Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[CH3:14][C:15]([OH:29])([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][CH:23]([C:15]([OH:29])([CH3:14])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:24][CH2:25]2)=[CH:8][CH:9]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CC(O)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(O)(c1ccc(F)cc1)C1CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
A mixture of 2.7 g of 4-chloro-4'-fluorobutyrophenone, 2.5 g of α-methyl-α-(4-piperidyl)-p-fluorobenzyl alcohol, 8 g of sodium carbonate, a crystal of sodium iodide and 30 ml of 4-methyl-2-pentanone is stirred and refluxed for 72 hours. The reaction mixture is worked up in the usual manner as described in the previous Examples. The product is isolated as described above and recrystallized from isopropanol to afford the 4'-fluro-4-[4-(α-hydroxy-α-methyl-p-fluorobenzyl)-piperidino]-butyrophenone, melting at 116°-118°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[C:28]4[CH2:29][CH2:30][CH2:31][CH2:32][C:27]=4[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[C:28]4[CH2:29][CH2:30][CH2:31][CH2:32][C:27]=4[S:26][C:24]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:23]/[S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@@](=O)/N=C/c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
(Ref: Angew. Chem. Int. Ed., 48:914-917 (2009)). To a stirred suspension of 3-chloro-2-fluorobenzaldehyde (1.308 g, 8.25 mmol) and Cs2CO3 (4.03 g, 12.38 mmol) in DCM (10 mL) was added a solution of (R)-2-methylpropane-2-sulfinamide (1 g, 8.25 mmol) in DCM (50 mL) dropwise for 10 min. The solution was then stirred for 2 h at rt. LC/MS indicated that the reaction was complete. The reaction mixture was then diluted with EtOAc (50 mL) and washed with brine (20 mL×3). The organic layers were dried over Na2SO4 and concentrated in vacuo to give (R,E)-N-(3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (2.3 g, 107%) as a clear oil. MS (ESI) m/z: 262.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccccc1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-fluorobenzyloxy)pyridine (1.98 g, 0.0091 mol), 4chlorophenyl isothiocyanate (1.83 g, 0.011 mol) and toluene (10 ml) was refluxed for 3.5 hours, cooled and treated with diethyl ether to induce crystallisation of the product. Yield 1.98 g (56%), m.p. 141°-143
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:18])=[N:6][CH:7]=1.C([BH3-])#N.[Na+].Cl.[CH3:33][C:34]([CH3:36])=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:34]([CH3:36])[CH3:33])=[O:18])=[N:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OCC1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)C(OC(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)C1CCNCC1

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylmethoxycarbonyl)amino]benzamide (100 mg, 0.199 mmol), acetone (0.075 mL), and sodium cyanoborohydride (50 mg, 0.80 mmol) yielded, after treatment with HCl, 25 mg of the title compound as a hydrochloride salt.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:16])[CH:5]([N:11]1[CH2:14][CH2:13][C:12]1=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.ClCCl>[N:17]([CH2:2][CH2:3][CH:4]([OH:16])[CH:5]([N:11]1[CH2:14][CH2:13][C:12]1=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(C(O)CCCl)N1CCC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(C(O)CCN=[N+]=[N-])N1CCC1=O
Yield: 73 %

Procedure:
A solution of ethyl 5-chloro-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate (3.45 g, 13.8 mmol) and sodium azide (1.10 g, 17 mmol) in dry dimethylsulphoxide (20 ml) was stirred between 55° and 65° C. for 5 hours. The reaction mixture was diluted with dichloromethane and the organic layer was washed three times with water before being dried (MgSO4) and evaporated. The residue was chromatographed on silica gel (Merck Art. 9385), eluting with ethyl acetate/hexane (2:1), to give ethyl 5-azido-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate as a pale yellow oil in 73% yield (2.59 g). Bulb to bulb distillation at 0.2 mmHg between 185°-195° C. further purified the product to a colourless oil. νmax (KBr) 3405, 2102 and 1733 cm-1 ; δH (CHCl3, 250 MHz) 1.31 (3H,t,J 7 Hz), 1.81 (1H,m), 1.87 (1H,m), 3.03 (2H,t,J 3 Hz), 3.40 (2H,m), 3.53 (2H,m), 4.00 (1H,d,J 3.5 Hz), 4.25 (3H,m) and 4.53 (1H,d,J 4.5 Hz, exchangeable). (Found: C, 46.93; H, 6.46; N, 21.83%. C10H16N3O4 requires C,46.87; H, 6.29; N, 21.86%).
Reaction SMILES: B(Cl)(Cl)Cl.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.ClC(Cl)(Cl)[C:16]#[N:17].C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[C:16]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[NH:5][CH2:6][CH2:7]2)#[N:17]
Reactant: c1ccc2c(c1)CCN2
Reactant: N#CC(Cl)(Cl)Cl
Agent: C[O-]
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#Cc1cccc2c1NCC2
Temperature: 55 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
22 g of BCl3 (187.8 mmol) in 120 ml of toluene (dried) was dissolved in a 750 ml round flask at -20°. 15.9 g of indoline (133.4 mmol) in 100 ml of toluene was added within 25 minutes and the temperature rose to 10°. This suspension was refluxed for 1 hour, then 110 ml of toluene was distilled off and the reaction mixture was cooled to 55° C. Then 38.4 g of trichloroacetonitrile (266 mmol) was added within 20 minutes and the resulting red solution was stirred for 20 hours at 60° C. After addition of methanol (110 ml) the reaction mixture was mixed within 1.5 hours with 60 g of a 30 percent methanolic sodium methanolate solution. After 1 hour of stirring the methanol was distilled off in a vacuum and then toluene (300 ml) and water (300 ml) were added. The aqueous phase was extracted several times with 200 ml of toluene. The combined toluene extracts were then washed with a 0.12N HCl (91 ml) and with water to remove the not reacted indoline. After concentration by evaporation of toluene 20.12 g of a brownish oil was obtained. The latter was then recrystallized in a hexane/pentanol mixture (80 ml; mixture ratio of hexane: pentanol=9:7) to obtain 11.47 g of a light brownish product with a purity of 99.4 percent corresponding to a yield of 60.5 percent relative to feedstock used. Other data concerning the product was:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH2:36][CH3:37]
Reactant: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CCCOC(=O)Cl
Product: CCCOC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid propyl ester was prepared from 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile using propyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 510.4 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N+:39]([O-:41])=[O:40])=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([N+:39]([O-:41])=[O:40])=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1)=[O:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-ethoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Ethoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: O[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(O)c(OC)n1
Product: COc1cnc(Cl)c(OC)n1

Procedure:
Treatment of the above-obtained 2-hydroxy-3,5-dimethoxypyrazine with phosphorus oxychloride by the method described in Preparation 13, Step B, gives 2-chloro-3,5-dimethoxypyrazine.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][SH:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)C.C(OCC)(=O)C>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][C:17]2[C:22]([C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([S:32]([C:35]([F:38])([F:36])[F:37])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cccnc1Cl
Reactant: SCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cccnc1SCc1ccncc1
Yield: 37 %

Procedure:
4-Pyridinemethanethiol hydrochloride (0.32 g, 2.0 mmol) and potassium carbonate (0.63 g, 4.5 mmol) were added to a solution of 2-chloro-N-(4-trifluoromethylsulfonylphenyl)pyridine-3-carboxamide (0.65 g, 1.8 mmol, Reference compound No. 2-2) in ethanol (10 mL) under a nitrogen atmosphere, then the mixture was stirred at 65° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), then the ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution (100 mL) and brine (100 mL), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the resulting residue was purified by silica gel column chromatography to give 0.29 g of the target compound as a white solid. (Yield 37%)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.O>CO>[OH:20][C:16]1[CH:15]=[C:14]([NH:13][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Nc1cccc(O)c1
Solvent: O
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(Nc2cccc(O)c2)n1
Yield: 97.7 %

Procedure:
A mixture of 188.6 g (1 mole) of 2-chloro-6-methoxy-3-nitropyridine and 262 g (2.4 mole) of m-aminophenol is heated in 500 ml of methanol gradually up to the reflux. After 2 hours of heating time, the mixture is cooled down, 1000 ml of water are stirred in, the crystals formed are filtered off by suction and are thoroughly washed with water. The compound is obtained in the form of orange colored crystals with a melting point of 156°-8° C. and in a yield of 97.7% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[S:32]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)4-trifluoromethyl-benzenesulfonamide was synthesized (84%) from 3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223), 2-chloro-4-trifluromethylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (br s, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.19 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.67 (td, J=7.8, 1.3 Hz, 1H), 7.54 (td, J=7.8, 1.0 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.22 (s, 2H), 4.48 (s, 2H). MS (EI): m/z 543 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=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.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][CH2:55][C@H:54]([NH2:58])[CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>O>[NH2:1][C:2]1[C:3]([C:9]([NH:58][C@H:54]2[CH2:55][CH2:56][CH2:57][N:52]([C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:51])[CH2:53]2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2nc(Br)cnc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
3-amino-6-bromopyrazine-2-carboxylic acid (3.63 g, 16.65 mmol), HATU (9.49 g, 25.0 mg) and DIEA (4.35 mL, 25.0 mmol) was added to a solution of (s)-3-amino-piperidine-1-carboxylic acid tert-butyl ester (4.00 g, 19.97 mmol, commercially available from Astatech or Arch Corporation). It was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and extracted with ethyl acetate (2×150 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by column chromatography to give 1,1-dimethylethyl (3S)-3-{[(3-amino-6-bromopyrazin-2-yl)carbonyl]amino}piperidine-1-carboxylate 5.00 g (75.0% yield): MS (EI) for C15H22BrN5O3: 401.12 (MH+).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[OH:1][CH:2]([CH2:3][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16]
Reactant: C1CCNCC1
Reactant: O=C1NCCc2c(OCC3CO3)cccc21
Solvent: CCO
Product: O=C1NCCc2c(OCC(O)CN3CCCCC3)cccc21
Yield: 66.7 %

Procedure:
A mixture of 3.0 g (13.7 mmol) of 3,4-Dihydro-5-(2-oxiranylmethoxy)-1(2H)-isoquinolinone, 1.4 g of piperidine (13.7 mmol), and 30 ml of ethanol was heated at reflux for five hours. The mixture was concentrated and the residue was recrystallized from ethanol/acetone (2/3) to give 2.78 g (67%) of the desired product; mp 162°-164°.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:14][CH2:13]3)[C:7](=[O:15])[CH:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.[CH3:20]S(C)=O.IC.CC([O-])(C)C.[Na+]>O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14]3)[C:7](=[O:15])[C:6]3([CH3:20])[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CC1
Reactant: CS(C)=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CC1)C2=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A round-bottomed flask equipped with a magnetic stirrer was added 2-chloro-5-cyclopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (121 mg, 0.431 mmol), DMSO (2 ml), and iodomethane (0.032 ml, 0.517 mmol). The mixture was cooled to 0° C. and added sodium 2-methylpropan-2-olate (49.7 mg, 0.517 mmol) and allowed to stir at 20° C. for 16 hours. The reaction solution was suspended in water, and the precipitate filtered. The collected solid was washed successively with small amount of ethanol and diethyl ether. The solid was collected and dried in-vacuo to afford 2-chloro-5-cyclopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.339 mmol, 79% yield) as a tan solid. MS [M+H] found 295.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:57][CH3:58])=[C:10]([CH2:19][NH:20][C:21](=[O:56])[CH2:22][CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]5[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[C@@H:44]([CH3:55])[CH2:43]5)[CH:36]=4)[CH:32]=[CH:33][CH:34]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)[F:62])=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:57][CH3:58])=[C:10]([CH2:19][NH:20][C:21](=[O:56])[CH2:22][CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]5[CH2:47][CH2:46][NH:45][C@@H:44]([CH3:55])[CH2:43]5)[CH:36]=4)[C:32]([F:62])=[CH:33][CH:34]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1cccc(-c2cccc(CN3CCN(C(=O)OC(C)(C)C)[C@@H](C)C3)c2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Process (A) To a mixture of 1,1-dimethylethyl (2S)-4-{[3′-({[5-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-5-oxopentanoyl]amino}methyl)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate in DCM (2 mL) was added TFA (1 mL). It was stirred at room temperature for about 1 hour. The solution was filtered. Initial purification via Gilson using TFA afforded a mixture, which was re-purified by Gilson using a NH4OH buffer to provide the desired product (20 mg). LC-MS m/z 713 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].O[CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1)[N:6]=[C:5]2[I:11]
Reactant: OC1CCOC1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2C1CCOC1
Yield: 56 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 3-hydroxytetrahydrofuran in 56% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.47-2.52 (2H, m), 3.95-4.00 (1H, m), 4.12-4.19 (2H, m), 4.19-4.28 (1H, m), 5.24-5.30 (1H, m), 7.12 (1H, dd, J=2.0, 8.4 Hz), 7.21 (1H, td, J=1.6, 8.8 Hz), 7.45 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccc(Cl)cc2)oc2ccccc12
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 2-(4-chlorophenyl)-3-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [N:1]12[CH2:11][S:10][CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3][N:4](C(OCC)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Ba+2]>O>[N:1]12[CH2:11][S:10][CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3][NH:4][CH2:5]1
Reactant: CCOC(=O)N1CC2CC3CSCN3C2C1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Agent: [K+]
Solvent: O
Product: C1NCC2C1CC1CSCN12

Procedure:
12.5 g (50 mmol) of ethyl 10-thia-1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate are heated under reflux overnight with 32 g of Ba(OH)2.8H2O in 225 ml of water. Potassium carbonate is added to the mixture, barium carbonate is filtered off with suction and the filtrate is extracted ten times using 100 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.