Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH2:21][OH:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:32]=2)O1>>[OH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)[CH:32]=1
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(CO)c(Br)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(CO)c(-c2ccnc(N3CCOCC3)c2)c1
Yield: 91 %

Procedure:
The method used to prepare example X was followed using 3-bromo-4-(hydroxymethyl)-N-(3-(trifluoromethyl)phenyl)benzamide and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine to afford 4-(hydroxymethyl)-3-(2-morpholinopyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)benzamide in a 91% yield. 1H NMR (400 MHz, <cd3od>) δ ppm 3.61-3.73 (m, 4H), 3.83-3.90 (m, 4H), 4.63 (s, 2H), 7.09-7.15 (m, 1H), 7.39-7.47 (m, 2H), 7.53-7.60 (m, 1H), 7.75-7.82 (m, 1H), 7.91-7.99 (m, 2H), 8.04-8.13 (m, 2H), 8.14-8.19 (m, 1H). LC/MS (m/z)=458.1 (MH+), Rt=0.73 min.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=[O:7].[CH2:11]([C:13]1([CH2:28][CH2:29][OH:30])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][CH2:15][O:14]1)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][CH3:27])[CH3:12]>C(Cl)Cl.[NH4+].[Cl-]>[CH2:11]([C:13]1([CH2:28][CH:29]([OH:7])[OH:30])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][CH2:15][O:14]1)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][CH3:27])[CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(O)O)OCC3
Temperature: 0 °C
Yield: 31.8 %

Procedure:
Dry DMSO (71 μL, 1.0 mmol, 2.0 eq) was added dropwise to a solution of oxalyl chloride (66 μL, 0.75 mmol, 1.5 eq) in CH2Cl2 (1 mL) at −78° C. After stirring for ten minutes, a solution of compound 1 (136 μL, 0.5 mmol) in CH2Cl2 (4 mL) was added dropwise, and the reaction was stirred for an additional thirty minutes at −78° C. before the addition of TEA (2.79 μL, 2.0 mmol, 4.0 eq). The reaction mixture was then allowed to warm slowly to 0° C., diluted with saturated NH4Cl, and extracted twice with Et2O. The combined organic phases were washed with water and brine, dried with Na2SO4, concentrated, and purified by column chromatography using a gradient of 50:50:EtOAc:Hexane to 100% EtOAc to give a white solid (46 mg, 32%): mp 158–159° C. 1HNMR (CDCl3, δ TMS): 0.50 (t, 3H), 1.25 (t, 3H), 1.50 (m, 1H), 1.82 (m, 1H), 2.04 (m, 1H), 2.17 (m, 1H), 2.33 (m, 1H), 2.58 (q, 2H), 2.88 (m, 2H), 3.77 (m, 1H), 3.91 (m, 1H), 4.19 (q, 1H), 4.33 (m, 1H), 7.02–7.15 (m, 3H, Ar—H), 7.66 (br, 1H, NH). MS−: m/z 288 ([M−H]−). Anal. (C17H23NO3): C, H, N.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]2[CH2:21][CH2:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]=3[CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].[C:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br)#[N:31].C(O)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:21][CH2:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:35][C:34]4[CH:37]=[CH:38][CH:39]=[C:32]([C:30]#[N:31])[CH:33]=4)[C:11]=3[CH2:10]2)=[O:8])=[CH:22][CH:23]=1)#[N:2]
Reactant: N#Cc1cccc(CBr)c1
Reactant: N#Cc1ccc(C(=O)N2CCc3c([nH]c4ccccc34)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N2CCc3c(n(Cc4cccc(C#N)c4)c4ccccc34)C2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 63.4 %

Procedure:
150 mg (0.5 mmol) of 2-(4-cyano-benzoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole were dissolved in 5 ml of dimethylformamide. 60 mg of potassium tert-butoxide were added and the mixture was stirred for 5 minutes, treated with 100 mg of 3-cyano-benzyl bromide and slowly heated up to 80° C. The mixture was acidified by addition of acetic acid and evaporated under reduced pressure. The residue was partitioned between methylene chloride and 10% aqueous sodium carbonate solution, dried and evaporated. Chromatography of the residue over 12 g of silica gel using 10% (v/v) of ethyl acetate in methylene chloride and crystallization from ethyl acetate/hexane yielded 132 mg of 2-(4-cyano-benzoyl)-9-(3-cyano-benzyl) -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole with m.p. 178-180° C.
Reaction SMILES: [C:1](=[O:8])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])[NH2:2].[CH2:9]=[C:10]([CH3:12])[CH3:11]>C(O)CCC>[C:10]([NH:2][C:1](=[O:8])[O:3][CH2:4][CH2:5][CH2:6][CH3:7])([CH3:12])([CH3:11])[CH3:9]
Reactant: C=C(C)C
Reactant: CCCCOC(N)=O
Solvent: CCCCO
Product: CCCCOC(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A stirred mixture of 117 g of butyl carbamate, 5 g of butanol, 15 g of ®LEWASORB AC-10 and 60 g of isobutene was heated to 70° C. in a stirred autoclave, and stirring was continued at this temperature for 4 hours. Thereafter, the catalyst was separated off and the mixture was distilled under reduced pressure. 161 g (93% of theory) of butyl N-tert.-butylcarbamate of boiling point 110°-111° C./20 mbar were obtained. No substantial amount of diisobutene was detected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CCOC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: Brc1ccccn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2ccccn2)c1
Temperature: 115 °C
Yield: 91.4 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (10 g, 42.1 mmol), 2-bromopyridine (8 g, 50.6 mmol), potassium carbonate (powder, 14 g, 101 mmol) and copper iodide (325 mesh powder, 6 g, 31.6 mmol) was heated at 115° C. for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. CH2Cl2 (100 mL) was added, and the resulting reaction mixture was filtered. The filtrate was washed with H2O (3×50 mL) followed by brine (100 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1/Hexane:EtOAc to give the title product (12.1 g, 91% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH:15]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>>[ClH:23].[ClH:23].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH2:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: NNC1CCNCC1
Temperature: 90 °C

Procedure:
A mixture of 0.1 mole of 4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (starting compound A6) and 150 ml of concentrated hydrochloric acid is heated at 90° C. for 60 min after which the clear solution is evaporated. The residue is washed with tetrahydrofurane, filtered off and dried under vacuum. M. p. 256–259° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37](C(OC(C)(C)C)=O)[CH:38]=2)O1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5]([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(-c3cn[nH]c3)cnc2N)cc1F
Temperature: 120 °C

Procedure:
To methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (For Synthesis see Example 34, Step 2) (100 mg, 0.307 mmol) in DME (3 mL) and 2 M sodium carbonate (0.75 mL, 1.5 mmol) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (90 mg, 0.307 mmol) followed by PdCl2(dppf)-CH2Cl2 adduct (25.04 mg, 0.031 mmol). The reaction mixture was heated in microwave at 120° C. for 15 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was proceeded to next step without purification (90 mg, 74%, 80% purity). LCMS (m/z): 314.1 (MH+), 0.595 min.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.COC(=O)[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[N:12][CH:11]=1.[OH-].[Li+].O1CCCC1>O1CCCC1.O>[N:12]1[CH:11]=[CH:10][CH:15]=[C:14]([O:16][C:2]2[CH2:6][CH2:5][O:4][N:3]=2)[CH:13]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: BrC1=NOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: c1cncc(OC2=NOCC2)c1

Procedure:
The enantiomers of 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-74a and III-74b were prepared in 2 steps according to the following procedures: racemic 3-bromo 4,5-dihydroisoxazole III-66 was reacted with 5-hydroxynicotinic acid methyl ester using Method 5. The resulting ester (1.0 equiv) was dissolved in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH<2 with 1N HCl to provide the racemic desired acid III-74 as a white solid which was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=395.5 m/z. Activity: A
Reaction SMILES: O[CH:2]=[C:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4](=[O:6])[CH3:5].C(Cl)(=O)C([Cl:14])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:14][CH:2]=[C:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4](=[O:6])[CH3:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)C(=CO)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(=O)C(=CCl)CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 4-hydroxy-3-isobutyl-but-3-en-2-one (28 g, 197 mmol) in chloroform (350 mL) a soution of oxalylchloride (44.3 g, 349 mmol) in chloroform (50 mL) is added slowly during 5 min. The resulting dark brown mixture is stirred at rt for 2 h before it is cooled to 0° C. and treated with ice (100 g) followed by 1 N aq. NaOH (100 mL). When the quite violent gas evolution ceases the phases are separated (the still acidic aq. phase is discarded). The organic phase is washed with 1N aq. NaOH (3×75 mL) and 1 N aq. NaH2PO4 (75 mL), dried (MgSO4), filtered and evaporated to give crude 4-chloro-3-isobutyl-but-3-en-2-one (31.6 g) as a dark brown oil; LC-MS: tR=0.97 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9][CH2:8][CH2:7][O:6]1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].CN(C=O)C>O>[C:10]1([C:5]2([CH2:4][CH2:3][CH2:2][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])[O:9][CH2:8][CH2:7][O:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCCCC1(c2ccccc2)OCCO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCC1(c2ccccc2)OCCO1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
Add 2-(3-chloropropyl)-2-phenyl-[1,3]dioxolane (38 g, 168 mmol) and potassium phthalimide (34.2 g, 184.4 mmol) to DMF (80 mL) and stir for 40 min at 150° C. Cool the reaction to RT, dilute with water (1 L) and extract the mixture with a mixture of EtOAc (500 mL) and hexanes (500 mL) and DCM (2 L). Dry (sodium sulfate), concentrate and recrystallize the solid from hot ethanol (600 mL). Filter and dry the residue under vacuum to isolate the title compound as a white solid (47.62 g, 84%).
Reaction SMILES: [BH4-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.NN.[CH2:16]([OH:27])[C@@H:17]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][OH:26])[OH:24])[OH:22])[OH:20])[OH:18].I([O-])(=O)(=O)=O.C([BH3-])#N.[Na+]>N1C=CC=CC=1>[O:26]=[CH:25][C@@H:23]([C@H:21]([C@@H:19]([C@@H:17]([CH2:16][OH:27])[OH:18])[OH:20])[OH:22])[OH:24]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Agent: [BH3-]C#N
Solvent: c1ccncc1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Sodium borohydride reduced dextrans are reacted with p-toluenesulfonyl chloride. The product, mainly 6-O-p-tolylsufonyldextran is converted into the 6-hydrazino-6-deoxydextran by refluxing with hydrazine and the product is coupled to the carboxylated microspheres. As dextran is mainly a 1-6 glycan, the nitrogen functions are mainly located at the original terminal primary hydroxyls; for instance Cl of the reducing end glucitol and C6 of the non-reducing end glucopyranoside. The periodate oxidized IgG is then directly coupled to the terminal hydrazines via reductive amination with sodium cyanoborohydride. This approach reduces the number of coupling steps considerably. The hydrazinodextrans are prepared in bulk and characterized in respect to molecular weight and substitution. Procedure: Dextran (10,000 MW) 32.4 g is dissolved in 200 ml of 95% pyridine and water is removed at 60° C. by rotary evaporation. To the swollen dextran in 2 hours is added 85 grams of p-toluenesulfonyl chloride and the mixture kept for 24 hours at 25° C. After addition of 100 grams of ice and 100 ml of methanol, the mixture is agitated in a blender and the powder is washed with 80% methanol and dried. Twenty-five grams of this material is refluxed for 7 days with 35 ml of anhydrous hydrazine under nitrogen. Excess hydrazine is removed in vacuo and the residue dissolved in 5% acetic acid, dialyzed against water, and lyophilized. This material is analyzed for sugar content and hydrazinosugars by ion exchange chromatography. To calibrate against known compounds the hydrazinodextran is reduced with excess Raney-nickel (1 g/g/10 ml water of hydrazinodextran) for 24 hours. After heating to 100° C., the catalyst is removed by filtration and the product dialyzed and lyophilized. Hydrolysis and analysis for constituents gives a high ratio of glucose: 6-amino-6-deoxyglucose : 1-amino-1-deoxy-D-glucitol (D-glucamine) [50:1]. Coupling of the hydrazinodextran to the succinylated microsphere would be accomplished using EDC as described under method 2 above.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O[CH2:13][CH:14]([CH2:16]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]2[C:6]([CH:13]=[CH:14][CH:16]=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Yield: 40.5 %

Procedure:
In a similar fashion using route 10 general procedure 20, 3-chloro-2-nitroaniline (1.0 g, 5.8 mmol), glycerol (1.65 g, 18.0 mmol), 3-nitrobenzensulfonic acid sodium salt (1.66 g, 7.5 mmol) and H2SO4/H2O (12 ml, 7:5) gave the title compound (490 mg, 40%) which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:15][NH:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl.S(=O)(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:15][N:16]([C:25](=[O:27])[CH3:26])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNCC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)CC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15.9 %

Procedure:
To 4-[1-(2-Fluoro-phenyl)-2-methylamino-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (425) (0.95 g, 2.81 mmol) in MeCl2(10 mL) was added TEA (0.43 mL, 3.10 mmol). The solution was cooled to 0° C. and allowed to stir for 15 min. Acetyl chloride (0.20 mL, 2.81 mmol) was then added. The reaction was allowed to stir at 0° C. for 35 min and then at room temperature for 132 h. Additional triethylamine (0.39 mL, 2.81 mmol), and acetyl chloride (0.2 mL, 2.81 mmol) were added. The reaction mixture was then diluted with 10% aq. sodium bisulfate (20 mL). The organic layer was separated and the aqueous portion was extracted with dichloromethane (3×). The organics are combined, dried with sodium sulfate and concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 2% (2M NH3 in MeOH) in MeCl2) yielding 0.17 g (16%) pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>CC(C)=O.O>[Cl:9][CH2:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:13]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)CCCl
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCCl)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a stirred solution of 2-aminophenol (2.18 g, 20 mmol) in acetone (20 mL) a solution of 3-chloropropionyl chloride (1.28 g, 0.87 mL, 10 mmol) in acetone (20 mL) was added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature for 0.5 h and then diluted with water (50 mL). Acetone was removed in vacuo, the precipitate formed was collected by filtration, washed with water, and dried to give the subtitle compound (1.53 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].S(Cl)([Cl:13])(=O)=O>C(O)(=O)C>[Cl:13][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1c(F)cccc1F
Solvent: CC(=O)O
Product: Nc1c(F)cc(Cl)cc1F
Temperature: 80 °C

Procedure:
35.5 g of 2,6-difluoroaniline were mixed with 200 ml of concentrated acetic acid, and the mixture was heated to 80° C. 42.4 g of sulfuryl chloride were mixed with approximately the same amount of concentrated acetic acid, and the mixture was added dropwise to the heated solution. The mixture was then heated at reflux for six hours. After cooling, the solution was concentrated under reduced pressure and the residue was stirred with water and pentane. The solid residue was filtered off and washed with water. The resulting solid was admixed with 200 ml of concentrated hydrochloric acid and heated at reflux for two hours. After cooling, the solution was carefully made slightly alkaline using aqueous sodium hydroxide solution, and the mixture was extracted three times with 100 ml of ethyl acetate each time. The organic phase was dried over sodium sulfate and freed from the solvent. Yield: 40 g;
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].Cl>N1C=CC=CC=1>[Cl:11][C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1nc(C(F)(F)F)c(Cl)s1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(C(F)(F)F)c(Cl)s1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 43.5 %

Procedure:
2-Amino-5-chloro-4-trifluoromethylthiazole (1.0 g) was dissolved in pyridine (5 ml) and 4-chloro-3-nitrobenzoylchloride (1.1 g) was added at room temperature with stirring. The mixture was stirred for 1 day at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-chloro-4-trifluoromethylthiazol-2-yl)-4-chloro-3-nitro-benzamide (0.83 g), m. p. 183-184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](O)=[O:14])=[CH:8][CH:7]=[CH:6]2.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:49][O:50][C:51](=[O:55])[CH2:52][NH:53][CH3:54].C(N1CCOCC1)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([C:16]([F:21])([F:22])[C:17]([F:20])([F:19])[F:18])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:53]([CH3:54])[CH2:52][C:51]([O:50][CH3:49])=[O:55])=[O:14])=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)O)cccc2c1C(F)(F)C(F)(F)F
Reactant: CNCC(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)c1cccc2c(C(F)(F)C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
The crude 6-methoxy-5-(pentafluoroethyl)-1-naphthalene carboxylic acid (3.65 g, 11.4 mmol), 1-hydroxybenzotriazole (2.31 g, 17.1 mmol), dry distilled dimethylformamide (35 ml) and dicyclohexylcarbodiimide (2.82 g, 13.7 mmol) were stirred at room temperature for 1 hour. The mixture was cooled to 0° C., a solution of sarcosine methyl ester hydrochloride (3.18 g, 22.8 mmol) in dimethylformamide (30 ml) and N-ethyl morpholine (2.92 ml, 22.8 mmol) was added and stirring continued for 2 hours at room temperature. After cooling to 0° C., the precipitate (dicyclohexyl urea) was removed by filtration, the filtrate evaporated and the residue purified by HPLC (ethyl acetate/hexane 1:1, Waters Prep LC 500A). 1.5 g of pure, and 2.5 g of less pure N-[[6-methoxy-5-(pentafluoroethyl)-1-naphthalenyl]carbonyl]-N-methylglycine, methyl ester were obtained. nmr (DMSO): δ2.75 & 3.25 (2s, 3H, N--CH3, rotamers); δ3.75 (s, 3H, OCH3); δ3.97 (s, 3H, OCH3); δ4.35 (broad, 2H, N--CH2 --CO); δ7.7 (m, 5H, Har). ms: m/e 405 (M+), 303, 195, 102.
Reaction SMILES: Cl[C:2](=[CH:5][S:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:3]#[N:4].O1CCCC1.O.[OH-].[Na+]>[Na+].[Cl-]>[N:8]1[CH:9]=[CH:10][CH:11]=[N:12][C:7]=1[S:6][C:5]#[C:2][C:3]#[N:4]
Reactant: N#CC(Cl)=CSc1ncccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#CC#CSc1ncccn1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Into a 250 ml reaction flask is added 2-chloro-3-(2-pyrimidyl)thio-2-propenenitrile (1.5 g, 0.007 moles), tetrahydrofuran (35 ml) and water (35 ml). The mixture is stirred at zero degree Celsius until the solid is completely dissolved and then aqueous sodium hydroxide solution (7.5 ml 1N NaOH, 0.0075 moles, diluted with 50 ml water) is added slowly with stirring at such a rate so as to maintain the reaction pH below 11. The resultant reddish brown solution is stirred at zero degree Celsius for three hours followed by one hour at room temperature and then diluted with 50 ml of saturated aqueous NaCl solution. The product is extracted twice with 100 ml portions of dichloromethane. The combined dichloromethane extract is dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated under vacuum to give 0.5 g of pale yellow solid (yield 40 percent, purity 90 percent by GC/MS) which is characterized by GC/MS and 1H NMR.