Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].C(O)(C)(C)C.[C:10]([O:14][OH:15])([CH3:13])([CH3:12])[CH3:11]>O>[C:2]([O:15][O:14][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OO
Reactant: CC(C)C
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OOC(C)(C)C

Procedure:
In accordance with the invention, isobutane oxidate comprised of both tertiary butyl alcohol and tertiary butyl hydroperoxide is reacted in the presence of a water soluble acid catalyst under conditions effective to form ditertiary butyl peroxide. The reaction mixture is phase separated in order to separately recover an aqueous phase containing tertiary butyl alcohol and the acid catalyst and an organic phase containing ditertiary butyl peroxide. The aqueous phase is distilled in order to recover tertiary butyl alcohol overhead and also to separate any water produced during the reaction or introduced in the reaction feed streams, and a concentrated aqueous acid stream is recovered and recycled to the peroxide-forming reaction. The organic phase containing product ditertiary butyl peroxide is then subjected to a series of separation steps including a water extraction step in order to recover product ditertiary butyl peroxide as well as such tertiary butyl alcohol as is contained in the organic phase.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH:10]([N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[C:32]([Cl:33])=[C:31]([CH3:34])[NH:30][C:29]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:35]([C:29]2[NH:30][C:31]([CH3:34])=[C:32]([Cl:33])[C:28]=2[Cl:27])=[O:36])[C@H:10]([N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(N=[N+]=[N-])C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])c(Cl)c1Cl
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Crude tert-butyl-4-amino-3-azidopiperidine-1-carboxylate (Intermediate 270, 3.3 mmol) was dissolved in anhydrous CH2Cl2 (10 ml) and DIEA (1.27 g; 1.6 ml; 9.9 mmol; 3 eq.). The solution was cooled to 0 C and 3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl chloride (736 mg; 3.5 mmol; 1.05 eq.) was added. The reaction was complete within 30 minutes. Dilute with CH2Cl2 and wash with H2O (×2), brine and dried over Na2SO4. Filter and concentrate. Purify by flash column chromatography (0-60% EtOAc/hexanes). Isolation gave 967 mg in 69% yield over the two-step sequence. LC/MS (ES−)[(M−H)+]: 415, 417 for C16H22Cl2N6O3.
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[NH:9][C:7](=[O:8])[CH2:6]2)[CH2:3][CH2:2]1.[Br-].[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N+:23]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][N:9]2[C:7](=[O:8])[CH2:6][C:4]3([CH2:5][CH2:1][CH2:2][CH2:3]3)[CH2:12][C:10]2=[O:11])[CH2:22][CH2:21]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCO
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 66.5 %

Procedure:
A mixture of 3,3-tetramethyleneglutarimide (7.5 g., 0.045 mole), 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane bromide (15.4 g., 0.045 mole), potassium carbonate (6.2 g., 0.045 mole) in 250 ml. of n-butanol is refluxed for a 21 hour period, filtered and evaporated to dryness. Residual material is warmed 45 minutes with acetic anhydride and evaporated to dryness. Water is added to the residue and the mixture basified with aqueous sodium hydroxide. Insolubles are collected and washed with water to provide 11.5 g. (66.5% yield) of 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl]-8-azaspiro[4.5]decane-7,9-dione as the free base, m.p. 90°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][C:20](=O)[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.C(N(CC)CC)C.C(O)(=O)C.Cl.[NH2:38][C@H:39]([CH:47]([CH3:49])[CH3:48])[C:40]([O:42]C(C)(C)C)=[O:41].C([BH3-])#N>ClCCl.ClCCl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][CH:20]([NH:38][C@@H:39]([C:40]([OH:42])=[O:41])[CH:47]([CH3:49])[CH3:48])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCC(=O)CC3)cc12
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCC(N[C@@H](C(=O)O)C(C)C)CC3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of Example 241B (125 mg, 0.372 mmol), triethylamine (0.114 mL, 0.818 mmol), acetic acid (0.106 mL, 1.858 mmol) and (R)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (0.401 mL, 1.858 mmol) in 4 mL 1:1 dichloromethane/methanol was added Biotage MP-cyanoborohydride resin (2.17 mmol/g, 678 mg, 1.487 mmol) and the mixture was shaken at room temperature overnight. The mixture was diluted with dichloromethane and the resin was filtered off, rinsing with dichloromethane and methanol. The crude material was purified by flash chromatography (Analogix280, eluting with a 0-4% methanol/dichloromethane gradient). The tert-butyl ester in 5 mL dichloromethane was treated with excess trifluoroacetic acid for 10 hours. The solvent was removed and the residue was dissolved in 5 mL methanol and treated with 2M hydrogen chloride in diethyl ether for 1 hour. The mixture was diluted with 50 mL diethyl ether and the solid was filtered and dried in vacuo to give the title compound as the hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 0.87-1.16 (m, 6H) 1.76-2.02 (m, 1H) 2.09-2.40 (m, 2H) 2.56-2.87 (m, 3H) 3.20-3.45 (m, 1H) 3.64-3.86 (m, 3H) 4.05 (s, 1H) 6.40 (s, 1H) 6.60 (s, 1H) 7.13-7.44 (m, 4H) 8.22-8.33 (m, 1H) 8.40 (d, J=1.83 Hz, 1H) 8.65-9.88 (m, 2H) 12.70 (d, J=3.97 Hz, 1H). MS (ESI): 438.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:14]2[C:23]3[O:22][CH2:21][CH2:20][O:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH:5](C(OC)=O)[CH2:4]1)#[N:2].CS(C)=O.[Cl-].[Na+]>O>[C:1]([C:3]1([C:14]2[C:23]3[O:22][CH2:21][CH2:20][O:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3c2OCCO3)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1OCCO2
Temperature: 150 °C
Reaction time: 5 h
Yield: 83.5 %

Procedure:
A mixture of Compound 1c (5.0 g, 15 mmol) obtained in Step C, DMSO(50 mL), water (5 mL), and sodium chloride (5.0 g) was stirred at 150° C. for 5 hours. The mixture was allowed to cool, and added water, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=3/1) to give Compound 1 (3.6 g, 86%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:21][N:22]([CH3:27])[CH2:23][C:24](Cl)=[O:25].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][N:13]([C:24](=[O:25])[CH2:23][N:22]([CH3:27])[CH3:21])[CH2:12][CH2:11]1
Reactant: CN(C)CC(=O)Cl
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCNCC2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(F)(COc2ncc(S(N)(=O)=O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide, 2•trifluoroacetic acid (0.131 g), 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g), and sodium carbonate (0.048 g) were combined in a 5-mL vial with N,N-dimethylformamide (3 mL) and stirred overnight at room temperature. Additional sodium carbonate (0.048 g) was added followed by 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g) and stirring was continued over a second night. The reaction mixture was concentrated under high vacuum, slurried in CH2Cl2, filtered, concentrated, chromatographed on amine functionalized silica gel with 0 to 4% methanol in CH2Cl2 as the eluent and dried in a vacuum oven at 80° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].Cl[C:25]1[CH:30]=NC=[CH:27][N:26]=1>O.CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:27]=[N:26][CH:25]=[CH:30][N:13]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: Clc1cnccn1
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Sc2cnccn2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of 9.6 g. 1-acetamido-2-nitro-4-thiocyanatobenzene in 60 ml. dimethylformamide is treated under nitrogen with 1.52 g. of sodium borohydride, the exothermic reaction being controlled so that the temperature does not exceed 30°C. After stirring the mixture at 20°-25°C. for 1 hour, 15 ml. of acetone is added, then, after 2 hours, 9.1 g. of 2-chloropyrazine is added. The mixture is warmed slowly and kept at 100°-110°C. for 3 hours, cooled and diluted with water. The product is filtered off and washed with water, pentane and recrystallized from methanol affording 1-acetamido-2-nitro-4-(pyrazin-2-ylthio)benzene.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[C:15]([OH:18])(=[O:17])[CH3:16].O[CH2:20][C@@:21]12[C@@H:38]3[C@H:29]([C@H:30]4[C@@:34]([CH2:36][CH2:37]3)([CH3:35])[C:33](=[O:39])[CH2:32][CH2:31]4)[CH2:28][CH2:27][C@H:26]1[CH2:25][C:24](=[O:40])[CH2:23][C@@H:22]2[CH3:41].[OH-].[Na+].OO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:15]([O:18][CH2:20][C@@:21]12[C@@H:38]3[C@H:29]([C@H:30]4[C@@:34]([CH2:36][CH2:37]3)([CH3:35])[C@@H:33]([OH:39])[CH2:32][CH2:31]4)[CH2:28][CH2:27][C@H:26]1[CH2:25][C@H:24]([OH:40])[CH2:23][C@@H:22]2[CH3:41])(=[O:17])[CH3:16]
Reactant: CC(=O)O
Reactant: C[C@H]1CC(=O)C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Product: CC(=O)OC[C@]12[C@@H](CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]31)C[C@H](O)C[C@@H]2C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran under nitrogen is cooled in a dry iceacetone bath to about -78° C. and 19-hydroxy-1α-methyl-5α-androstane-3,17-dione acetate in tetrahydrofuran is slowly added. The reaction mixture is stirred for two hours at this temperature, warmed to 0° C. and stirring continued for an additional two hours. The reaction mixture is decomposed by the addition of a 3 N sodium hydroxide solution followed by the addition of a 30% hydrogen peroxide solution. Care is taken that the solution temperature remains below 10° C. during decomposition. Solid potassium carbonate is added to the reaction mixture and the tetrahydrofuran decanted therefrom. The solid residue is washed with tetrahydrofuran and the combined solutions are dried over sodium sulfate, filtered and evaporated to dryness. The residue is crystallized from an acetone-hexane solution to yield 1α-methyl-5α-androstane-3α,17β,19-triol 19-acetate.
Reaction SMILES: [Na].[CH3:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.O1CCCC1.[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>O>[CH3:2][CH:3]1[CH2:4][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][N:8]1[C:21]([O:22][CH2:23][CH3:24])=[O:25]
Reactant: CC1CN(Cc2ccccc2)CCN1
Reactant: CCOC(=O)Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(Cc2ccccc2)CC1C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
580 parts of a sodium bydroxide solution 1N in water were cooled in an ice bath and then there were added 44 parts of 3-methyl-1-(phenylmethyl)piperazine and 82.8 parts of tetrahydrofuran. A solution of 27.13 parts of ethyl carbonochloridate in 103.5 parts of tetrahydrofuran was added dropwise at a temperature at about 5° C. Upon completion, stirring was continued for 4 hours in an ice bath. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 55 parts (87.8%) of ethyl 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate as a residue (int. 36).
Reaction SMILES: C([NH:4][OH:5])(=O)C.CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[C:19]([O:21][CH2:22][O:23][CH3:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>CN(C)C=O.CC(C)=O.C(Cl)(Cl)Cl.CCOC(C)=O>[NH2:16][C:15]1[C:14]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:13]=2[O:5][N:4]=1
Reactant: CC(=O)NO
Reactant: COCOc1ccc(C#N)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COCOc1ccc2c(N)noc2c1
Reaction time: 16 h
Yield: 125.9 %

Procedure:
To a stirred solution of acetohydroxamic acid (3.88 g) in N,N-dimethylformamide (DMF) (120 ml) was added potassium tertiarybutoxide (tBuOK) (5.80 g) under N2. After one hour of stirring 2-fluoro-4-(methoxymethoxy)-benzonitrile (6.0 g) was added. Stirring continued for 16 hours. TLC (silica gel) in 10% acetone/CHCl3 showed the presence of starting material. An additional 1 equivalent of acetohydroxamic acid and tBuOk were added in DMF (120 ml). After one hour the reaction was diluted with EtOAc (2 l), filtered, washed filtrate with brine (4×11), dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) was performed eluting with 2.5% acetone/CH2Cl2 solution affording 8.1 g of the product, m.p. 88-89° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)[C:5]([Cl:8])=[N:6][CH:7]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2cc(Br)cnc2Cl)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cc(Br)cnc1Cl)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
N-(5-Bromo-2-chloropyridin-3-yl)-4-methoxybenzamide (1.4 g, 81% purity, 3.32 mmol) was dissolved in 80 mL dichloromethane. A solution of boron tribromide (1M in dichloromethane, 16.6 ml, 16.6 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure to give 1.2 g (100% yield) of the title compound as an orange solid. Purity 91%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(N2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(N2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-morpholinobenzonitrile (200 mg, 1.06 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), and LiAlH4 (400 mg, 10.53 mmol, 10.00 equiv). The resulting solution was stirred for 3 h at 60° C. The reaction was then quenched with 1 N NaOH. The solids were removed by filtration. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined, dried over NaSO4, and concentrated under vacuum. The product was obtained as 120 mg (58%) of a yellow solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 7.26 (m, 2H). 6.91 (m, 2H), 3.87 (m, 6H), 3.16 (m, 4H).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH:8][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:7])[CH3:6].[Br:15]N1C(=O)CCC1=O>O>[CH:5]([NH:8][C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)([CH3:7])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Nc1ncccn1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Nc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
75 ml of acetic acid, 13.7 g (0.1 mole) of 2-isopropylamino-pyrimidine and 17.8 g (0.1 mole) of N-bromosuccinimide are poured into a 1 liter reaction vessel. The reaction mixture is stirred for 1 hour at room temperature and then poured into iced water. The resultant precipitate is filtered off, washed with water and dried. 20 g (yield 92%) of the title compound was obtained as a white powder melting at 90° C. Elemental analysis showed that the compound had the expected empirical formula of C7H10N3Br.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]=1[N+:19]([O-])=O)[CH3:2].[Sn](Cl)(Cl)(Cl)Cl>C(O)(=O)C.CO>[NH2:19][C:8]1[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][C:7]=1[S:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:22][CH3:23]
Reactant: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1N
Temperature: 50 °C
Yield: 73.1 %

Procedure:
(E)-Methyl 3-(4-(2-(diethylamino)ethylthio)-3-nitrophenyl)acrylate (736 mg, 2.2 mmol) was suspended in 15 mL solution of glacial acetic acid-Methanol. Under stirring, Tin Chloride (4.9 g, 21.7 mmol) was added and the resulted solution was heated to 0-100° C. for 0.5-5.0 hours. Cooling it then to room temperature. Removing the solvent under reduced pressure. Slowly add saturated sodium carbonate (20 mL) and dichloromethane (20 mL) to the residue with thoroughly stirring for 10-120 min. The organic layer was separated and dried with MgSO4. Removing off MgSO4 and the filtrate was concentrated into an oil. The product was purified through chromatography. 496.3 mg of (E)-methyl 3-(3-amino-4-(2-(diethylamino)ethylthio)-phenyl)acrylate was obtained. Yield: 73.9%. TLC: 0.31 (DCM:MeOH=9:1). MP: 153.2° C.-154.6° C. HPLC: 98.5%; tR=7.82 min (LC/PDA: Diamonsil C18 5μ 150×4.6 mm, flow rate 1.0 mL/min, grade: 10-100% B, 12 minutes; mobile phase A: H2O; mobile phase B: acetonitrile; UV254). 1HNMR (400 MHz, CDCl3) δ: 7.56 (1H, d, J=16 Hz), 7.39 (1H, d, J=8 Hz), 7.28 (1H, s), 6.87 (1H, dd, J=8 Hz and 16 Hz), 6.39 (1H, d, J=16 Hz), 4.51 (2H, s), 3.81 (3H, s), 3.05 (6H, m), 1.29 (6H, t, J=7.2 Hz); MS (m/z): 309 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>ClCCCl>[Cl:9][CH2:10][C:11]([NH:8][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=1)=[O:12]
Reactant: Cc1cc(N)ncn1
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Product: Cc1cc(NC(=O)CCl)ncn1
Temperature: 80 °C

Procedure:
6-Methyl-pyrimidin-4-yl amine (545 mg) was suspended in DCE (5 mL) and chloroacetylchloride (0.4 mL) was added dropwise. The reaction was heated in a microwave at 80° C. for 5 mins. The reaction mixture was cooled, filtered and a solid obtained. The reaction was repeated a second time and both batches of solid were combined, washed with dichloromethane then suspended in dichloromethane and sat. NaHCO3 (aq.) was added. The organic phase was collected and the aqueous layer extracted with dichloromethane (×2). The combined organic layer was dried over sodium sulphate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the sub-titled compound as a yellow solid (120 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:8]([C:9](OCC)=[O:10])=[CH:7][N:6]=1.[BH4-].[Na+].[Cl-].[Li+].C(O)C>C1COCC1>[F:21][C:2]([F:1])([F:20])[CH2:3][O:4][C:5]1[N:6]=[CH:7][C:8]([CH2:9][OH:10])=[CH:14][C:15]=1[C:16]([F:19])([F:17])[F:18]
Reactant: CCOC(=O)c1cnc(OCC(F)(F)F)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1cnc(OCC(F)(F)F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.5 %

Procedure:
To a mixture of ethyl 6-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)nicotinate (250 mg, 0.79 mmol), sodium borohydride (158 mg, 3.94 mmol), and lithium chloride (167 mg, 3.94 mmol) in THF (3 mL) is added ethanol (3 mL), and the mixture is stirred at room temperature for 4 hours. After cooling to 0° C., the reaction is quenched with water (100 mL) and extracted with EtOAc (100 mL). The separated organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 62 mg (29% yield) of the title compound as green oil.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:11][C:12]([O-:14])=[O:13].[Na+].Cl>>[C:12]([CH2:11][N:1]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][N:4]([CH2:11][C:12]([OH:14])=[O:13])[CH2:3][CH2:2]1)([OH:14])=[O:13]
Reactant: C1CNCCNCCN1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To an aqueous solution of TACN (0.16 mols in 58 mL water) is added an aqueous solution of sodium chloroacetate (0.71 mols sodium chloroacetate in 68 mL of water). This solution is stirred at 80° C. overnight while maintaining the pH at 9-10. After cooling to ambient temperature the pH of the solution is adjusted to 2.5 with aqueous HCl. The resulting precipitate is collected by filtration, washed with acetone, and dried in vacuo to afford the mono-hydrochloride salt of 1,4,7-tricarboxymethyl-1,4,7-triazacyclononane.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]OC[CH2:35]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH:19]([CH2:35][CH2:34][CH3:38])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccs1)CCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccs1)CCC3
Yield: 85 %

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.261 g; 0.760 mmol), LHMDS 1N in THF (0.836 mL; 0.836 mmol), 1-iodopropane (0.111 mL; 1.140 mmol) in DMF (3.0 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.249 g (85%) of the title compound as a yellow oil.