Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][OH:37])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH3:47][S:48]([O:37][CH2:36][C@@H:12]1[CH2:13][C@H:14]([S:16][C:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][N:11]1[C:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:39][CH:38]=1)=[O:10])(=[O:50])=[O:49]
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COS(C)(=O)=O)cc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
A solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol (22.33 g: 41.37 mmole) is diluted with dichloromethane (300 ml) and the mixture is cooled to -30° C. To this mixture, triethylamine (6.92 ml: 1.2 eq.) and methanesulfonyl chloride (3.52 ml: 1.1 eq.) are added, and the mixture is stirred for 20 minutes. The reaction mixture is successively washed with dilute hydrochloric acid and water, dried over magnesium sulfate, and filtered. The filtrate is concentrated in vacuo to give crude (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (27.81 g: 45.02 mmole). Yield: 100%. NMR δ(CDCl3) ppm: 2.89(s, 3H), 3.81, 3.83(2×s, 3H), 4.85 to 5.07(m, 2H). IR ν (CHCl3) cm-1 : 1725, 1690, 1610.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:47]#[CH:48])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:47]#[CH:48])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(Oc2ccc(C(=O)OC)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 72.7 %

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-methoxycarbonyl-phenoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.45 g, 0.63 mmol) was reacted with trimethylsilyl acetylene (0.45 g, 6.3 mmol), CuI (3 mg), triethylamine (2.63 mL, 18.9 mmol), and dichlorobis(triphenylphosphine) palladium (0) (35.3 mg, 0.05 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(4-methoxycarbonyl-phenoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.28 g, 73%)
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12.[Li+].[Br-]>>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [Br-]
Agent: [Li+]
Product: O=C1CCCCCCCCCCC1
Reaction time: 3 h
Yield: 100 %

Procedure:
Soviet Union (SU) Patent No. 407,874 discloses an isomerization reaction of an epoxycyclododecane compound in the presence of anhydrous LiBr without using a solvent. In examples disclosed in the SU patent, it is reported that when the isomerization was carried out at a reaction temperature of 120 to 130° C. for 18 hours or at a temperature of 200° C. for 3 hours, the target cyclododecanone was obtained in a yield of about 100% in the former or 83.3% in the latter. In the former case, the reaction time was too long and thus the reaction conditions may not be practical. Also, in the latter case, a by-product having a high boiling temperature was produced and a discoloration of the reaction liquid was found. When the catalyst is recycled and repeatedly used, the high boiling temperature product accumulated in the reaction system causes the reaction to be affected and a specific procedure for removing the high boiling temperature product to be necessary.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:31]=[CH:30][C:15]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22](=[O:29])[CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22](=[O:29])[CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:30][CH:31]=1)=[O:6]
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1

Procedure:
Using o-methylbenzoic acid and 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one as starting materials, the procedure of Reference Example 3 was repeated to obtain 2-methyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide.
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[O:4][C:5]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)([CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[Cl:44][C:45]1[CH:57]=[CH:56][C:48]2[N:49]([CH:53]([CH3:55])[CH3:54])[C:50]([SH:52])=[N:51][C:47]=2[CH:46]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:44][C:45]1[CH:57]=[CH:56][C:48]2[N:49]([CH:53]([CH3:55])[CH3:54])[C:50]([S:52][C:2]3[C:3](=[O:21])[O:4][C:5]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)([CH2:9][CH2:10][CH:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[CH2:6][C:7]=3[OH:8])=[N:51][C:47]=2[CH:46]=1
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Reactant: O=C1OC(CCC2CCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: CC(C)n1c(SC2=C(O)CC(CCC3CCCC3)(C3CCCC3)OC2=O)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-cyclopentyl-6-(2-cyclopentyl-ethyl)-4-hydroxy-5,6-dihydro-pyran-2-one from Step 2 of example C(28) was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 0.84-2.28 (m, 28H), 2.31 (d, J=17.0, 1H), 2.66 (d, J=17.0, 1H), 3.96 (brs, 1H), 4.55-4.67 (m, 1H), 6.93 (d, J=8.5, 1H), 7.12 (s, 1H), 7.46 (d, J=8.5, 1H); Anal. Calcd. For C27H35ClN2O3S: C, 64.46; H, 7.01; N, 5.57; Found: C, 64.85; H, 7.30; N, 5.76. ESIMS (MH+): 504.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:24])[NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11](=[O:24])[NH:12][CH2:13][CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCN(CCc1ccccc1)C(=O)CBr
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of bromoacetyl bromide (0.25 mL, 2.92 mmol) in CH2Cl2 (10 mL) at -10° C. was added a solution of 2-(phenylethylamino)ethyl carbamic acid tert-butyl ester (0.7 g, 2.65 mmol) and triethylamine (0.41 mL, 2.92 mmol) in CH2Cl2 (10 mL) dropwise. The mixture was stirred at -10° C. for 30 min, before removal of the solvent in vacuo. The residue was partitioned between EtOAc (2×30 mL) and water (30 mL). The combined organic layers were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (2:1→1:1), to afford the title amide (0.81 g, 79%) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ 1.44 (9H, s), 2.86-2.94 (2H, m), 3.10-3.94 (8H, m), 4.59 and 4.92 (1H, 2×br s), 7.15-7.37 (5H, m). MS (ES+) (385/387, M+).
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:14])[C:4]([O:6][C:7]1([CH2:12][CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].[CH3:15]I>[Ag-]=O.CN(C)C=O>[CH3:15][O:1][CH2:2][C:3](=[CH2:14])[C:4]([O:6][C:7]1([CH2:12][CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: C=C(CO)C(=O)OC1(CC)CCCC1
Reactant: CI
Agent: O=[Ag-]
Solvent: CN(C)C=O
Product: C=C(COC)C(=O)OC1(CC)CCCC1
Temperature: 50 °C
Reaction time: 30 h
Yield: 62 %

Procedure:
A mixture of 19.8 g of 1-ethylcyclopentyl α-(hydroxymethyl)acrylate, 40.0 g of methyl iodide, 30.0 g of silver (I) oxide and 50 g of N,N-dimethylformamide was stirred at 50° C. for 30 hours. The solids were filtered off, followed by conventional aqueous workup. The solvent was distilled off in vacuo. Purification by distillation (boiling point 53° C./16 Pa) gave 1-ethylcyclopentyl α-(methoxymethyl)acrylate represented by formula (10). The yield was 62%.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O.Br>ClCCl>[CH3:1][C@H:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: C[C@H](N)c1ccccc1
Reactant: OCCBr
Agent: Br
Solvent: ClCCl
Product: C[C@@H]1NCCc2ccccc21
Temperature: 51 °C
Reaction time: 50 h
Yield: 143.7 %

Procedure:
176.20 g(1449 mmole) of (S)-(-)-α-methylbenzylamine was dissolved in 185 ml of dichloromethane and 218.04 g(1748 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 658 ml(5750 mmole) of 48% aqueous hydrobromic acid solution was added thereto and the solution thereby obtained was allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature to remove 580 ml of water as the by-product and aqueous hydrobromic acid solution. The residue was dissolved in 760 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 150 ml of ethyl acetate and then dried to obtain 306.5 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C1COCC1>[S:1]1[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: c1csc(-c2cccs2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a stirred solution of 2,2′-bithiophene (10.0 g, 60.24 mmol) in dry THF (150 ml) was added n-butyllithium (2.5 M in hexanes, 20.0 ml, 50.0 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 6-bromohexyloxy-tert-butyldimethylsilane (14.75 g, 50.0 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. ammonium chloride, and the reaction mixture was extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water, brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was chromatographyed (silica gel, petroleum/ethyl acetate from 100:0 to 20:1), to afford the product as a pale green oil (15.07 g, 79%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.08 (m, 1H, Ar—H), 7.03 (m, 1H, Ar—H), 6.92 (m, 2H, Ar—H), 6.61 (d, J=3.6 Hz, 1H, Ar—H), 3.55 (t, J=6.2 Hz, 2H, OCH2), 3.34 (t, J=6.8 Hz, 2H, ArCH2), 1.25-1.85 (m, 8H, CH2), 0.86 (s, 9H, CH3), 0.01 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 145.1 (quat.), 138.0 (quat.), 134.8 (quat.), 127.6 (CH), 124.7 (CH), 123.7 (CH), 123.4 (CH), 122.9 (CH), 63.0 (OCH2), 33.8 (CH2), 32.9 (CH2), 32.7 (CH2), 28.0 (CH2), 26.0 (CH3) 25.1 (CH2), 18.4 (quat.), −5.2 (CH3); MS (m/e): 380 (M+, 27%), 323 (63), 179 (100), 75 (37).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](I)[C:15]2[C:10](=[CH:11][CH:12]=[N:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:29])[C:15]2[C:10](=[CH:11][CH:12]=[N:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=c1c2ccncc2c(I)cn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2ccncc12
Temperature: 95 °C
Yield: 31.8 %

Procedure:
A mixture of 2-benzyl-4-iodo-2,6-naphthyridin-1(2H)-one (0.070 g, 0.19 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.041 g, 0.29 mmol) and Na2CO3 (0.062 g, 0.58 mmol) in toluene (15 mL), ethanol (15 mL) and water (2 mL) was degassed. Pd(PPh3)4 (0.022 g, 0.19 μmol) was then added and the reaction was heated at 95° C. for 17 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with ethyl acetate (30 mL). The organic phase was washed with water then brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) followed by trituration with diethyl ether to give 2-benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,6-naphthyridin-1(2H)-one (0.020 g, 32%) as an off-white solid: mp 159-161° C.; 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=5.4 Hz, 1H), 8.65 (s, 1H), 8.30 (d, J=5.4 Hz, 1H), 7.30-7.40 (m, 5H), 7.04 (s, 1H), 5.26 (s, 2H), 2.26 (s, 3H), 2.09 (s, 3H); ESI MS m/z 332 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[CH:15]([O:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1)([CH3:17])[CH3:16]
Reactant: CC(C)Oc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CC(C)Oc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 45 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 350. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (m, 1H) 7.6 (m, 2H) 7.35 (m, 1H) 7.0 (m, 4H) 6.68 (m, 2H) 5.5 (m, 1H) 4.62 (m, 1H) 3.71 (m, 2H) 2.85 (m, 2H) 1.32 (d, 6H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]([CH3:12])=[C:7]([OH:11])[C:8]=1[CH2:9]Br.[OH2:13]>>[BrH:1].[Br:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]([CH3:12])=[C:7]([OH:11])[C:8]=1[CH2:9][OH:13]
Reactant: Cc1ncc(CBr)c(CBr)c1O
Reactant: O
Product: Br
Product: Cc1ncc(CBr)c(CO)c1O

Procedure:
4,5-Bis(bromomethyl)-3-hydroxy-2-methylpyridine (2)(3 g, 0.008 mol) was stirred in water (24 ml) at 45-50° C. for 40 min. The solution was filtered and evaporated under vacuum. The obtained residue was crystallized from ethanol. The yield was 1.2 g (50%). The position of bromomethyl- in pyridine-ring was verified by qualitative analysis with 2,6-dichloroquinone-4-chloroimide (Harris and Folkers (1939) J. Am. Chem. Soc. 61: 247). M.p. 158-159° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:21]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)#[N:22]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C#N)ccc2NC1C(F)(F)F
Temperature: 80 °C
Yield: 48 %

Procedure:
N,N-Dimethylformamide (5 mL) was degassed with nitrogen for thirty minutes in a three neck round bottom flask equipped with a condenser, temperature monitoring, nitrogen purge and heating mantle. Ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example 158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792 mmol) were added to the N,N-dimethylformamide and stirred vigorously for ten minutes. Tetrakis(triphenylphosphine)palladium(0) (0.068 g, 0.53 mmol) was added and the contents gently warmed to 80° C. for 2 hours under a nitrogen atmosphere. Ethyl acetate (20 mL) was added, followed by extraction with aqueous 2 N ammonium hydroxide (2×10 mL), water (2×10 mL), saturated ammonium chloride (2×10 mL), dried over sodium sulfate and solvent removed in vacuo to yield a yellow solid. The product was purified by flash chromatography (silica gel, ethyl acetate-hexanes, 3:1) to yield, upon concentration of the appropriate fractions, ethyl 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (188 mg, 48%): mp 211-212° C. 1H NMR (CDCl3/300 MHz) 7.68 (s, 1H), 7.43 (m, 2H), 6.69 (d, 1H, J=8.3 Hz), 5.22 (m, 1H), 4.98 (br s, 1H), 1.30 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). EIHRMS m/z 314.1147 (M+NH4+, Calc'd 314.1116). Anal. Calc'd for C14H11F3N2O2: C, 56.76; H, 3.74; N, 9.46. Found: C, 56.44; H, 4.03; N, 9.29.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:18][CH2:19][CH3:20])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:32][CH:13]([CH3:12])[C:14]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH2:18][CH2:19][CH3:20])=[O:15]
Reactant: CCCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl 2-methylpropanoate (700 mg, 2.3 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 36 (100 mg, 13% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.95 (m, 8H), 1.08 (d, J=4.0 Hz, 3H), 1.10 (d, J=4.0 Hz, 3H), 1.21-1.41 (br. m, 5H), 1.68-1.73 (m, 4H), 1.89-1.91 (m, 2H), 2.13 (tt, J=12, 3.2 Hz, 1H), 2.79-2.88 (m, 3H), 6.65 (t, J=5.6 Hz, 1H), 7.45 (t, J=(t, J=6.0 Hz, 1H), 12.04 (s, 1H). MS (ESI) m/z 366.21 (M+Na)+; 342.16 (M−H)−.
Reaction SMILES: C[O:2][CH:3]1[CH2:7][CH:6]([CH3:8])[CH2:5][O:4]1.C(O)C(=C)C.[H][H]>[Cr]([O-])([O-])=O.[Cu+2].O>[CH3:8][CH:6]([CH2:7][CH2:3][OH:2])[CH2:5][OH:4].[CH3:8][CH:6]1[CH2:5][O:4][C:3](=[O:2])[CH2:7]1
Reactant: [H][H]
Reactant: COC1CC(C)CO1
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: C=C(C)CO
Solvent: O
Product: CC(CO)CCO
Product: CC1COC(=O)C1
Yield: 70 %
Yield: 4 %

Procedure:
The process is carried out as in Examples 1 - 5 using 50.0 grams of a methanolic co-distillate (boiling range 66° - 78° C) containing 14.8 grams of 2-methoxy-4-methyltetrahydrofuran derived from methallyl alcohol as described in step (a), 30 ml of water and 5.0 grams of powdered copper chromite (Catalysts and Chemicals Co.). The mixture is heated at 180° C under 1000 psi of hydrogen for one hour. Analysis of the product mixture shows the presence of 9.3 grams of 2-methyl-1,4-butandiol (70% yield) and about 0.5 grams of 3-methyl-4-butyrolactone (4% yield).
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1)=[N+]=[N-].[H][H]>CO.[Ni]>[NH2:1][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: [H][H]
Reactant: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Ni]
Solvent: CO
Product: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Yield: 99.9 %

Procedure:
A solution of 14.7 g (60 mmol) of (S)-3-azido-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 200 ml of methanol was treated with 1.0 g of Raney-nickel and shaken in a hydrogen atmosphere at pressures of 49.5-51 psi and temperatures of 25.3-29.5° for nine hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give 13.2 g of the title compound.
Reaction SMILES: S[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10].N1C(=O)NC(=O)NC1=O.C([O-])([O-])=O.[K+].[K+].[Br:32]C(Br)CCCCC>CS(C)=O>[Br:32][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]
Reactant: O=c1[nH]c(=O)n(CCCCCCS)c(=O)[nH]1
Reactant: CCCCCC(Br)Br
Agent: O=C([O-])[O-]
Agent: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n(CCCCCCBr)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A scheme for the synthesis of Mercaptohexyl Isocyanuric Acid (MH-ICA) is shown in FIG. 10A. 6-Bromohexyl isocyanuric acid was synthesized using methods and materials known in the art (see, e.g. Berl et al., Chem. Eur. J. 2000, 6, 1938-1946; and Hoeben et al., Org. Biomol. Chem. 2006, 4, 4460-4462). Briefly, 1-2 Cyanuric acid (6.2 g, 48 mmol) and ground K2CO3 (1.66 g, 12.0 mmol) were dissolved in DMSO (200 mL). After the mixture was stirred for 30 min, dibromohexane (2.98 g, 12.0 mmol, 0.25 equiv.) was added and was heated to 60° C. for 16 h. Upon cooling down the reaction to room temperature, the mixture solution was partitioned between diethyl ether and saturated KHSO4. The organic fraction was collected and the solvent was removed by rotary evaporator. Recrystallization of the residue from hexane yielded 6-bromohexyl isocyanuric acid which was extensively rinsed with hexane. The product (450 mg) was obtained in high purity. 1H NMR (500 MHz, DMSO-d6) δ: 11.38 (s, 2H), 3.62 (t, 2H), 3.52 (t, 2H), 1.78 (m, 2H), 1.50 (m, 2H), 1.38 (m, 2H), 1.27 (m, 2H) ppm; 13C NMR (125 MHz, DMSO-d6) δ: 149.85, 148.64, 40.28, 35.09, 32.12, 27.21, 27.15, 25.22 ppm. ESI-MS (M+): 293.98 (calculated 293.13).