Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@:10]1([OH:29])[C:22]2[CH:21]=[C:20]3[N:16]([CH2:17][CH2:18][C:19]43OCC[O:23]4)[C:15](=[O:27])[C:14]=2[CH2:13][O:12][C:11]1=[O:28])[CH3:9]>C(OCC)(=O)C>[CH2:8]([C@:10]1([OH:29])[C:22]2[CH:21]=[C:20]3[N:16]([CH2:17][CH2:18][C:19]3=[O:23])[C:15](=[O:27])[C:14]=2[CH2:13][O:12][C:11]1=[O:28])[CH3:9]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC12OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To 90 ml of 90% trifluoroacetic acid, 3.5 g of (4S)-4-ethyl-6,6-(ethylenedioxy)-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,10(4H)-dione were added at room temperature over 5 minutes, followed by stirring at the same temperature for 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, followed by the thorough removal of the solvent by a vacuum pump. To the residue so obtained was added 20 ml of ethyl acetate. The crystals precipitated were collected by filtration, whereby 2.4 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:11](=[N:13][S:14]([CH2:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH3:12].C[Mg]Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:11]([NH:13][S:14]([CH2:16][CH:17]([CH3:18])[CH3:19])=[O:15])[CH3:12]
Reactant: CC(=NS(=O)CC(C)C)C(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: C[Mg]Br
Solvent: ClCCl
Product: CC(C)CS(=O)NC(C)C(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 6 h

Procedure:
To a solution of N-[3-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-1-methylpropylidene]-2-methylpropanesulfinamide (Step D, 0.51 g, 1.3 mmol) in 6 mL CH2Cl2 at −60° C. was added methylmagnesium bromide (3 M in ether, 0.90 mL, 2.7 mmol). After stirring at −60° C. for 6 h, the reaction was allowed to warm to room temperature overnight. The resulting mixture was partitioned between saturated aqueous ammonium chloride (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 30 to 50% EtOAc in hexane to give the title compound as one pure faster elating enantiomer and a 1:1 mixture of slower co-eluting diastereomers. The addition of the methyl Grignard reagent was apparently stereoselective for one of the sulfinamide diastereomers. Faster eluting isomer: 1H NMR (500 MHz, CD3OD): δ 7.30 (d, 1H), 7.22 (d, 2H), 7.12 (d, 2H), 7.03 (dd, 1H), 6.94 (d, 1H), 3.62 (m, 1H), 3.56 (dd, 1H), 2.97 (dd, 1H), 1.23 (s, 9H), 1.04 (d, 3H). LC-MS: m/e 432 (M+H)+ (4.2 min). Slower eluting isomers (1:1): 1H NMR (500 MHz, CD3OD): δ 7.33/7.30 (d, 1H), 7.21/7.18 (d, 2H), 7.06/7.04 (d, 2H), 6.99/6.97 (dd, 1H), 6.79/6.75 (d, 1H), 3.70-3.55 (m, 1H), 3.07/2.97 (m, 1H), 2.90/2.80 (dd, 1H), 1.32/0.95 (s, 9H), 1.49/1.10 (d, 3H).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1>[OH:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:2]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:1]
Reactant: C1COCCN1
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)CO1
Solvent: C1COCCO1
Product: O=C(N[C@@H](CO)CC(=O)N1CCOCC1)OCc1ccccc1
Yield: 32.4 %

Procedure:
A solution of EXAMPLE 21B (13.5 g, 57.4 mmol) and morpholine (10.0 mL, 115 mmol) in dioxane (100 mL) was stirred at 70° C. for 18 hours. The solution was concentrated and purified by silica gel chromatography eluting with 10% methanol/ethyl acetate to provide the desired product 6.0 g, 86%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].[NH2:28][CH2:29][C@H:30]1[CH2:34][CH2:33][C:32](=[O:35])[N:31]1[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:28][CH2:29][C@H:30]2[CH2:34][CH2:33][C:32](=[O:35])[N:31]2[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)CC[C@@H]1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1C(=O)CC[C@@H]1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (110 mg, 0.30 mmol), (R)-tert-butyl 3-(2-(aminomethyl)-5-oxopyrrolidin-1-yl)propylcarbamate (125 mg, 0.46 mmol), HOBT (107 mg, 0.46 mmol), and HBTU (174 mg, 0.46 mg) in RB flask was added DMF and the mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete and the mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (R)-tert-butyl 3-(2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)-5-oxopyrrolidin-1-yl)propylcarbamate (72 mg, 39%). LRMS (M+H+) m/z 615.2.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C=O)C.CCOC(C)=O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:3][C@@H:4]2[CH2:5][CH2:6][C@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 4.39 g, 109.7 mmol) was added in portions over 1 min to a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (18 g, 104.5 mmol) and 1-fluoro-4-nitrobenzene (11.1 mL, 109.7 mmol) in DMF (200 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 5 mins and then warmed to ambient temperature and stirred for 2 h. Water (750 mL) and EtOAc (300 mL) were then added and the layers were separated. The aqueous layer was extracted with EtOAc (2×300 mL) and the combined organic layers were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to leave a residue. The crude residue was purified by column chromatography, using a gradient of 10-40% EtOAc in isohexane as eluent, to give the title compound as a yellow oil (6.95 g, 23.7 mmol, 23%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].B#B>O1CCCC1>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14]
Reactant: COc1ccc(CC#N)c(C)c1OC
Agent: B#B
Solvent: C1CCOC1
Product: COc1ccc(CCN)c(C)c1OC
Reaction time: 8 h

Procedure:
A mixture of 42 g (0.219 m) of the phenylacetonitrile 100 ml of tetrahydrofuran was mixed with 400 ml of 1 molar diborane in tetrahydrofuran then heated at reflux for 21/2 hours. After cooling the mixture was quenched with 150 ml of methanol. After sitting overnight, the mixture was stripped. An excess of 10% hydrochloric acid was added followed by heating on the steambath for 2 hours. After cooling, ether was added. The mixture was stirred for 1/2 hour and evaporated. The remaining aqueous layer was made basic with 10% sodium hydroxide, extracted with ether which was dried and evaporated to give 2-methyl-3,4-dimethoxyphenethylamine.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Cl)=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([OH:25])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[C:11]([CH2:12][O:25][C:23]2[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=2[CH3:26])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1O
Reactant: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CCl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of 7-bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 7, 801 mg, 2.52 mmol), 5-fluoro-2-methylphenol (330 μL, 3.02 mmol), and potassium carbonate (524 mg, 3.79 mmol) was suspended in anhydrous N,N-dimethylformamide (10 mL) and stirred at 80° C. overnight. After cooling down, ethyl acetate (80 mL) and water (50 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (945 mg) as a colorless solid. (Yield 92%)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[OH:22][C:23]1([CH3:31])[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:23]([OH:22])([CH3:31])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(O)CN[C@H](C(N)=O)C1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: CC1(O)C[C@@H](C(N)=O)N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1
Yield: 76.1 %

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with (2S)-4-hydroxy-4-methylpyrrolidine-2-carboxamide hydrochloride (Example 132 b, 15.3 mg, 84.4 μmol) to obtain the title compound (22 mg, 76%) as off-white solid; MS (EI): m/e=411.5 [MH+].
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])=S.[N:17]#[C:18][NH2:19].[Pb]>>[C:18]([NH:19][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])#[N:17]
Reactant: CNC(=S)NCCCSCc1[nH]cnc1C
Reactant: N#CN
Agent: [Pb]
Product: CNC(=NCCCSCc1[nH]cnc1C)NC#N
Yield: 15 %

Procedure:
The reaction of N-methyl-N'-[3-((4-methyl-5-imidazolyl)methylthio)propyl]thiourea (5.9 g.) with lead cyanamide (17.5 g.) by a procedure similar to that described in Example 3(b) afforded N-cyano-N'-methyl-N"-[3-((4-methyl-5-imidazolyl)methylthio)propyl]guanidine (0.91 g.), m.p. 156°-158°, following chromotography on silica gel with successive elution by chloroformethyl acetate (1:1), ethyl acetate and ethyl acetate isopropyl alcohol (5:1) and final recrystallisation from isopropyl alcohol-ether. (Found: C, 49.5; H, 7.0; S, 12.0. C11H18N6S requires: C, 49.6; H, 6.8; S, 12.0).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 127 mg of 4-methanesulfonyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.06 (s, 3H), 7.31 (d, 1H, J=2.0 Hz), 7.45 (m, 2H), 7.58 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.99 (b, 4H), 8.88 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.29 (b, 1H). MS: m/z 451.9 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][C:36]([C:42]#[N:43])=[CH:37][CH:38]=4)[CH:33]=3)[S:22]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:45][C:46]([O:48][CH3:49])=[O:47].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][C:36]([C:42]#[N:43])=[CH:37][CH:38]=4)[CH:33]=3)[S:22]([N:25]([C:26]([O:27][CH2:28][CH3:29])=[O:30])[CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:23])=[O:24])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CBr
Reactant: CCOC(=O)NS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(CC(=O)OC)S(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.1 %

Procedure:
Ethyl N-[N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]carbamate (1 g) was dissolved in 10 ml of dimethylformamide, 376 mg of methyl bromoacetate and 339 mg of potassium carbonate were added to the solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was evaporated, water was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (8:2) as the eluent to give 1.097 g of methyl N-[N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]-N-ethoxycarbonylglycinate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[OH:17])=O)=[CH:4][CH:3]=1.Cl.[NH2:19]O.C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[O:17][N:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2c(-c3ccc(Br)cc3)noc2c1
Temperature: 85 °C
Yield: 95.1 %

Procedure:
A mixture of 4.25 g of (4-bromo-phenyl)-(2,4-dihydroxyphenyl)-methanone, 3.22 g of hydroxylamine.hydrochloride and 2.85 g of sodium acetate in 100 ml of ethanol is heated under reflux. The reaction mixture is concentrated, treated with 100 ml of saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic extracts are washed with saturated sodium chloride solution, dried and evaporated. The residue is treated with 200 ml of ethanol. After the addition of 1.1 g of p-toluenesulphonic acid the mixture is heated to 85° C. for 24 hrs. For the working-up, the reaction mixture is concentrated and the residue is taken up in 250 ml of ethyl acetate and washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution. The organic phase is dried and evaporated. There are obtained 4.0 g of 3-(4-bromo-phenyl)-benzo[d]isoxazol-6-ol, MS: m/e 289 (M+H+, 1 Br).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][C:11]#[N:12].[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=34)[N:22]=2)[CH2:15]1>C(O)C>[C:11]([CH2:10][C:9]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=34)[N:22]=2)[CH2:15]1)=[O:8])#[N:12]
Reactant: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: CCO
Product: N#CCC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.3 %

Procedure:
3-[(2,5-Dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as described in BE875054(A1), 40 mg, 0.20 mmol) was added to a stirred solution of 3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 7b, 60 mg, 0.16 mmol) in ethanol (1.2 mL) and the mixture was stirred at ambient temperature for 20 hours. The solvent was then removed under reduced pressure and the residue was taken-up in a mixture of dichloromethane and 4% aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried (MgSO4) and the solvent evaporated in vacuo. The crude product was purified by flash chromatography (chloroform to 40:1 chloroform/methanol) to give the title compound (20 mg, 27%) as a solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=O)C.[Li+].[BH4-].O>C1COCC1>[F:17][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][CH:6]2[CH2:4][OH:3])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CCOC(=O)C1CC1c1ccc(OC)c(F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CC2CO)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid-ethyl ester (0.71 g, 2.98 mmol) was dissolved in anhydrous THF (10 mL), LiBH4-2.0M THF solution (3 mL, 5.96 mmol) was added thereto, and the mixture was stirred at 50° C. for 2 hours. After the termination of the reaction, the reactant was cooled to room temperature, added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and then concentrated under reduced pressure to obtain the title compound (0.519 g, 88%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([C:34]([F:37])([F:36])[F:35])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[CH:24]=[C:23]([C:34]([F:36])([F:37])[F:35])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.3 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.41 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.31 g, 63%). MS (ISN) 489.1 [(M−H)−]; mp 182° C.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[O:27]1[CH2:28][CH2:29][N:24]([C:21]([C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[O:23])[CH2:25][CH2:26]1
Reactant: O=C(O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylic acid, the product of Example 54 (40 mg, 0.121 mmol), morpholine (12 μL, 0.133 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (51 mg, 0.133 mmol) were combined in dichloromethane (2 mL). Triethyl amine (52 μL, 0.374 mmol) was added and mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane and washed with a 1 N aqueous sodium hydroxide solution. The organic layer was absorbed on silica gel and the mixture was purified by column chromatography eluting with a gradient of methanol and dichloromethane (2-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.41-1.54 (m, 2 H) 1.59-1.70 (m, 4 H) 1.94-2.12 (m, 1 H) 2.24-2.38 (m, 1 H) 2.39-2.60 (m, 4 H) 2.95-3.11 (m, 1 H) 3.37-3.48 (m, 1 H) 3.49-3.61 (m, 1 H) 3.61-3.80 (m, 9 H) 3.81-3.93 (m, 1 H) 7.33 (dd, J=8.31, 1.87 Hz, 1 H) 7.55 (d, J=8.14 Hz, 1 H) 7.73 (d, J=1.70 Hz, 1 H); MS (ESI+) m/z 401.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([N:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][CH:10]=[CH2:11])=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>CCO>[CH2:12]([N:8]([CH2:9][CH:10]=[CH2:11])[C:7]1[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: C=CCN(CC=C)c1ccc(N)cc1
Yield: 73.9 %

Procedure:
A mixture of 4-nitro-N,N-di(prop-2-en-1-yl)aniline (12.22 g, 55.98 mmol) and tin (II) chloride dihydrate (64.45 g, 279.9 mmol) in EtOH (280 ml) was stirred and heated under reflux for 21 h. The cooled reaction mixture was concentrated under reduced pressure to a volume of 100 ml, and neutralised by the addition of 5 M NaOH. The precipitate was removed by filtration and the filtrate was extracted with EtOAc (4×200 ml). The combined organics were washed with brine (2×200 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a brown oil that was purified by chromatography (1:1 Hexane/EtOAc) to give the title compound (7.79 g, 74%) as a brown oil.
Reaction SMILES: [C:1]([N:4]([CH2:22][CH3:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[N+:19]([O-])=O)(=O)[CH3:2]>C(O)(=O)C.C(O)C.[Fe]>[CH2:12]([O:11][C:7]1[C:6]2[N:19]=[C:1]([CH3:2])[N:4]([CH2:22][CH3:23])[C:5]=2[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(C(C)=O)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCn1c(C)nc2c(OCc3ccccc3)cccc21
Yield: 34.2 %

Procedure:
To a solution of N-acetyl-3-benzyloxy-N-ethyl-2-nitroaniline (1.37 g) in acetic acid (11 ml) and ethanol (2.7 ml) was added iron (2.43 g), and the mixture was refluxed for 4 hours. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue was added saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (hexane—ethyl acetate) to give 4-benzyloxy-1-ethyl-2-methyl-1H-benzimidazole (397 mg).