Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[C:5]([C:8]#[N:9])[C:6]#[N:7])[CH3:4].[CH3:10][C:11]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:12]=1[NH2:13]>C(O)(C)C>[NH2:7][C:6]1[N:13]([C:12]2[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=2[CH3:10])[CH:2]=[C:3]([CH3:4])[C:5]=1[C:8]#[N:9]
Reactant: CC(CBr)=C(C#N)C#N
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CC(C)O
Product: Cc1cc(C)c(-n2cc(C)c(C#N)c2N)c(C)c1

Procedure:
A mixture 2-(2-bromo-1-methyl-ethyl idene)-malononitrile and 2,4,6-trimethylaniline (17.330 g, 91.24 mmol) in 40 mL of isopropanol was stirred at room temperature for 15 hours. The reaction mixture was concentrated to dryness and diluted with chloroform and water. The chloroform layer was neutralized with dilute sodium hydroxide and washed with brine, separated, dried and concentrated to give 33.000 g of brown oily solid. The solid was purified through silica gel column chromatography to give 9.35 g (47.5%) of the title compound as an orange-yellow solid. 1H NMR (CDCl3) δ 2.0(s, 6H), 2.15(s, 3H), 2.35(s, 3H), 3.75(brs, 2H), 5.8(s, 1H), 6.95(s, 2H) ppm.
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][O:43][NH2:44]>>[CH2:36]([O:35][C:33]([NH:32][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:40]=[CH:41][C:9]([C:1](=[N:44][O:43][CH3:42])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:25][CH:24]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:34])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCOC(=O)NC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reactant: CON
Product: CCCCOC(=O)NC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
Starting from the compound obtained in Step B, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1.O>[CH2:14]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
1,4-dioxa-spiro[4.5]decan-8-ol (11.0 g, 70 mmol) in dry tetrahydrofuran (50 ml) is added dropwise to a stirred suspension of 60% sodium hydride disperse in mineral oil (2.80 g, 70 mmol) in dry tetrahydrofuran (50 ml). Once the addition is complete the reaction mixture is stirred for 2 hours at room temperature. A solution of benzyl bromide (13.2 g, 77 mmol) in dry tetrahydrofuran (50 ml) is added dropwise over a period of 20 minutes and stirred at room temp overnight. The reaction mixture is poured into water (200 ml), neutralised with 0.5 N aqueous hydrochloric acid and extracted with methylene chloride (2×100 ml). The combined organic layer was dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is absorbed onto silica gel and purified on flash chromatography to give 8-benzyloxy-1,4-dioxa-spiro[4.5]decane (16 g).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH:31]=[N:32][NH:33]C(=O)CN1C(=O)C2C(=CC=CC=2)C1=O)[C:17](=O)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH:31]=[N:32][N:33]=[C:17]2[CH2:18][N:19]2[C:20](=[O:29])[C:21]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:26]3[C:27]2=[O:28])=[C:9]([CH:14]=1)[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Yield: 6.6 %

Procedure:
A stirred mixture of 1,3-dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide (8.0 g, 0.0123 mole) and toluene (200 ml) is treated with trifluoroacetic acid (0.9 ml) and heated to 100°-110°C for 1.5 hours. The mixture is concentrated in vacuo, and the residue is mixed with cold water and chloroform and made alkaline with aqueous sodium hydroxide. This mixture is extracted with chloroform; the extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel (400 g) with 1.5% methanol-98.5% chloroform. The product thus obtained is crystallized from methylene chloride-methanol to give: 2.54 g, melting point 228°- 228.5°C. and 0.361 g, melting point 229°-230°C. (53% yield) of 5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone. The analytical sample has a melting point 229.5°-230.5°.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:16]([C:17]4[C:22]([C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:14]=[C:13]1[C:8]=3[CH:9]=[CH:10][CH:11]=[CH:12]1.CN(C)C=O.[Br:28]N1C(=O)CCC1=O>O>[Br:28][C:14]1[CH:15]=[C:16]2[C:7](=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)[C:6]1[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=1[C:22]1[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)ccc1c3ccccc3c3ccccc3c21
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2c3ccccc3c3ccccc3c2c2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A flask was charged with 5.21 g of benzo[g]chrysene and 50 mL of N,N-dimethylformamide. An N,N-dimethylformamide (10 mL) solution of 4.00 g of N-bromosuccinimide was added to the mixture. The mixture was stirred at 80° C. for 8 hours. After cooling the mixture to room temperature, the reaction solution was poured into 200 mL of water. A solid that precipitated by this operation was collected by filtration, and washed with water and methanol. The resulting solid was purified by silica gel column chromatography to obtain 5.87 g of the target 10-bromobenzo[g]chrysene (yield: 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[O:9]1CCC[CH2:10]1>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:10]=[O:9])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(F)cn1

Procedure:
The title compound was prepared according to the methods of preparations 1 and 2, starting from 2-bromo-5-fluoropyridine. This gave crude material containing tetrahydrofuran and diethyl ether which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.57 (1H, dt), 8.03 (1H, dd), 8.62 (1H, d), 10.04 (1H, s); LRMS (APCI+) 126 [MH+].
Reaction SMILES: [F:1][CH:2]([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[OH:9][C@:10]([CH3:46])([CH2:44][OH:45])[C:11](=[O:43])[C@@H:12]([NH:20][C:21](=[O:42])[C@@H:22]([NH:26][C:27](=[O:41])[C@@H:28]([NH:32][C:33]([C:35]1[S:39][C:38]([CH3:40])=[N:37][CH:36]=1)=[O:34])[CH2:29][O:30][CH3:31])[CH2:23][O:24][CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][CH:2]([F:8])[CH2:3][S:4]([O:45][CH2:44][C@:10]([OH:9])([CH3:46])[C:11](=[O:43])[C@@H:12]([NH:20][C:21](=[O:42])[C@@H:22]([NH:26][C:27](=[O:41])[C@@H:28]([NH:32][C:33]([C:35]1[S:39][C:38]([CH3:40])=[N:37][CH:36]=1)=[O:34])[CH2:29][O:30][CH3:31])[CH2:23][O:24][CH3:25])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:6])=[O:5]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: O=S(=O)(Cl)CC(F)F
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)CC(F)F

Procedure:
Prepared according to procedures described above, by reacting 2,2-difluoroethanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C27H36F2N4O10S2 m/z: 679 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]([OH:2])[CH:12]=[CH:11]3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc3c(-c4ccccc4)c(OC)ccc3c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(-c2ccc3c(-c4ccccc4)c(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-methoxy-6-(4-methoxyphenyl)-1-phenylnaphthalene (0.36 g, 1.06 mmol) in CH2Cl2 (25 mL) at 0° C. was slowly added boron tribromide (3.2 mL of 1N in CH2Cl2). The mixture wag allowed to warm slowly to room temperature and was stirred overnight. The resulting solution was poured into water (100 mL) and extracted with ethyl acetate (3×150 mL).; The combined, organic layers were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, evaporation of thesolvent, and purification by silica column chromatography (25% ethyl acetate-hexanes) followed by preparative reverse-phase HPLC and drying under vacuum at 105° C. yielded 0.14 g (42%) of the:title compound as a white solid: mp 142–146° C.; 1H NMR (DMSO-d6): δ 6.86 (2H, d, J=8.50 Hz), 7.26–7.42 (5H, m), 7.48–7.61 (5H, m), 7.84 (1H, d, J=8.96 Hz), 8.02 (1H, d, J=1.46 Hz), 9.52 (2H, s); MS (ESI) m/z 311 (M−H)−.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][C:43]([F:46])([F:45])[F:44])[CH2:4][CH2:3]2.[OH-].[Na+]>O1CCOCC1.CO>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][C:43]([F:44])([F:45])[F:46])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCC(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCC(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 66 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((3,3,3-trifluoropropyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.032 g, 0.050 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.2 mL, 0.200 mmol). The mixture was heated to 75° C. for 22.5 h then was cooled to rt. The mixture was diluted with methanol, was filtered through a plug of glass wool and was purified by Prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((3,3,3-trifluoropropyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (0.022 g, 0.033 mmol, 66.8% yield) as a white solid. LCMS: m/e 626.6 (M+H)+, 1.87 min (method 2). 1H NMR (400 MHz, Acetic acid d4) 67.99 (d, J=8.28 Hz, 2H), 7.25 (d, J=8.28 Hz, 2H), 5.33 (d, J=4.77 Hz, 1H), 4.82 (s, 1H), 4.70 (s, 1H), 3.36-3.51 (m, 2H), 2.81-2.97 (m, 3H), 2.12-2.28 (m, 4H), 1.72 (s, 3H), 1.17 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.82-2.11 (m, 18H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=[CH:10][C:5]=2[NH:4][C:3](=S)[CH2:2]1.[NH2:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[F:18][C:17]1[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH:2]=[C:3]4[NH:28][CH2:29][CH2:30][C:31](=[O:32])[N:4]4[C:5]=3[CH:10]=2)=[N:13][C:14]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[N:15][CH:16]=1
Reactant: NCCC(=O)O
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)NC(=S)CO4)n2)c1
Product: O=C1CCNC2=COc3ccc(Nc4nc(Nc5cccc(O)c5)ncc4F)cc3N12

Procedure:
In a manner analogous to the preparation of N4-[2,4-dihydro-1-oxo-4H-imidazo[2,1-c][1,4]benzoxazin-8-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, N4-[2H-1,4-benzoxazin-3(4H)-thione-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (400 mg, 1.04 mmol) and β-alanine (500 mg) gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-oxo-1,2,3,6-tetrahydropyrimido[2,1-c][1,4]benzoxazin-9-yl]-2,4-pyrimidinediamine as a white solid. 1H NMR (acetone-d6): δ 2.68 (t, J=7.2 Hz, 2H), 3.71 (t, J=7.2 Hz, 2H), 4.62 (t, J=1.2 Hz, 2H), 6.42 (ddd, J=1.2 and 2.4 and 7.5 Hz, 1H), 6.98-7.08 (m, 3H), 7.38 (t, J=2.4 Hz, 1H), 7.62 (dd, J=2.4 and 8.7 Hz, 1H), 7.96 (d, J=3.3 Hz, 1H), 8.12 (s, 1H), 8.16 (s, 1H), 8.52 (d, J=2.7 Hz, 1H), 8.65 (s, 1H); 19F NMR (282 MHz, acetone-d6): δ −168.04.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:27]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:28])=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)C1CCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)C3CCC3)ccc2n1
Yield: 30 %

Procedure:
As described for Example 56, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (96 mg, 0.33 mmol) was converted, using cyclobutanecarboxylic acid instead of cyclopropylacetic acid, to the title compound (33 mg, 30%) which was obtained as a light brown foam. MS: m/e=373.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH:8]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:9](=[O:12])[CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28]([OH:30])=[O:29].[F-].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:17]([O:16][C:14]([NH:13][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[C:9](=[O:12])[CH2:10][O:30][C:28](=[O:29])[C:27]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:26]=1[CH3:25])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(=O)CBr
Reactant: Cc1cccc(C)c1C(=O)O
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A heterogeneous solution containing 3-benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert-butyl ester, 109, (9.89 g, 24.7 mmol), 2,6-dimethyl benzoic acid (4.45 g, 29.6 mmol), and KF (3.58 g, 61.8 mmol) in 250 mL of DMF is stirred at rt for 12 h. The solution is diluted with EtOAc, washed with water, saturated NaHCO3, and brine, dried (MgSO4), and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel (hexane/EtOAc) yields 11.3 g of the desired product as a white solid.
Reaction SMILES: [CH2:1]=[O:2].[C:3]12[CH2:9][C:6]([CH2:7][CH2:8]1)=[CH:5][CH:4]=2.[CH:10]([OH:12])=[O:11]>OS(O)(=O)=O>[CH:10]([OH:12])=[O:11].[CH:10]([OH:12])=[O:11].[OH:2][CH2:1][CH:9]1[CH:6]2[CH2:5][CH:4]3[CH:8]([CH:7]2[OH:11])[CH:3]13
Reactant: C1=C2CCC(=C1)C2
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: OCC1C2CC3C(C2O)C13
Yield: 84 %

Procedure:
To a stirred solution of 39.9 g paraformaldehyde in formic acid (800 ml) and conc. H2SO4 (15 ml) under nitrogen and at 20° C. was added dropwise 132 g norbornadiene while keeping the temperature between 20°-25° C. After 1.5 hr the reaction was quenched by adding to 800 ml of ice-water. Extraction with ether (3×750 ml), washing the organic layer with water (1×250 ml), brine (3×250 ml) and drying (Na2SO4) afforded the crude 3-hydroxymethyl tricyclo [2.2.1.02,6- ]heptan-5-ol bisformate (1') as an oil. Distillation, after a forerum of bp. 40° C./15 mm, gave 235 g pure tricyclenebisformate, bp. 104° C./0.3 mm (84% yield).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][N:16]=1.Cl>O.CO>[C:17]1([C:14]2[O:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:23])=[O:4])=[N:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCc1ncc(-c2ccccc2)o1
Reaction time: 4 h
Yield: 85.3 %

Procedure:
Add a solution of sodium hydroxide (1.80 g, 45.0 mmol) in water (30 mL) to a solution of 7-(5-phenyloxazol-2-yl)heptanoic acid methyl ester (9.0 g, 31.3 mmol) in methanol (30 mL) at room temperature and stir the mixture for 4 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (500 mL). Wash the combined organic layers with water (3×100 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Crystallize the residue from ethyl acetate/hexanes to afford 7-(5-phenyloxazol-2-yl)heptanoic acid (7.3 g, 85%): APCI mass spectrum m/z 272 [C16H19NO3−H]−.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH2:21])[CH2:16]1>N1C=CC=CC=1>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH2:16]1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CC1CCCC(N)C1
Solvent: c1ccncc1
Product: CC1CCCC(NC(=O)c2cnc3ccccc3n2)C1
Yield: 78.4 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 3-methylcyclohexylamine (119 mg, 0.90 mmol), and pyridine (5 mL) yielding 190 mg (78%) of (161):
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17](O)[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]>CC(C)=O.[Cl-].[Zn+2].[Cl-]>[OH:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[C@H:19]([CH2:18][CH2:17][C:16]3[C@@H:15]2[CH2:14][C@H:13]([OH:28])[C@@:12]2([CH3:29])[C:11]=3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)=O
Product: C[C@H](CCC(=O)O)[C@H]1CCC2=C3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@@]21C
Temperature: 110 °C

Procedure:
A mixture of cholic acid (11.4 g) and zinc chloride (13 g) in acetone (50 ml) is heated so as to distil off solvent, then heated at an external temperature of 110° C. for about 1.5 hours. The mixture is poured into water, extracted with ether and the organic solution dried over magnesium sulfate, dried, filtered, and concentrated in vacuo. The crude is purified by flash chromatography to give the desired product.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:18]O>>[CH3:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([O:10][CH3:18])=[O:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To methanol (150 ml) at 0° C. under nitrogen was added dropwise thionyl chloride (4.0 ml, 54.8 mmol) over 2 min. The mixture was stirred at 0° C. for 15 min, before adding a solution of 2-methyl-5-nitrobenzoic acid (4.99 g, 27.5 mmol) in methanol (50 ml) by cannula over 5 min. The mixture was then allowed to warm to room temperature before heating at 50° C. for 18 h under nitrogen. The solvents were evaporated in vacuo and the residue stirred with water (100 ml) and dichloromethane (100 ml). The aqueous layer was basified with potassium carbonate, separated and reextracted with more dichloromethane (100 ml). The two organic extracts were combined, dried (MgSO4), and evaporated in vacuo to leave the title compound (5.24 g, 98%) as a white solid. 1H NMR (360 MHz, CDCl3) δ 2.72 (3H, s), 3.96 (3H, s), 7.44 (1H, d, J=8.3 Hz), 8.24 (1H, dd, J=8.4 and 2.6 Hz), 8.78 (1H, d, J=2.6 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH2:19]2)=[CH:14][CH:13]=1.[C:35](O)([C:37]([F:40])([F:39])[F:38])=[O:36].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[F:38][C:37]([F:40])([F:39])[C:35]([N:25]1[CH2:26][CH2:27][N:22]([CH:18]2[CH2:19][C:20]3[CH:21]=[C:12]([N:3]4[C:4](=[O:11])[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[C:2]4=[O:1])[CH:13]=[CH:14][C:15]=3[CH2:16][CH2:17]2)[CH2:23][CH2:24]1)=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCc3ccc(N4C(=O)c5ccccc5C4=O)cc3C2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1c1ccc2c(c1)CC(N1CCN(C(=O)C(F)(F)F)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with tert-butyl 4-[7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate (300 mg, 0.65 mmol) and a stir bar was added TFA (2 mL). The mixture was allowed to stir at RT for 1 hour. LC showed complete removal of the Boc group. TFA was removed under reduced pressure, and the residue was dissolved in DCM (5 mL). To the solution was added pyridine and trifluoroacetic anhydride (0.27 mL, 2.0 mmol). LC showed formation of the desired product within 30 minutes. The product was purified by MPLC.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>Br.CC(O)=O>[Br:16][CH2:2][C:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1cnc(NC(=O)C(C)(C)C)s1
Reactant: [Br-]
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1ncc(C(=O)CBr)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 20z (0.26 g, 1.15 mmol) was dissolved in 33% HBr in HOAc (100 mL), pyridinium tribromide (0.37 g, 1.15 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice water and the solid was collected by filtration to yield 21z which was in the next step without purification (0.34 g, 97%). 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 4.27 (s, 2H), 1.36 (s, 9H).