OAc)2 (49 mg, 0.22 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (141 mg, 0.29 mmol), K2CO3 (609 mg, 4.40 mmol) and pivalic acid (68 μL, 0.59 mmol) in DMA (4 mL) was heated to 120° C. for 1 h in a microwave reactor. The mixture was then filtered and the filtrate was concentrated in vacuo. Purification of the obtained residue by flash chromatography (SiO2, AcOEt/MeOH 99:1 to 90:10) afforded the title compound (140 mg) as a beige powder. UPLC-MS: MS 296.1 (M+H+); UPLC rt 0.60 min.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1>>[CH3:18][C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Product: Cc1ccc(C(=O)N[C@H](C(=O)O)C(C)C)cc1

Procedure:
Racemic valine and p-toluoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.[CH3:6][Si:7]([CH3:37])([C:33]([CH3:36])([CH3:35])[CH3:34])[O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C.CCCCCC.O.C(O)(=O)C>[C:2]([O:22][C@H:12]1[C@H:11]([CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C@@H:10]([CH2:9][O:8][Si:7]([CH3:6])([CH3:37])[C:33]([CH3:34])([CH3:36])[CH3:35])[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13]1)(=[O:1])[CH3:3]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Reactant: C1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
An anhydrous tetrahydrofuran (482 mL) solution of the compound 3 (79.6 g) and triphenylphosphine (57.6 g) was cooled to around −40° C. in a dry ice-methanol bath. To this solution was added acetic acid (12.6 mL), and a 40% diethyl azodicarboxylate/toluene solution (100 mL) was then added dropwise over 15 minutes. The mixture was stirred at room temperature for 4.5 hours, the reaction mixture was then poured into water (1600 mL), a mixed solution of hexane (550 mL) and ethyl acetate (550 mL) was added, and the mixture was stirred. The two layers were separated, and the organic layer was then washed with water (540 mL) and a saturated saline (540 mL), dried with anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain a titled compound (69.7 g) having the following physical property values.
Reaction SMILES: C([N:8]1[CH2:23][CH2:22][CH2:21][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]([OH:20])=[C:10]2[CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25]([N:8]1[CH2:23][CH2:22][CH2:21][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]([OH:20])=[C:10]2[CH2:9]1)=[O:26])[CH3:29]
Reactant: Oc1c2c(nc3ccccc13)CCCN(Cc1ccccc1)C2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCCc2nc3ccccc3c(O)c2C1
Yield: 9 %

Procedure:
11-Hydroxy-2,3,4,5-tetrahydro-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester was prepared from 2-benzyl-11-hydroxy-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and ethyl chloroformate analogous to Example 208. Yield: 9% of theory; m.p. 285° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH2:36][N:37]([CH2:40][C:41]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:2]4([CH3:1])[O:6][C:5]5=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]5[CH2:3]4)=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)=[O:42])[CH2:38][CH2:39]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: CC1(COc2ccc(N3CCNCC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCN(c3ccc(OCC4(C)Cn5cc([N+](=O)[O-])nc5O4)cc3)CC2)CC1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of 2-methyl-6-nitro-2-(4-piperazin-1-yl-phenoxymethyl)-2,3-dihydro-imidazo[2,1-b]oxazole (200 mg, 0.34 mmol) and 4-carboxymethyl-piperazine-1-carboxylic acid tert-butyl ester (136 mg, 0.55 mmol) in DMF is treated with TBTU (179.8 mg, 0.55 mmol), triethyl amine (0.23 ml, 1.65 mmol) and stirred for 2 h. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated. The residue is purified by preparative TLC (10% methanol in dichloromethane to give 4-(2-{4-[4-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butyl ester as yellow oil (152 mg, 78%). ESI MS m/z 585 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 4.48 (d, J=Hz), 4.18 (d, J=Hz, 1H), 4.14-4.02 (m, 2H), 3.82-3.71 (m, 4H), 3.56-3.38 (m, 4H), 2.91 (s, 2H), 2.52-2.42 (m, 4H), 1.75-1.62 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[OH:27][CH2:28][CH2:29][NH2:30]>>[OH:27][CH2:28][CH2:29][NH:30][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][S:23](=[O:26])[CH2:24][CH2:25]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[N:7]=1
Reactant: CN(c1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: NCCO
Product: CN(c1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-(N-methyl-anilino)-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine (melting point: 237°-239° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: C(=C1C=CC(C([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=O)=CC1)C1C=CC=CC=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(OO)(C)(C)C>C1COCC1>[C:18]([OH:20])(=[O:19])[C:17]1[CH:21]=[CH:22][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(C(=O)C2=CCC(=Cc3ccccc3)C=C2)cc1
Agent: CC(C)(C)OO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled solution of 4-(4'benzylidene benzoyl)-benzoic acid (1.40 g) in THF was added a solution of 1,1'-carbonyldiimidazole (0.7 g) in THF (10 ml), with stirring. After 2 hours, a solution of t-butylhydroperoxide (0.5 g of 80%) in THF (10 ml) was added slowly. Stirring was continued for a further hour at 0° C. after which the solution was filtered and the solvent removed. The resulting oil was purified by column chromatography (silica) using dichloromethane as eluant. The resultant colourless oil solidified on overnight refrigeration to give a product having a melting point of 72°-76° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1(S([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42](B(O)O)=[CH:41]2)(=O)=O)C=CC=CC=1.[OH-].[K+]>>[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:41]1
Reactant: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(-c4c[nH]c5ccccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide from Example 121 (115 mg) was reacted with 1-(phenylsulfonyl)-3-indoleboronic acid via General Procedure A to yield 31.8 mg 123 following phenylsulfonyl group deprotection with aqueous potassium hydroxide at 50° C. for 2 hours then reverse phase HPLC purification. MS (Q1) 515.3 (M)+