Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[CH3:8][C:9]1[C:16]([CH3:17])=[C:15]([OH:18])[C:14]([CH3:19])=[CH:13][C:10]=1[CH:11]=[O:12].[Cl-].[NH4+]>C(OCC)C>[OH:18][C:15]1[C:14]([CH3:19])=[CH:13][C:10]([CH:11]([CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[OH:12])=[C:9]([CH3:8])[C:16]=1[CH3:17]
Reactant: Cc1cc(C=O)c(C)c(C)c1O
Reactant: C[Si](C)(C)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cc(C(O)C[Si](C)(C)C)c(C)c(C)c1O
Temperature: 0 °C

Procedure:
Mix magnesium turnings (240 mg, 10 mmol) and anhydrous ethyl ether under an inert atmosphere. Add a solution of chloromethyltrimethylsilane (1.9 g, 10 mmol) in anhydrous ethyl ether. Stir until the magnesium metal dissolves. Add a solution of 2,3,5-trimethyl-4-hydroxybenzaldehyde (1.7 g, 10 mmol) in anhydrous ethyl ether. Stir until reaction is complete. Cool the reaction mixture to 0° C. and add saturated ammonium chloride solution. Separate the ether layer, wash with water and dry (MgSO4). Evaporate to give 4-hydroxy-2,3,5-trimethyl-α-[(trimethylsilyl)methyl]benzenemethanol and purify by silica gel chromatrography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:34])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc(Br)cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of the compound (1.16 g) obtained in step 1 in DMF (22 mL) was added sodium hydride (60% in oil, 175 mg) at 0° C., and the mixture was stirred for 10 min. Then, methyl iodide (681 μL) was added, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→90% ethyl acetate/hexane) to give tert-butyl (3R,4R)-4-{[(4-bromophenyl)carbonyl](methyl)amino}-3-(3,4-dichlorophenyl)piperidine-1-carboxylate (1.09 g, 92%) as a white powder.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.[I:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br>C1COCC1>[CH3:1][S:2]([CH2:5][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([I:11])[CH:13]=1)(=[O:4])=[O:3]
Reactant: BrCc1cccc(I)c1
Reactant: CS(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)CCc1cccc(I)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl sulfone (1 eq.) in 60 mL of anhydrous THF (0.2 M) was added, at −78° C., n-butyl lithium (1.6 M hexane solution, 1.2 eq.) over a period of 10 min. The resulting mixture was stirred at −78° C. for 1 h. To the now yellow solution was added, at −78° C., 3-iodobenzyl bromide (I eq.). The reaction mixture was then slowly warmed to RT over 16 h. The reaction was carefully quenched with 10% aq. HCl and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a viscous oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) followed by trituration with hexanes afforded the title compound as a white crystalline solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[C:9](=[O:17])[CH2:10][CH2:11][CH2:12][C:13]=3[NH:14]2)=[CH:6][CH:5]=1.[CH3:18]I>CN(C=O)C>[Br:3][C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[C:9](=[O:17])[CH2:10][CH2:11][CH2:12][C:13]=3[N:14]2[CH3:18])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2[nH]c3cc(Br)ccc3c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)cc31)C(=O)CCC2
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.342 g, 8.55 mmol) was added to a solution of 7-bromo-2,3-dihydro-1H-carbazol-4(9H)-one (2.46 g, 9.35 mmol) in DMF (33 mL) at room temperature under N2 and stirred for 15 min. Methyl iodide (1.99 mL, 14.0 mmol) was added to the solution, and the resulting solution was stirred for 2 h at ambient temperature. The mixture was quenched with H2O (80 mL), upon which a solid precipitated out of solution. The solids were collected by filtration and were washed thoroughly with water followed by hexanes to provide the title compound (2.43 g, 94%) as a tan solid: 1H NMR (500 MHz, DMSO-d6) δ 7.90 (d, J=8.5 Hz, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.32 (dd, J=8.5, 1.5 Hz, 1H), 3.71 (s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.15-2.10 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12]>>[F:9][C:10]([F:17])([F:16])[C:11]([NH:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCc1cccs1
Product: O=C(NCCc1cccs1)C(F)(F)F
Yield: 86 %

Procedure:
In close analogy to the procedure described above, 2-Thiophen-2-yl-ethylamine is reacted with ethyl trifluoracetate to provide the. title compound.
Reaction SMILES: O.[OH-].[Ba+2:3].[OH-].[P:5](=[O:9])([OH:8])([OH:7])[OH:6].[OH-].[Ba+2].[OH-]>O>[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Ba+2:3].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Ba+2:3].[Ba+2:3]
Reactant: O=P(O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 1 h

Procedure:
Barium phosphate was prepared by the following procedure. Barium hydroxide monohydrate (5.0 g, 26.4 mmoles) was dissolved in 3000 ml of distilled water and allowed to stir for one hour. Phosphoric acid (2.0 g of 85%w phosphoric, containing 17.6 mmoles of the acid) was diluted with 100 ml of distilled water and added dropwise to the barium hydroxide solution over an eight minute period. A milky white suspension formed and remained as the suspension was stirred for four hours. The suspension was filtered through a Buchner funnel to recover solid which was washed with 1200 ml of distilled water and filtered to dryness. The solid was placed in a vacuum oven at 120° C. and 20mm of mercury for several hours to effect more complete dryness. The white solid was analyzed by X-ray powder diffraction and found to contain Ba3 (PO4)2 as the only crystalline product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:41]([N:44]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1)[CH2:45][CH2:46][CH3:47])[CH2:42][CH3:43]>C(Cl)(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][N:44]([CH2:45][CH2:46][CH3:47])[CH2:41][CH2:42][CH3:43])=[CH:50][CH:51]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCCN(CCC)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
In chloroform (20 ml) and DMF (8.0 ml), 4-(t-butoxycarbonylaminomethyl)benzoic acid (1.95 g) was dissolved. Then, the solution was added with WSCI hydrochloride (1.50 g) and HOBt (1.08 g), followed by stirring at room temperature at 1 hour. The reaction solution was added with the compound (1.23 g) obtained in Example 19-2 and chloroform (10 ml), followed by stirring at room temperature for 15 hours. The solvent was distilled off and the residue obtained was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (2.86 g) as a yellow oily substance.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].C[O-].[Na+].C(O)(=O)C>CO>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3=[CH:1][CH:2]=[C:3]([OH:4])[C:5]4[O:9][C@H:8]5[C:10]([CH2:12][CH2:13][C@@H:14]2[C@:7]5([C:6]=43)[CH2:21][CH2:20]1)=[O:11]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 7 °C

Procedure:
A 100 mL Schlenk tube was charged with methanol (50 mL), morphine free base (5.0 g, 17.52 mmol) and sodium methoxide (47.4 mg, 0.876 mmol). The mixture was stirred and heated to reflux under nitrogen for 15 min then treated with the solution of the catalyst added by a pipette. The resulting brown solution was stirred and heated to reflux under nitrogen for 1 hour, cooled to 7° C. in an ice bath, treated with acetic acid (0.05 mL, 0.876 mmol), stirred for another 30 min and filtered. The filtered solid was washed with isopropanol (3×8 mL) and dried in an oven at 95° C. to give hydromorphone free base as a white solid. The yield was 4.12 g, 82.4%.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[CH2:15]([S:19]Cl)[CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1>[CH3:1][N:2]([S:19][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4]
Reactant: CNC(=O)Nc1cc(C(C)(C)C)on1
Reactant: CCCCSCl
Solvent: c1ccncc1
Product: CCCCSN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 8 h
Yield: 10.9 %

Procedure:
To a solution of 1-methyl-3-(5-t-butyl-3-isoxazolyl)urea (1.97 g) in pyridine (30 ml), butylsulfenyl chloride (1.08 mol equivalent) is added at -30° to -40° C. The resultant mixture is allowed to stand at -30° to -40° C. for 6 hours and at room temperature overnight. The reaction mixture is chromatographed on a column of silica gel, whereby 1-methyl-1-butylthio-3-(5-t-butyl-3-isoxazolyl)urea (0.31 g) is obtained as an oil. I.R.: 1698, 1606 cm-1 (CCl4).
Reaction SMILES: [OH-].[Na+].[C:3]1([N:9]2[C:17]3[N:16]=[CH:15][NH:14][C:13]=3[C:12](=[O:18])[NH:11][C:10]2=[O:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.CO>[CH2:20]([N:14]1[C:13]2[C:12](=[O:18])[NH:11][C:10](=[O:19])[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:17]=2[N:16]=[CH:15]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)c2nc[nH]c12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]c(=O)n(-c2ccccc2)c2ncn(Cc3ccccc3)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 0.53 g (13.2 mmol) of sodium hydroxide in 5.3 ml of water was added to a suspension of 3.0 g (13.2 mmol) of 3-phenylxanthine in 18 ml of methanol and the mixture was stirred at 70° C. for 1 hour. It was then treated dropwise with 1.56 ml (13.2 mmol) of benzyl bromide and stirred at 70° C. for 7 hours, the precipitate was filtered off with suction after cooling, washed with water and dissolved in 50 ml of 1 N sodium hydroxide solution, insoluble matter was filtered off and the solution was adjusted to pH 8-9 using 4 N hydrochloric acid. The resulting precipitate was filtered off with suction, washed with water and purified by flash chromatography on a silica gel column, dichloromethane/methanol (79/1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:17]([CH2:18]O)=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:20][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:34])=O>ClCCl>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:17]([CH2:18][Cl:34])=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:20][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](Cn1ncc2ccc(OCC(=O)OC(C)(C)C)c(CO)c21)O[Si](C)(C)C(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C[C@H](Cn1ncc2ccc(OCC(=O)OC(C)(C)C)c(CCl)c21)O[Si](C)(C)C(C)(C)C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a stirred solution of the product from Step A (2.78 g, 6.18 mmol) in anhydrous dichloromethane (100 mL) was added thionyl chloride (0.68 g, 9.27 mmol). After 1.5 h more thionyl chloride was added (0.23 mL) and stirring was continued for 20 min. Evaporation of this mixture under high vacuum gave an oil (2.90 g) which was used in next reaction without further purification.
Reaction SMILES: [BrH:1].[C:2]([C:5]1[S:6][C:7]2[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1)(=[NH:4])[NH2:3].BrBr>Br>[C:2]([C:5]1[S:6][C:7]2[C:13](=[O:14])[CH:12]([Br:1])[CH2:11][CH2:10][C:8]=2[N:9]=1)(=[NH:3])[NH2:4]
Reactant: N=C(N)c1nc2c(s1)C(=O)CCC2
Reactant: Br
Agent: BrBr
Product: N=C(N)c1nc2c(s1)C(=O)C(Br)CC2
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
2-Bromo-1,3-cyclohexadione prepared in Example 1, Route 1 (A) was reacted with amidinothiourea in the similar manner to that of Example 1, Route 1(B) to give 2-amidino-4,5-dihydrobenzothiazole-7(6H)-one hydrobromide. The hydrobromide (3.4 g) was dissolved into conc. hydrobromic acid (20 ml), and one equivalent of bromine was added dropwise at a temperature of 85° C. The mixture was stirred at a temperature of 80° C. to 90° C. for 30 minutes, cooled and filtered. The solids were neutralized with sodium carbonate to give the titled compound (3.17 g, 67%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:16][CH:15]3[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:16][CH:15]3[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C2

Procedure:
The product from Example 10A (200 mg) was treated with 10% Pd/C (20 mg) in a 1:1 mixture of methanol:ethanol (5 mL) under a hydrogen atmosphere (1 atm). After filtration to remove the catalyst, the filtrate was concentrated and the residue triturated with diethyl ether to afford the title compound as a violet solid.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[C-:12]#[N:13].[Na+]>CS(C)=O>[CH3:4][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:11])[CH2:2][C:12]#[N:13]
Reactant: [C-]#N
Reactant: CC(C)(CCl)c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(CC#N)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-chloro-2-methyl-2-phenylpropane (150 g, 0.889 mol) and NaCN (54.46 g) in DMSO (250 mL) was heated at 100 ° C for 3 weeks. The resulting solution was concentrated to half the initial volume, H2O (400 mL) was added and it was extracted with Et2O (3x). The combined organic extractes were dried and concentrated to a crude product (115.1 g), which was directly used in the next step as obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[C:4]([NH:13][C:14]([NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])[CH:3]=1.O.[NH2:26][NH2:27]>CCO>[NH2:9][C:8]1[C:7]2[C:6]([CH2:10][O:11][CH3:12])=[N:5][C:4]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:3][C:2]=2[NH:27][N:26]=1
Reactant: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12

Procedure:
A solution of (R)-1-(4-chloro-5-cyano-6-(methoxymethyl)pyridin-2-yl)-3-(1-phenylethyl)urea (151.4 mg, 0.439 mmol) and hydrazine hydrate (75 μl, 1.546 mmol) in EtOH (4 ml) was heated to 100° C. in a sealed vial for 18 hr. The mixture was concentrated in vacuo and purified via flash chromatography (0-20% MeOH/EtOAc) to provide (R)-1-(3-amino-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd for C17H21N6O2 [M+H]+ 341. found 341. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.97 (s, 1H), 7.33 (m, 4H), 7.22 (m, 1H), 7.14 (s, 1H), 5.35 (s, 2H), 4.85 (t, J=7.1, 1H), 4.65 (m, 2H), 3.31 (s, 3H, overlaps with H2O peak), 3.15 (d, J=5.1 Hz, 1H), 1.39 (d, J=7.1 Hz, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13]([N:16]([C:18]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[C:25]([O:32][S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2)[CH3:17])(=[O:15])=[O:14])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13]([N:16]([C:18]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[C:25]([O:32][S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:34])=[O:35])=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2)[CH3:17])(=[O:15])=[O:14]
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCNC(=O)OC(C)(C)C)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCN)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 5-(4-(tert-butoxycarbonylamino)-N-methylbutylsulfonamido)-8-(tosyloxy)-1,6-naphthyridine-7-carboxylate (Example 3.1; 5.52 mmol) in dichloro methane (5 mL) was added trifluoro acetic acid (5 mL) at 0° C. After addition the reaction was warmed to room temperature. The solvent was evaporated and the residue was co-evaporated with toluene (3×). The resulting residue was dried under vacuum and used in the next step (Example 3.3) without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:21].F[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][C:24]=1[F:34].C([O-])([O-])=O.[Na+].[Na+].O>CS(C)=O>[CH2:19]([C:16]1[CH:15]=[N:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:34])[C:3]3=[O:21])[CH2:8][CH2:9]2)=[N:18][CH:17]=1)[CH3:20]
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CCc1cnc(N2CCC(N3CC[C@H](N)C3=O)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(=O)(=O)CC)cc4F)C3=O)CC2)nc1
Yield: 31.4 %

Procedure:
A solution of ((S)-3-amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (100 mg, 0.35 mmol), 1,2-difluoro-4-(ethylsulfonyl)benzene (0.2 g, 1.0 mmol), and Na2CO3 (110 mg, 1.0 mmol) in DMSO (2 mL) was stirred at 130° C. for 18 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified over silica gel (10% methanol in EtOAc) to yield (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(4-(ethylsulfonyl)-2-fluorophenylamino)pyrrolidin-2-one (50 mg, 0.11 mmol, 30%). Mass spectrum (apci) m/z=476.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2[CH:31]=[CH:32][CH:33]=[N:34]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:34][CH:33]3[CH2:31][CH2:32]3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NC1CC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), cyclopropylamine (15 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C14H18ClN5O2, 324.12. found 324.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:13]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carbothioamide (2.06 g), ethyl 2-butynoate (0.95 mL), tributylphosphine (1.35 mL), tetrahydrofuran (50 mL) and toluene (100 mL) was stirred at 50° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 85/15, volume ratio) to give the title compound (1.36 g, 51%) as a pale yellow amorphous solid. MS 490 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24])=[O:15])=[CH:6][CH:7]=1
Reactant: NC(CO)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Br)cc1
Product: COc1ccc(C(=O)NC(CO)CO)cc1/C=C/c1ccc(Br)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-43 and 2-amino-1,3-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39](O)=[O:40])[N:34]=1>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][N:35]3[CH:36]=[CH:37][C:33]([C:32]([F:42])([F:31])[F:43])=[N:34]3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: O=C(O)Cn1ccc(C(F)(F)F)n1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(NC(=O)Cn3ccc(C(F)(F)F)n3)ccn2)c2cnccc21

Procedure:
Prepared according to the method described for Method M (Example 206) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 27) and [3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Preparation 74). The residue was purified using alumina eluting with 2% MeOH in DCM to afford the title compound.