Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19](C([O-])=O)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(C(=O)[O-])C4)c3n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cnc3nnn(CC4CCCNC4)c3n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (0.45 g, 0.89 mmol) was dissolved in CH2Cl2 (5 ml), and then TFA (5 ml) was added, followed by stirring at room temperature overnight. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the next reaction was advanced without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[CH:6]1[C:5]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:11])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Solvent: Clc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
passing the recovered unreacted p-chlorobenzene sulfonic acid into a reaction zone while passing monochlorobenzene countercurrent to the p-chlorobenzene sulfonic acid thereby forming additional 4,4'-dichlorodiphenyl sulfone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.Cl.[NH:19]1[C@@H:23]([CH2:24][OH:25])[CH2:22][CH2:21][C@H:20]1[CH2:26][OH:27].C(=O)([O-])O.[Na+]>CC(C)=O.CC(C)=O.O.O>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([N:19]2[C@@H:23]([CH2:24][OH:25])[CH2:22][CH2:21][C@H:20]2[CH2:26][OH:27])[N:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Reactant: OC[C@@H]1CC[C@H](CO)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (2.2 g, 8.0 mmol) in acetone (40 mL) was added to magnetically stirred ice water (60 mL). The mixture was treated with a solution of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (1.0 g, 6.0 mmol) in acetone/water (20 mL, 3:1), followed by a suspension of sodium hydrogen carbonate (1.0 g, 12 mmol) in water (12 mL). After 30 minutes of stirring at 0° C., the mixture was treated with an additional quantity of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (0.26 g, 1.6 mmol) in water (3 mL), followed by sodium hydrogen carbonate (0.35 g) in water (5 mL). The suspension was allowed to stir overnight while regaining room temperature. The title compound was isolated by Buchner filtration, washed with water, and dried under house vacuum. Compound identification by mass spectrometry was achieved via the analysis of the product reaction product of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol with excess morpholine in ethanol. MS (ES+)=417.2 (M+morpholine−Cl)+
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:53])[CH:26]([C:28]1[CH:33]=[CH:32][C:31](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:30][CH:29]=1)[CH3:27]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:53])[CH:26]([C:28]1[CH:29]=[CH:30][C:31]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:32][CH:33]=1)[CH3:27]
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.08 g, 0.27 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.086 g, 0.29 mmol), triethyl amine (3 mL), copper(I)iodide (0.026 g, 0.14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.057 g, 0.08 mmol) followed by flash column chromatography over silica gel (230–400 mesh), the title compound was obtained as a brown oil (0.067 g, 54%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O>[CH3:15][S:16]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](C)O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
24.11 G (0.2041 mol) of ethyl L-(+)-lactate and 50 ml of anydrous pyridine were stirred in an ice bath. 17.0 Ml (25.2 g, 0.220 mol) of methanesulfonyl chloride was added dropwise over a period of 20 minutes, and the mixture was stirred for 1 hour at the same temperature and for 1 hour at room temperature. 200 Ml of water was added, and extraction was performed with methylene chloride (50 ml, 3 times). The extract was washed with water (50 ml), then dried with anhydrous magnesium sulfate, and vacuum concentrated. The red-colored oily residue was vacuum distilled, and 32.20 g of ethyl (-)-2-methanesulfonyloxypropionate was obtained in the form of a colorless liquid with bp 97°-102° C./2 Torr. Yield 82.0%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(O[CH:12](OCC)[CH2:13][Cl:14])C>>[Cl:14][CH2:13][CH:12]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6][CH2:7][O:8]1
Reactant: CCOC(CCl)OCC
Reactant: OCCc1cccs1
Product: ClCC1OCCc2sccc21

Procedure:
The title compound was synthesized from 2-(thiophen-2-yl)ethanol and chloroacetaldehyde diethyl acetal according to General Procedure A.
Reaction SMILES: [F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH2:17])[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH:17][C:19]4[N:27]=[CH:26][N:25]=[C:24]5[C:20]=4[N:21]=[CH:22][NH:23]5)[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1
Reactant: C[C@H](N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)C1=NC=C2C=C(F)CCC3=C2N1CC3
Temperature: 90 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of (S)-1-(5-fluoro-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen-1-yl)ethylamine (70 mg, 0.30 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (71.8 mg, 0.30 mmol), and DIPEA (0.153 mL, 0.90 mmol) in n-butanol (1.5 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (5 mL) and cooled in an ice bath. HCl in isopropanol (1.25 M, 3 mL) was added and the mixture stirred at 0° C. for 1.5 h and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5 M NH3 in MeOH, further purification by column chromatography (Si—PCC, gradient 2-12% 2M NH3/MeOH in DCM) afforded 405 as a white solid (72.8 mg, 69%). LCMS (Method K): RT 2.68 min [M+H]+ 352.0. 1H NMR ((CD3)2SO, 400 MHz): 12.93 (1H, bs), 8.24 (1H, s), 8.15 (1H, s), 7.89 (1H, d, J=7.9 Hz), 7.43 (1H, dd, J=8.7, 4.8 Hz), 6.99 (1H, dd, J=10.8, 8.8 Hz), 5.83 (1H, bs), 4.31-4.29 (2H, m), 3.04-3.01 (2H, m), 2.08-1.94 (4H, m), 1.66 (3H, d, J=6.7 Hz)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>[OH:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Oc1cccc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.491 g (4.5 mmol) 3-aminophenol is heated under nitrogen atmosphere for 1 h at 90° C. and for 3 h at 120° C. The reaction mixture is then taken up in a mixture of 30 ml acetate and 20 ml 20% aqueous potassium carbonate solution while stirring for about 4 h, and the filtration material is digested for 20 min in 20 ml of boiling methanol. After cooling to RT, filtration, washing of the filter residue with methanol, and drying under HV (8 h, 130° C.), title compound is obtained with a water content of 1.94%; m.p. 217-219° C.; ESI-MS: (M+H)+=329.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17].Cl>CCOCC.CCCCCC>[Br:8][C:4]1[N:3]=[C:2]([CH:16]=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
2,6-Dibromopyridine (25 g, 0.105 mol) is suspended in 200 ml of ether. The solution is cooled to -78° C. and n-butyllithium (65.6 ml, 1.6M, 0.105 mol) in hexane is added slowly dropwise over a 1.5 hour period. After 5 minutes, dimethylformamide (8.4 g, 0.115 mol) in 13 ml of ether is added slowly dropwise over one hour. The reaction is allowed to stir at -78° C. for 1.5 hours. The mixture is warmed to -25° C. and 40 ml of 6N hydrochloric acid is added. The mixture is allowed to warm to room temperature. The aqueous phase is extracted three times with ether and the combined organics are washed once with water, dried over sodium sulfate and evaporated. Trituration with pentane afforded 15.0 g of the title compound as a tannish-white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>>[OH:32][CH2:31][C:30]([NH:29][C:15]([C:14]1[CH:18]=[CH:19][N:20]=[CH:21][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:28]=[N:27][CH:26]=[N:25][CH:24]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:11])=[O:17])([CH3:34])[CH3:33]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 2-amino-2-methylpropan-1-ol, providing the title compound was obtained as yellow solid (33%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:29]([F:32])([F:31])[F:30])([CH3:3])[CH3:2].C1C(=O)N([Cl:40])C(=O)C1>C(Cl)Cl>[Cl:40][C:14]1[C:13]2[CH:12]=[C:11]([O:10][CH2:9][C:8]3[CH:27]=[CH:28][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([C:29]([F:32])([F:30])[F:31])[CH:7]=3)[CH:19]=[CH:18][C:17]=2[N:16]2[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:15]=12
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CCC2CC(=O)O)cc1C(F)(F)F
Reaction time: 0.25 h

Procedure:
To a solution of the 1st enantiomer (described as the enantiomer isolated and having the retention time of 29.8 min per the conditions reported in Example 1.25) of 2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acid (0.049 mmol) in DCM (0.5 mL) at 0° C. was added NCS (0.049 mmol). The reaction was stirred for 15 minutes. The mixture was diluted with DCM and washed with water (twice) and saturated sodium thiolsulfate (aq). The organics were dried over Na2SO4, filtered, and concentrated to give the title compound as a yellow solid. LCMS m/z=482.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.06 Hz, 6H), 2.24-2.35 (m, 1H), 2.51-2.59 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.36, 4.11 Hz, 1H), 3.62-3.74 (m, 1H), 3.96-4.05 (m, 1H), 4.11-4.19 (m, 1H), 4.74-4.83 (m, 1H), 5.10 (s, 2H), 6.86 (dd, J=8.78, 2.34 Hz, 1H), 6.96 (d, J=2.40 Hz, 1H), 7.28 (d, J=8.72 Hz, 1H), 7.31 (s, 1H), 7.65-7.72 (m, 2H), 12.35 (bs, 1H).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.CC1(C)[O:33][C@@H:32]([CH:34]=O)[CH2:31][O:30]1.Cl.CO.Cl>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:34][C@H:32]([OH:33])[CH2:31][OH:30])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)OC[C@H](C=O)O1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Br
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC[C@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde. The protecting group is cleaved off as described by means of a 1.25 N HCl/methanol solution. The product was converted into the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Product: CCOC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 160 °C

Procedure:
A mixture of ethyl 4-aminobenzoate (1.00 g, 6.05 mmol) and 2-fluoronitrobenzene (0.64 mL, 6.05 mmol) was heated at 160° C. for 18 h. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—70:30, to give the title compound. MS: m/z=287 (M+1).
Reaction SMILES: [CH:1]1([C:5]([OH:7])=O)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[C:43](=[O:50])[N:44]([CH3:49])[CH:45]=[C:46]([Br:48])[CH:47]=1>C(Cl)Cl>[Br:48][C:46]1[CH:47]=[C:42]([NH:41][C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[O:7])[C:43](=[O:50])[N:44]([CH3:49])[CH:45]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: O=C(O)C1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(Br)cc(NC(=O)C2CCC2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.8 %

Procedure:
To a mixture or cyclobutanecarboxylic acid (200 mg, 2.0 mmol), HATU (1.14 g, 3.0 mmol) and DIPEA (516 mg, 4.0 mmol) in DCM (8 mL) was added 3-amino-5-bromo-1-methylpyridin-2(1H)-one (330 mg, 1.62 mmol). The reaction mixture was stirred at 25° C. for 5 hours. The resulting mixture was evaporated under reduced pressure and the residue was purified on a silica-gel column eluting with 20:1 DCM/methanol to afford 101a (230 mg, 54%). MS-ESI: [M+H]+ 285.1
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[C:21]([NH:28][CH2:29][C:30]#[CH:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[C:24]([O:23][C:21](=[O:22])[NH:28][CH2:29][C:30]#[C:31][C:13]1[CH:12]=[N:11][C:7]2[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]3[C:2]([Cl:1])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])[C:6]=2[CH:14]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Clc1cccc(Cl)c1CN1CCNc2ncc(I)cc21
Product: CC(C)(C)OC(=O)NCC#Cc1cnc2c(c1)N(Cc1c(Cl)cccc1Cl)CCN2

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (1.951 g) was coupled with N-boc propargylamine as in General Procedure 5 to give the title compound as an orange solid. LCMS: m/z=447.53 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.40 (9H, s), 2.86 (2H, m), 3.27 (2H, m), 3.95 (2H, d, J=5.6 Hz), 4.46 (2H, s), 6.86 (1H, s), 6.89 (1H, s), 7.29 (1H, m), 7.42 (2H, m), 7.54 (2H, d, J=8.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1ccc(N)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1N
Yield: 74 %

Procedure:
A mixture of 2-amino-5-methyl benzoic acid (10 g) in methanol (50 ml) containing conc. sulfuric acid (5.5 ml) was heated for 19 hours under reflux. The solvent was distilled off, and the residue was dissolved in water. The solution was neutralized with an aqueous sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was dried and concentrated to afford a pale brown oil (8.1 g, 74%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:30])[N:12]([CH3:29])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][S:32]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:30])[N:12]([CH3:29])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1)(=[O:34])=[O:33]
Reactant: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a solution of 3-hydroxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (428.2 mg, 1.01 mmol) (obtained as described in Reference Example 58(4)) in methylene chloride (21.4 ml) were added methanesulfonyl chloride (0.25 ml, 3.23 mmol) and triethylamine (0.45 ml, 3.23 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (15:1) as the eluant to afford 3-methanesulfonyloxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (480.1 mg, yield 93%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH2:14][OH:15])[C:12]([CH3:17])([CH3:16])[CH2:11][CH:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][C:3]=1[CH3:26]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH:14]=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][CH:10]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21])[CH:9]=2)=[CH:4][C:3]=1[CH3:26]
Reactant: Cc1cc(C2=CC(O[Si](C)(C)C(C)(C)C)CC(C)(C)C2CO)ccc1F
Solvent: CS(C)=O
Product: Cc1cc(C2=CC(O[Si](C)(C)C(C)(C)C)CC(C)(C)C2C=O)ccc1F
Yield: 49.9 %

Procedure:
In a manner similiar to Scheme I, 16 (43.5 g, 0.115 mol) was treated with sulfur trioxide pyridine complex (56.0 g, 0.345 mol) in anhydrous DMSO and workup provided 21.6 g of brown oil which was taken forward without additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=1[C:29]([F:32])([F:31])[F:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=4[C:4]=3[CH:3]=2)=[CH:23][C:22]=1[C:29]([F:30])([F:31])[F:32]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1cc(CCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.7 %

Procedure:
A mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (222 mg, 0.856 mmol), 1-chloro-4-(chloromethyl)-2-(trifluoromethyl)benzene (240 mg, 1.048 mmol), and cesium carbonate (165 mg, 0.856 mmol) in DMF (5 mL) was stirred at room temperature. After 3 days, more cesium carbonate (165 mg, 0.856 mmol) was added. After stirring for an additional 2 d, the mixture was extracted with water and CH2Cl2. The organics were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (258 mg). LCMS m/z=452.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.2 Hz, 3H), 2.06-2.14 (m, 1H), 2.47-2.54 (m, 1H), 2.71-2.86 (m, 4H), 3.51-3.57 (m, 1H), 4.17-4.25 (m, 2H), 5.10 (s, 2H), 6.82 (dd, J=8.8, 2.5, 1H), 6.96 (d, J=2.5 Hz, 1H), 7.21 (dd, J=8.8, 0.32 Hz, 1H), 7.49-7.52 (m, 1H), 7.58 (dd, J=8.2, 2.6 Hz, 1H), 7.80 (d, J=1.92 Hz, 1H), 8.48 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH:15]=O)[CH:7]=[N:6]2.CO.ClCCCl.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[BH4-].[Na+]>>[CH:23]1([NH:29][CH2:15][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCCC1
Reactant: COc1cc2ncc(C=O)nc2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COc1cc2ncc(CNC3CCCCC3)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.067 M solution of 6,7-dimethoxy-2-quinoxaline carboxaldehyde in 2:1 MeOH/1,2-dichloroethane (7.5 mL, 0.5 mmol) is added cyclohexylamine (0.11 mL, 0.9 mmol). The reaction is allowed to stir at room temperature overnight, then NaBH4 (0.038 g, 1 mmol) is added and the reaction mixture is stirred overnight. The mixture is then concentrated and chromatographed (50% EtOAc/hexanes-approximately 5% MeOH in 50% EtOAc/hexanes). The oil is dissolved in EtOAc/hexanes and treated with HCl in EtOH. The resulting solution is concentrated and the solids are triturated with isopropanol to provide a white solid after drying in vacuo at 60° C. (m.p. 185-190° C., dec.). Anal. Calcd. for C17H23N3O2 • HCl: C, 60.44; H, 7.16; N, 12.44; Found: C, 60.48; H, 6.88; N, 12.07.