Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[C:13]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1)=[O:14]>C1COCC1>[O:24]=[C:20]1[CH2:19][C:18]2[C:22](=[CH:23][C:15]([C:13]([C:12]3[CH:11]=[C:10]([NH:9][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:7])[CH:27]=[CH:26][CH:25]=3)=[O:14])=[CH:16][CH:17]=2)[NH:21]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: O=C(Cl)c1cccs1
Solvent: C1CCOC1
Product: O=C1Cc2ccc(C(=O)c3cccc(NC(=O)c4cccs4)c3)cc2N1
Temperature: 25 °C
Yield: 84 %

Procedure:
A dry 250 mL flask was charged with Thiophene-2-carbonyl chloride (1.14 g, 7.77 mmol) and THF (60 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.508 g, 5.978 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the Thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a tan solid (1.82 g, 5.02 mmol, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:44]1([S:50]([C:53]2[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=2)[C:56](O)=[O:57])(=[O:52])=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(OCC)(=O)C.CN(C=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:56](=[O:57])[C:55]2[CH:59]=[CH:60][CH:61]=[C:53]([S:50]([N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)(=[O:52])=[O:51])[CH:54]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: CC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
1-(4-aminophenyl)ethanone (151 mg), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (565 mg) and N,N-diisopropylethylamine (0.39 mL) were added in that order to a DMF (4.0 mL) solution of 3-(piperidin-1-ylsulfonyl)benzoic acid (200 mg), and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction liquid, washed three times with water, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 80%, gradient) to give the entitled compound (117 mg, 41%) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])[N:5]=[N:4][C:3]=1[C:22]([OH:24])=O.[NH:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1>>[O:31]=[S:28]1(=[O:32])[CH2:29][CH2:30][N:25]([C:22]([C:3]2[N:4]=[N:5][C:6]([O:8][CH2:9][C:10]3[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:12][O:13][C:14]=3[CH3:15])=[CH:7][C:2]=2[CH3:1])=[O:24])[CH2:26][CH2:27]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)O
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)N1CCS(=O)(=O)CC1
Yield: 72 %

Procedure:
As described for example 44, 4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.61 mmol) was converted, using thiomorpholine 1,1-dioxide instead of 4-amino-tetrahydropyran, to the title compound (SiO2, heptane:ethyl acetate=100:0 to 60:40, 195 mg, 72%) which was obtained as a colourless crystalline solid. MS: m/e=443.2 [M+H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.COCCOC.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:21]=[CH:20][N:19]=1
Reactant: OB(O)c1ccccc1F
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: COCCOC
Product: Fc1ccccc1-c1cc(Cl)ncn1
Temperature: 80 °C
Reaction time: 9 h
Yield: 33.5 %

Procedure:
A reaction vessel was charged with 0.258 g of tetrakistriphenylphosphine palladium, 1.143 g of 2-fluorophenylboronic acid, and 3.153 g of tripotassium phosphate n-hydrate, to which 36 ml of 1,2-dimethoxyethane, 9 ml of water, and 1.106 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 9 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.519 g of 4-chloro-6-(2-fluorophenyl)pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:20]=[C:11]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Reactant: Nc1ccccc1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Bromo-1H-indazole-3-carbaldehyde (50 mg, 0.222 mmol) and o-phenylene diamine (24 mg, 0.222 mmol) were dissolved in dry THF (10 mL). One drop of 2N HCl was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and then diluted with ethyl acetate (30 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR (400 MHz, CDCl3): δ 8.73 (d, 1H, J=1.2 Hz), 7.80 (m, 1H), 7.48-7.45 (m, 2H), 7.37 (d, 1H, J=8.8 Hz), 7.23 (m, 2H); ESI-MS [M+H]+: 313.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:11]>CO>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)(=[O:11])[CH3:9]
Reactant: Fc1ccc(I)cc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc(F)cc2)c([N+](=O)[O-])c1

Procedure:
4-fluoroiodobenzene and 4-bromo-3-nitroacetophenone were reacted in an analogous manner to that described in Example 1 (a) to give the novel intermediate 4-acetyl-4'-fluoro-2-nitrobiphenyl, m.p. 88° - 90°C. (from methanol). This compound was reduced with stannous chloride in concentrated hydrochloric acid in an analogous manner to that described in Example 1 (b) to give the novel intermediate 4-acetyl-2-amino-4'-fluorobiphenyl, m.p. 88° - 91°C. (from methanol). The amino group in this compound was converted to methoxy in the following way:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=O)[CH2:15][C:16](=[O:18])[CH3:17])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=[S:29])[CH2:15][C:16](=[O:18])[CH3:17])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=O)CC(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-4-methanesulfonyl-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as brown solid. MS (ESI): m/z=308.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C([Li])CCC.CCCCCC.[I:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[CH2:7][C:8](=[O:9])[CH2:10][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([I:25])=[CH:27][CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CC(=O)CCc1ccc(I)cc1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
t-butylacetoacetate (1.5 mL, 9.2 mmol) was added dropwise over 2 minutes to a stirred suspension of sodium hydride (60% mineral oil suspension; 400 mg, 10.0 mmol) in tetrahydrofuran at 0° C. under nitrogen. After stirring for 10 minutes n-butyl lithium in hexane (1.6 M; 6.0 mL, 9.6 mmol) was added then stirring continued for a further ten minutes. The resulting solution was treated dropwise with a solution of 4-iodobenzyl bromide (2.97 g, 10.0 mmol) in tetrahydrofuran (4 mL) and then warmed to room temperature. The reaction was stirred for 40 minutes at room temperature and then quenched with 6 M HCl (5 mL). The resulting mixture was extracted with diethyl ether (3×50 mL). The organic phases were combined, washed with brine (50 mL) and dried (MgSO4) then the solvent evaporated under reduced pressure. The residue was purified via flash chromatography on silica gel (1:20 to 1:10 ethyl acetate/cyclohexane) to give the title compound (1.88 g, 54%) as a yellow oil. LC/MS: 3.66 min; z/e 375, calcd (M+1) 375. 1H NMR (400 MHz; CDCl3): 7.6 (2H), 6.93 (2H), 3.33 (2H), 2.85 (4H), 1.45 (9H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[N:41]=[C:42]([CH2:65][CH3:66])[C:43]([NH:48][C@H:49]2[C@@H:53]([OH:54])[CH2:52][N:51]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])[CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47].[F:67][CH2:68][CH2:69]Br>>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[N:41]=[C:42]([CH2:65][CH3:66])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:69][CH2:68][F:67])[CH2:52][N:51]([C:55]([O:57][CH2:58][C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)=[O:56])[CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: FCCBr
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate and 2-fluoro-1-bromo ethane, and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.41–7.25, 5.18, 4.81, 4.67, 4.55, 4.17, 4.06, 3.80–3.62, 3.39–3.29, 2.69, 2.47, 1.28, 1.15; IR (diffuse reflectance) 2971, 2386 (w), 2350 (w), 2338 (w), 2039 (w), 2014 (w), 1710 (s), 1699 (s,b), 1569, 1499, 1467 (s), 1450, 1428, 1420, 1397, cm−1; HRMS (FAB) calcd for C28H31Cl2FN4O3+H 561.1835, found 561.1808.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH2:26]1COCC1>C(=O)([O-])O.[Na+]>[CH3:8][C:6]1[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:26])=[CH:16][CH:15]=2)[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 87 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)acetate (200 mg; 0.688 mmol) and piperidine (0.272 mL; 2.75 mmol) in THF (2 mL) was placed in a sealed tube and heated under microwave irradiation at 110° C. for 1 h. The reaction mixture was diluted with a saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 186 mg (87%) of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate. ESI/APCI(+): 340 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1.[CH:37]1([N:40]2[CH:45]=[CH:44][C:43](I)=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1>>[CH:37]1([N:40]2[CH:45]=[CH:44][C:43]([C:20]3[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]4[CH2:10][CH2:9][C@@:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12]4=[O:14])[CH3:16])=[CH:22][CH:21]=3)=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Reactant: O=c1cc(I)ccn1C1CC1
Product: C[C@@H](c1ccc(-c2ccn(C3CC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 1-cyclopropyl-4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 23 Step 9. LC-MS Method 2 tR=1.05 min, m/z=505; 1H NMR (CDCl3) δ 0.88 (m, 2H), 1.12 (s, 3H), 1.15 (s, 1H), 1.17 (s, 1H), 1.21 (s, 3H), 2.18-2.29 (m, 2H), 2.30-2.34 (m, 1H), 2.42 (d, 1H), 2.54 (d, 1H), 2.90 (m, 1H), 3.35 (m, 1H), 5.70 (m, 1H), 6.32 (m, 1H), 6.68 (m, 1H), 6.98 (m, 1H), 7.09 (d, 2H), 7.18 (t, 1H),7.25-7.36 (m, 4H),7.50 (t,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[CH3:27][OH:28]>O1CCCC1>[CH3:12][C:5]1[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:7][C:2]2[NH:1][C:27](=[O:28])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[C:3]=2[CH:4]=1
Reactant: CO
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1OC(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(cc1OC(C)C)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 85 %

Procedure:
A solution of 1,1-dimethylethyl 4-({2-amino-5-methyl-4-[(1-methylethyl)oxy]phenyl}amino)-1-piperidinecarboxylate (D75) (0.16 mmol, 60 mg) in tetrahydrofuran (0.5 mL) was treated with N,N′-carbonyldiimidazole (0.24 mmol, 38.5 mg, 1.5 eq) under argon at room temperature, then the mixture was heated at 50° C. for 1 h, concentrated under reduced pressure, and the residue was treated with 10% aqueous sodium carbonate solution and extracted twice with ethyl acetate. The organics were combined, dried and concentrated under reduced pressure. The residue was finally purified by chromatography on silica (ethyl acetate/petrol ether then methanol) to give the title compound (0.14 mmol, 53 mg, 85% yield). M+H 390.3, 334.3, 316.3 (full molecule and fragments for loss of tert-butyl group and loss of Boc group).
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[C:4](=[O:10])[CH2:3][O:2]1.Cl.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-:23].[Na+]>O>[C:4]([CH2:3][O:2][CH2:1][C@@H:6]1[CH2:7][CH2:8][CH2:9][N:5]1[C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])([OH:10])=[O:23]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [OH-]
Reactant: O=C1COCC2CCCN12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)COC[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4-(3H)-one, 5 g (0.0354 mol), is suspended in a solution of 20 ml of concentrated hydrochloric acid and 20 ml of water and refluxed for four hours, cooled to room temperature and extracted with 200 ml of dichloromethane. The aqueous layer is separated, evaporated in vacuo, the residue dissolved in 200 ml of water, and the pH adjusted with a 10% aqueous solution of sodium hydroxide to pH 10-10.5. The solution is cooled to 5° C. and 7.25 g (0.0425 mol) of benzylchloroformate is added dropwise while the pH is maintained at pH 10 with a 10% aqueous solution of sodium hydroxide. The mixture is stirred one hour, extracted with 100 ml of diethylether, the aqueous layer is separated, and the pH is adjusted to pH 3-4 by the addition of a 10% aqueous solution of hydrochloric acid. The mixture is extracted with dichloromethane 3×200 ml. The dichloromethane layer is separated, washed with a saturated aqueous solution of sodium chloride, 3×200 ml, separated, dried over sodium sulfate, evaporated and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (S)-phenylmethyl 2-[(carboxymethoxy)methyl]-1-pyrrolidinecarboxylate, 8 g; [α]D25 -52.7° (c 1.1, methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)NC(=O)[CH2:5]2.[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2)([O-])=O.NC1C=C2C(=CC=1)NC(=[O:35])C2>>[C:5]([NH:12][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2)(=[O:35])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Cc2cc(NC(=O)c3ccccc3)ccc2N1

Procedure:
5-Bromo-2-oxindole, 5-nitro-2-oxindole and 5-amino-2-oxindole can be prepared as described in Beckett et al., Tetrahedron, 24, 6093 (1968). 5-Amino-2-oxindole can be acylated to give 5-alkanamido-2-oxindole and 5-benzamido-2-oxindole, using standard procedures.
Reaction SMILES: [CH3:1][C:2]1([NH:7][CH2:8][C@@H:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:15](N=N[N:19]=3)[CH:16]=2)[OH:10])[CH2:6][CH2:5][CH2:4][CH2:3]1.[ClH:20].[Cl:21][Sn]Cl>CO>[ClH:21].[ClH:20].[NH2:19][C:14]1[N:15]=[CH:16][C:11]([CH:9]([CH2:8][NH:7][C:2]2([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]2)[OH:10])=[CH:12][CH:13]=1
Reactant: CC1(NC[C@H](O)c2ccc3nnnn3c2)CCCC1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CO
Product: CC1(NCC(O)c2ccc(N)nc2)CCCC1
Reaction time: 16 h

Procedure:
To a solution of 349 mg of (R)-α-[[(1-methyl cyclopentyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol and 0.11 ml of 12 N HCl in 28 ml of methanol, 609 mg of SnCl2 108 2H2O was added and the resulting mixture heated at reflux with stirring for 16 hours. The reaction mixture was concentrated to dryness and the residue partitioned between 25 ml of 80:20 methylene chloride:methanol and 5 ml of 2.5 N NaOH solution. The layers were vigorously stirred and then separated. The aqueous layer was repeatedly extracted with methylene chloride/methanol. The combined extracts were dried with anhydrous magnesium sulfate and concentrated to give 473 mg of crude product. Purification was affected on silica gel prep Tlc plates (80:20:1 methylene chloride: methanol:NH4OH) to give 153 mg of product. Treatment with ethanolic HCl solution followed by precipitation with ether afforded the hydrochloride salt, 140 mq. Analysis: Calc'd. for C13H21N3O·2HCl:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1)[CH2:6][CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2].[CH2:33]([SH:36])[CH2:34][SH:35].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>CC(O)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1)[CH2:6][CH2:7][C:8]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)[S:36][CH2:33][CH2:34][S:35]1)[CH3:2]
Reactant: CCOC(=O)C(CCC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc(OC)nc1
Reactant: SCCS
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(CCC1(CCCCc2ccc3c(n2)NCCC3)SCCS1)c1cnc(OC)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 3-3a (7.6 g, 17.4 mmol) and 1,2-ethanedithiol (17.5 mL, 208.6 mmol) in 25 mL AcOH was added BF3.OEt2 (17.5 mL, 138.1 mmol) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at 0 C for 0.5 hr, then at rt for 3.5 hr. The reaction mixture was slowly poured into ice-cooled 300 mL NaHCO3 (sat.) and extracted with diethyl ether (2×200 mL). The organic layers were combined and washed with brine and dried over Na2SO4. After removal of the solvent, the residue was purified by flash chromatography on silica gel (100% EtOAc) to afford the desired product 4-1a as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[C:13]2[C:5]([N:6]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][O:16][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]3=4)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]#[N:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][O:16][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]=2[C:14]=1[O:15][CH2:32][C:33]#[N:34])[C:7]3=4
Reactant: N#CCBr
Reactant: Oc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 90.2 %

Procedure:
To a mixture of 8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.286 g, 0.851 mmol) in DMF (5.0 mL) is added potassium carbonate (0.59 g, 4.25 mmol) and bromoacetonitrile (0.3 mL, 4.25 mmol). The mixture is heated at 85° C. for 1 h, then cooled and partitioned between water and Et2O. The organic layer is washed three times with water (50 mL), dried over magnesium sulfate and concentrated. Column chromatography (60 g silica gel) using CH2Cl2/hexane (1/1) as eluent gave 0.2876 g (90%) of 2-[(8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39].[OH-].[Na+].O>CC(C)=O>[Cl:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2cccc(O)c2)cc1
Reactant: ClCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2cccc(OCCCCCCl)c2)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
4-(3-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (283 mg, 0.6 mmol), 1-bromo-5-chloropentane (598 mg, 3.2 mmol) and aqueous 2N-NaOH solution (1 ml) were dissolved in acetone (3 ml) and then refluxed for 6 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=8:1) to obtain 307 mg (yield: 94%) of the title compound as a colorless oil.