Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[C:19]([CH3:20])=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[N:29]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C>[CH3:25][O:24][C:22](=[O:23])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]1[C:19]([CH3:20])=[CH:18][C:14]([C:15](=[O:16])[NH2:29])=[CH:13][C:12]=1[CH3:21]
Reactant: COC(=O)[C@H](Cc1c(C)cc(C(=O)O)cc1C)NC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1c(C)cc(C(N)=O)cc1C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Into a stirrng solution of the benzoic acid from Step B (3.00 g, 8.54 mmol), PyBOP (6.68 g, 12.8 mmol) and HOBt (1.74 g, 12.8 mmol) in DMF (36 mL) was added DIPEA (5.96 mL, 34.2 mmol) and NH4Cl (0.92 g, 17.1 mmol). The resulting mixture was stirred at rt for 40 min before being partitioned between aqueous NH4Cl solution and EtOAc. The separated organic phase was washed with 2 N citric acid aqueous solution, saturated aqueous NaHCO3 solution and brine, and dried over Na2SO4 overnight. After concentration, the residue was purified by flash column chromatography (eluent: EtOAc) to give the title amide. 3.00 g, 100%; 1H NMR (300 MHz, CDCl3): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J=7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J=8.7 Hz), 5.65 (1H, br s), 6.09 (1H, br s), 7.46 (2H, s); MS(ES+) (relative intensity): 250.9 (100) (M−Boc)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C.O>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][O:8][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[O:3][C:2]=1[CH3:1])=[O:9]
Reactant: COCCOCCl
Reactant: Cc1cc(C(=O)O)c(C)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOC(=O)c1cc(C)oc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
A 2 L round-bottomed flask equipped with a mechanical stirrer was charged with 2,5-dimethyl-3-furoic acid (81.0 g, 0.58 mol) and potassium carbonate (95.9 g, 0.69 mol) in DMF (500 mL). An ice bath was used to cool the reaction as 2-methoxyethoxymethyl chloride (72.2 g, 0.58 mol) was added portionwise. The reaction was stirred for 5 h at rt. The mixture was then diluted with water (1.5 L) and extracted with EtOAc (2×600 mL). The combined organics were washed with water (2×900 mL) and saturated sodium chloride solution (1 L), dried over MgSO4, filtered and concentrated to afford compound 803A (103 g, 82%) as a yellow oil. 1H NMR(CDCl3): δ=6.23 (s, 1H), 5.47 (s, 1H), 3.84 (m, 2H), 3.56 (m, 2H), 3.38 (s, 3H), 2.51 (s, 3H) and 2.20 ppm (s, 3H).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:27]=1>>[C:1]1([C@H:7]([CH3:11])[C:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[N:18][C:17]=3[CH:27]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Reactant: C[C@H](C(=O)O)c1ccccc1
Product: C[C@H](C(=O)Nc1ccc2oc(-c3ccncc3)nc2c1)c1ccccc1

Procedure:
Similarly prepared as per compound 8, using starting materials (S)-2-phenylpropanoic acid and compound 4 (R, =2-pyridine) to obtained title compound Q48 as white solid (77%). 1H NMR (CDCl3, 400 MHz) δ 1.52 (d, J=7.2 Hz, 3H), 3.67 (q, J=7.2 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.21-7.35 (m, 5H), 7.69 (s, 1H), 7.83 (s, 1H), 7.91 (d, J=5.6 Hz, 2H), 8.68 (d, J=5.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 18.9, 31.1, 42.7, 48.0, 110.8, 112.2, 119.7, 120.5, 121.1, 127.7, 127.8, 128.1, 129.3, 134.3, 135.6, 141.1, 142.1, 147.7, 148.4, 149.1, 150.8, 161.4, 172.9; ESI-HRMS for C21H18N3O2(M+H)+ calcd. 344.1399. found 344.1397 purity (% ee >99, tR=8.07 min).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:28]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1>>[CH:25]1([C:21]2[CH:22]=[C:23]([CH3:24])[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][S:28]5(=[O:35])=[O:34])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=2)[CH2:27][CH2:26]1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCCS3(=O)=O)cc2C#N)CC1
Yield: 66.1 %

Procedure:
Using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (425 mg) described in Preparation Example 189 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (317 mg) was obtained.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][Cl:14])[CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C@@H](CC(O)=O)C(O)=O>>[Si:1]([O:8][C@H:9]([CH2:13][Cl:14])[CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCl)CC=O
Agent: O=C(O)C[C@H](O)C(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@H](CCl)CC=O

Procedure:
(S)-3-(tert-Butyldimethylsilyloxy)-4-chlorobutanal was prepared by the same route as (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal starting from (S)-2-hydroxysuccinic acid. 1H NMR (400 MHz, CDCl3) δ 9.72 (dd, J=1.6, 2.2 Hz, 1H), 4.33-4.28 (m, 1H), 3.46 (dd, J=4.7, 11.1 Hz, 1H), 3.39 (dd, J=6.4, 11.1 Hz, 1H), 2.68 (dd, J=1.5, 4.7 Hz, 1H), 2.62 (dd, J=2.3, 6.8 Hz, 1H), 0.79 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:10]=3
Reactant: O=c1ccn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCCN1CCCCC1
Product: O=c1ccn2c3c(cc(OCCN4CCCCC4)cc13)Sc1ccc(Br)cc1-2
Yield: 86.4 %

Procedure:
According to Example 34, the compound (170 mg) produced in Example 58 was reacted with 1-(2-chloroethyl)piperidine (169 mg) to obtain the title compound (194 mg; 86%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[CH2:22][CH2:23][C:24](O)=[O:25].C(Cl)(C(Cl)=O)=O.[Cl-].[Al+3].[Cl-].[Cl-].C(COC)OC>ClCCCl.O>[OH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:7]=[C:6]3[CH2:22][CH2:23][C:24](=[O:25])[C:4]=1[C:5]=23
Reactant: COc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccc(C)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(O)ccc42)C(=O)CC3)cc1
Reaction time: 0.33 h

Procedure:
To a DCE (600 ml) solution of 3-(5-methoxy-1-p-toluenesulfonyl-indol-3-yl)propionic acid (28.9 g, 77 mmol) was added, while stirring under ice-cooling, (COCl)2 (8.3 ml, 95 mmol), and the mixture was stirred for about 2.5 hours at room temperature. The reaction mixture was concentrated, and the residue was dissolved in DCE (100 ml). The solution was added to a suspension of aluminum chloride powder (33.9 g, 254 mmol) in DCE (430 ml) at 5° C. taking 20 minutes. The mixture was left standing as it was at 5° C. for one hour, then stirred for 2.5 hours at room temperature. To the reaction mixture were added, under ice-cooling, dimethoxyethane (300 ml) and water (300 ml). Resulting precipitates were filtered off, then the organic layer was separated. The aqueous layer was subjected to extraction with chloroform (200 ml). The extract solution was combined with the organic layer, which was washed with an aqueous saline solution. The resultant organic layer was dried (anhydrous sodium sulfate), then the solvent was distilled off under reduced pressure to leave 25 g of crude crystals. The crude crystalline product was subjected to silica gel column chromatography, eluting with chloroform, to obtain crystals, followed by recrystallization from chloroform-n-hexane to afford the title compound (m.p.210°-211° C.).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(C)(C)C.Cl.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:46][C:47]1[C:56]2[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=2[N:50]=[CH:49][CH:48]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CC(O)=O.O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH:11]2[C:12]3[C:17](=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH2:18][CH2:19][N:10]2[CH2:9][CH2:8][NH:7][C:6]([NH:46][C:47]2[C:56]3[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=3[N:50]=[CH:49][CH:48]=2)=[O:5])=[CH:30][CH:29]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CCNC(=O)OC(C)(C)C)CC2
Reactant: Nc1ccnc2c1CCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CCNC(=O)Nc1ccnc3c1CCCC3)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of {2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid tert-butyl ester (example 106.1, 0.22 g, 0.5 mmol) in glacial AcOH (1 mL) is added conc. HCl (0.1 mL). After 5 min, the reaction mixture is partitioned between CHCl3 (20 mL) and 1 N NaOH (15 mL). The organic phase is evaporated. The residue is taken up in DMSO (2 mL) and treated with CDI (0.2 g, 0.6 mmol, 1.2 eq). The reaction mixture is stirred at rt for 3 h, and then 4-amino-5,6,7,8-tetrahydroquinoline (example C4, 0.19 g, 0.6 mmol) is added. To the resulting solution is added in a single portion NaHMDS (2 M in THF, 1.25 mL, 2.5 mmol). The reaction mixture is stirred at rt for 30 min, then H2O (0.4 mL) is added. The reaction mixture is evaporated and the residue purified by preparative HPLC to provide the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[C:15]1([CH2:21][CH2:22][CH:23]=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:3][C@H:2]([C@@H:23]([OH:24])[CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: O=CCCc1ccccc1
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@@H](O)CCc1ccccc1

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with 3-phenylpropanal. 1H-NMR (CDCl3, 400 MHz): δ 8.06 (m, 1H); 7.25 (m, 8H); 4.11 (dt, 1H, J=4,7); 3.96 (dq, 1H, J=3,7); 2.91 (m, 1H); 2.70 (m, 1H); 1.95 (m, 1H); 1.81 (m, 1H); 1.34 (t, 3H, J=7).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][NH2:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccccc1Cl
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1Cl

Procedure:
ninhydrin, 4-(2-chlorophenyl)-semicarbazide hydrochloride
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]1[C:13]2=[CH:14][NH:15][C:16]([C:17]3[S:18][CH:19]=[C:20]([CH3:22])[N:21]=3)=[C:12]2[C:11](=[O:23])[N:10]([CH3:24])[C:9]1=[O:25].Br[CH2:27][CH:28]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>CN(C)C(=O)C.O>[Si:42]([O:41][CH:28]([CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])[CH2:27][N:15]1[C:16]([C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[C:12]2[C:13]([N:8]([CH3:7])[C:9](=[O:25])[N:10]([CH3:24])[C:11]2=[O:23])=[CH:14]1)([C:45]([CH3:48])([CH3:46])[CH3:47])([CH3:44])[CH3:43]
Reactant: Cc1csc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1
Reactant: CC(C)(C)[Si](C)(C)OC(CBr)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(CN2C(=O)c3ccccc3C2=O)O[Si](C)(C)C(C)(C)C)n1
Temperature: 50 °C

Procedure:
Cesium carbonate (115 mg, 0.351 mmol) was added to a solution of 1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Intermediate Gc) (53.4 mg, 0.176 mmol) and 2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)propyl)isoindoline-1,3-dione (70 mg, 0.176 mmol) in N,N-dimethylacetamide (1273 μl). The mixture was heated at 50° C. for 18 hours, then cooled to room temperature and diluted with water (30 ml). The mixture was extracted with ethyl acetate (3×30 ml), the combined organic extracts were washed with brine (90 ml), dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:34]=[C:22]4[N:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:34]=[C:22]4[N:21]=3)=[CH:18][CH:19]=2)[CH2:11][C:10]([CH3:12])([OH:13])[CH2:9]1
Reactant: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(-c3nc4nc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CC(N)(c2ccc(-c3nc4nc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 7-1 (54 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 7-2.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][N:19]2[CH:10]([C:11](=[O:36])[NH:12][C:13]3[C:18]2=[N:17][CH:16]=[C:15]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:25][CH2:24]2)[CH:14]=3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:15]3[CH:14]=[C:13]4[C:18]([N:19]5[CH:10]([C:11](=[O:36])[NH:12]4)[CH2:9][NH:8][CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:28][CH2:27]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCNCC12
Temperature: 25 °C
Yield: 8.9 %

Procedure:
7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-10-oxo-1,3,4,9,10,10a-hexahydro-2,4-a,5,9-tetraaza-phenanthrene-2-carboxylic acid tert-butyl ester (250 mg, 0.487 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3 mL) was added while stirring at room temperature. The reaction was stirred for 16 h and concentrated to a residue. The residue was dissolved in DMF and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (17.8 mg, 8.8%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.68 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.14-7.30 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.33 (d, J=11.4 Hz, 1H), 3.97 (dd, J=11.0, 3.4 Hz, 1H), 3.45 (dd, J=12.5, 2.9 Hz, 4H), 3.32-3.36 (m, 4H), 3.16 (d, J=9.6 Hz, 1H), 3.06-3.13 (m, 4H), 2.72-2.87 (m, 3H). [M+H] calc'd for C26H33ClN6O3, 413; found, 413.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH:18](OCC)(OCC)[O:19][CH2:20][CH3:21]>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])=[CH:18][O:19][CH2:20][CH3:21])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1

Procedure:
A mixture of (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (8.3 g, 32 mmol) and triethyl orthoformate (16 mL, 96 mmol) in acetic anhydride (20 mL) was refluxed under N2 for 16 h. Solvents were removed by distillation (keep the temperature of oil bath below 180° C.). The residue was purified by chromatography on silica gel (1:1 ethyl acetate/hexanes) to provide the desired product as a mixture of isomers (a mixture of trans- and cis-isomers, 5.3 g, 53%) as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[NH2:8][C:7](=[C:11]([C:10](=[O:9])[CH2:16][CH:17]([OH:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]([NH:14][CH3:15])=[O:13])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)C(C(=O)CC(O)c1ccccc1)=C(N)c1ccccc1

Procedure:
A mixture of 30.0 grams (0.093 mole) of 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide, 600 milliliters of ethanol and 3.0 grams of 10 percent Palladium on carbon in hydrogenated at 50 p.s.i. until 1 equivalent of hydrogen is absorbed (about 5 hours). The mixture is filtered and the filtrate evaporated in vacuo. The residue is then crystallized from methylene chloride petroleum ether to give 2-(α-aminobenzylidene)-5-hydroxy-N-methyl-3-oxo-5-phenylvaleramide, m.p. 72° C. - 76° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[C:15]=1[CH3:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+].Cl>O.CN(C=O)C>[CH3:16][C:15]1[C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:17])[C:5]=2[CH:4]=[CH:3][C:2]=1[O:1][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(O)ccc2c(=O)c3ccccc3oc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCC(=O)O)ccc2c(=O)c3ccccc3oc12
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A mixture of 1.0 g of 3-hydroxy-4-methyl-9-oxo-9H-xanthene, 1.5 g of potassium carbonate, 1.8 g of ethyl bromoacetate and 20 ml of DMF was agitated at 60°-70° C. for 2 hours. After cooling the mixture, 2 g of sodium hydroxide and 40 ml of water were added, and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.0 g of 4-methyl-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 244°-247° C. This compound gave a mass spectrum having a molecular ion peak at m/e 284.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:29])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]1.[N+:30]([O-])([OH:32])=[O:31].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:29])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH2:26]1)[N+:30]([O-:32])=[O:31]
Reactant: O=[N+]([O-])O
Reactant: CCN1CCN(c2ncccc2C(=O)NCCCCCCCCCCCO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CCN1CCN(c2ncccc2C(=O)NCCCCCCCCCCCO[N+](=O)[O-])CC1
Reaction time: 5 h
Yield: 42 %

Procedure:
5.45 g of N-(11-hydroxy-1-undecanyl)-2-(4-ethyl-1-piperazinyl)nicotinamide were suspended in 100 ml of acetonitrile and to the suspension was added dropwise under ice-cooling a mixed solution of 2.0 ml of fuming nitric acid and 5.2 ml of acetic anhydride and stirred for 5 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 2.52 g (42%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[P:31](Cl)(=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34].C(N(CC)CC)C>O1CCCC1>[CH2:33]([O:32][P:31]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:29][CH:30]=1)([O:35][CH2:36][CH3:37])=[O:38])[CH3:34]
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)Oc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52693.6 %

Procedure:
2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (268 mg), diethyl phosphorochloridate (0.16 mg), and triethylamine (0.28 ml) were dissolved in tetrahydrofuran (8 ml) and the solution was stirred at room temperature for 14 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was then washed with water, dried, and concentrated, and the residue was crystallized from hexane to provide the title compound as colorless solid (270 mg).
Reaction SMILES: [Li].[C:2](#[N:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(O)(C)C.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl-].[NH4+]>N.C1COCC1>[C:20]([O:19][C:17](=[O:18])[CH2:16][C:3]1([C:2]#[N:9])[CH:8]=[CH:7][CH2:6][CH:5]=[CH:4]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CC1(C#N)C=CCC=C1
Reaction time: 0.42 h
Yield: 73 %

Procedure:
Lithium (1.73 g, 249 mmol) was added in portions to a stirred solution of benzonitrile (10.2 mL, 10.3 g, 99.9 mmol) and t-BuOH (9.6 mL, 7.4 g, 100 mmol) in NH3 (50 mL) and THF (10 mL) under N2 at −78° C. After stirring for 25 minutes, t-butyl bromoacetate (29.5 mL, 39.0 g, 200 mmol) was added dropwise. After 1 hour, ammonium chloride (41.8 g, 781 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature while the NH3 was removed with a stream of N2. Water (125 mL) was added and the mixture extracted with MTBE (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Flash chromatography (SiO2, CH2Cl2-1:14 MTBE:CH2Cl2) afforded 16.0 g (73%) of product as an oil.