Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:29][CH2:30][CH3:31])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1>C(O)C.[Pd]>[CH2:29]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]2[C:3]([N:4]=1)=[CH:2][N:10]=[CH:9][N:8]=2)[CH2:30][CH3:31]
Reactant: CCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCc1nc2cncnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
6-Chloro-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine (0.030 g) was dissolved in ethanol (2 ml) and was stirred under an atmosphere of hydrogen in presence of Pd-C(10%)(0.01 g) for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness giving the pure desired product as a glass like solid (0.020 g). NMR(CD3OD): 6 1.0 (t, 3H, J=7.4 Hz), 1.8 (m, 2H), 2.88 (t, 2H, J=7.4 Hz), 5.56 (s, 2H), 7.1-7.34 (m, H), 7.45-7.7 (m, 4H), 8.90 (s, 1H), 8.98 (s, 1H). FAB-MS: m/e 397 (M+H). Analysis calculated for C22H20N8 : C, 66.00; H, 5.00; N, 28.00. Found: C, 5.57; H, 5.34; N,27.67.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[CH3:5].C([BH3-])#N.[Na+]>C(O)(=O)C.C(=O)([O-])O.[Na+]>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[CH:4]([NH:3][O:2][CH3:1])[CH3:5]
Reactant: CON=C(C)[C@@H]1C[C@H]1c1c(F)cccc1Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC(C)[C@@H]1C[C@H]1c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a stirred solution of trans 1-[2-(2-chloro-6-fluoro-phenyl)-cyclopropyl]-ethanone O-methyl-oxime (1.1 g; 4.6 mmol) prepared as described in example P21, in acetic acid (10 ml) at ambient temperature was added portionwise sodium cyanoborohydride (0.60 g; 9.3 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in sodium hydrogen carbonate saturated solution (50 ml) and extracted with dichloromethane (3×50 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 1:99) to afford 0.85 g (75% of theory) of trans N-{1-[2-(2-chloro-6-fluoro-phenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine as a mixture of diastereomeres in form of a clear viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH2:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:21][CH3:22])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(NC(=O)OC(C)(C)C)c1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)c1cc(Br)cn(C)c1=O
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of the title compound from Example 110, step 1 (150.0 mg, crude) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mmol, 60% in oil) in portions at 0° C. and stirred for 30 min. Then iodoethane (234.0 mg, 1.5 mmol) was added dropwise at 0° C. The reaction mixture was stirred for 2 h at 30° C. It was then quenched with saturated aqueous NH4Cl (15 mL), extracted with ethyl acetate (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the title compound (120.0 mg, crude) as a light green solid which was carried forward without purification.
Reaction SMILES: C(O[CH:4]([CH:26]([C:32](OCC)=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:12]=1)[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])C.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:6]([C:5]1[CH:4]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32](=[O:33])[N:12]2[C:11]=1[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]1[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=1[CH3:23])(=[O:10])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(=O)C(c1cccc(-c2c(C)cc(C)cc2C)n1)C(OCC)C(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC(=O)c1cc(C(=O)OCC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Temperature: 100 °C
Yield: 37 %

Procedure:
Diethyl [1-ethoxy-2-(6-mesitylpyridin-2-yl)-3-oxohexyl]malonate (0.045 g, 0.10 mmol) was dissolved in acetic acid (3 mL). The reaction was heated at 100° C. for 20 minutes. Acetic acid was stripped off via rotavap. Saturated sodium bicarbonate was added and the solution was extracted with ethyl acetate. The organics were dried, concentrated, and flash chromatographed (20% ethyl acetate/hexanes) to give 0.015 g (37% yield) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24](=O)[CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:37][N:38]([CH2:40][CH2:41][NH:42][C:43]([NH2:45])=[S:44])[CH3:39]>C(O)C>[CH3:37][N:38]([CH3:39])[CH2:40][CH2:41][NH:42][C:43]1[S:44][C:23]2[CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:13][CH:14]=3)=[O:19])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]=2[N:45]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Reactant: CN(C)CCNC(N)=S
Agent: Cl
Solvent: CCO
Product: CN(C)CCNc1nc2c(s1)CCN(C(=O)c1ccc(NC(=O)c3ccccc3-c3ccccc3)cc1)c1ccccc1-2
Yield: 58.8 %

Procedure:
Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro1H-1-benzazepin-1-yl)carbonyl]benzanilide and 300 mg of dimethylaminoethylthiourea hydrochloride and using ethyl alcohol as the reaction solvent, the procedure of Example 5 was repeated and the resulting residue was recrystallized from ethyl acetate-diethyl ether to obtain 300 mg of 4'-[(2-dimethylaminoethylamino-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide.2 HCl.
Reaction SMILES: N1C=CC=CC=1.O=S(Cl)Cl.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O>C1COCC1>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: OCCCCCCCCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCl
Temperature: 60 °C
Reaction time: 24 h
Yield: 0.5 %

Procedure:
1 g (0.0015 mol, equivalent weight=666 gram per mole repeat unit) polymer 5 was placed into a 50 ml Schlenk and dissolved in THF anhydrous (30 ml). The Schlenk was connected to a trap with a NaOH solution (2M) for absorption of HCl and SO2. Then pyridine anhydrous 0.5 ml (0.0062 mol), and SOCl2 0.3 ml (0.0041 mol) were added dropwise at room temperature into the Schlenk. The temperature was slowly increased and maintained at 60° C. for 3 h. Excess of SOCl2 and THF were distilled off under vacuum at 50° C. for 30 minutes, the resulting crude acid chloride polymer. Then freshly distilled THF (30 ml) was added to dissolve the acylated polymer. After 30 minutes needed for complete dissolution of polymer, a solution of excess 8-chloro-1-octanol 1.05 ml (2 mol.eq, 0.0062 mol) was added dropwise to the polymer solution at room temperature under vigorous stirring, and allowed to stir for 24 h. The polymer was recovered by precipitating into distilled water. The product purification was made by dissolution in hot CH2Cl2, precipitation in ethanol and drying at 50° C. in vacuum oven to obtain Polymer 9 as a brown solid (1.39 g, yield 95%) with the following characteristics:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C.CCOC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ClCCCCCCn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a mixture of NaH (0.249 g, 10.0 mmol) in DMF (5.00 mL) was added a solution of 1-H-indole (0.585 g, 5.00 mmol) in DMF (2.00 mL) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and warmed up to room temperature. To the reaction mixture 1-bromo-6-chlorohexane (0.998 g, 5.00 mmol) was added dropwise via syringe and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3×10 mL), brine (10 mL), dried over MgSO4, concentrated in vacuo and purified by chromatography using hexane:EtOAc (97.5:2.5) to give the desired product (0.900 g, 76.0%): 1H NMR (400 MHz, CDCl3) δ 7.76-7.54 (m, 1H), 7.47-6.96 (m, 4H), 6.60-6.34 (m, 1H), 4.13 (t, 2H, J=6.8 Hz), 3.50 (t, 2H, J=5.6 Hz), 1.98-1.79 (m, 2H), 1.79-1.64 (m, 2H) 1.54-1.17 (m, 4H).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9](=[O:26])[C:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])=[N+]=[N-])[NH:6][C:5]1=[O:27])[CH3:3]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:5](=[O:27])[N:6]2[C@@H:7]1[CH2:8][C:9](=[O:26])[CH:10]2[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:14])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Temperature: 78 °C

Procedure:
A suspension of (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one (56.4 mg, 0.15 mmol) and rhodium (II) acetate (0.1 mg) in dry benzene (3 ml) is deoxygenated by bubbling through nitrogen for 10 minutes. The mixture is then heated to 78° C. for 1 hour. During heating the solid starting material gradually goes into solution. The mixture is then cooled, filtered to remove the catalyst, and the filtrate is concentrated in vacuo to yield (5R,6S) p-nitrobenzyl 6-[(R)-1-hydroxyethyl]-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate, 51 mg. (98%) as a colorless oil which slowly crystallized at room temperature (22° C.).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:23]3[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=3[C:25]([OH:27])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:35]1C=CC=CC=1.[OH-].[NH4+]>C(#N)C.O>[C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:23]3[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=3[C:25]([NH2:35])=[O:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N(CCCCN1CC=C(c2ccccc2)CC1)c1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N(CCCCN1CC=C(c2ccccc2)CC1)c1cc([N+](=O)[O-])ccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
A mixture of 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzoic acid (1.53 g), N,N'-disuccinimidoyl carbonate (924 mg) and pyridine (285 mg) in dry acetonitrile (20 ml) was stirred for 3 hours at room temperature. Then, to the mixture was added 28% ammonium hydroxide (1.4 ml) on an ice-bath. After 1 hour, the reaction mixture was diluted with water, and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (30 g). Elution with a mixed solvent of chloroform and methanol (50:1 V/V) gave 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzamide (600 mg) as caramel.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([NH:26][C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:3]4[CH2:4][CH2:5][CH:6]([N:9]5[C:17]6[C:12](=[N:13][CH:14]=[CH:15][CH:16]=6)[NH:11][C:10]5=[O:18])[CH2:7][CH2:8]4)[CH:21]=3)=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(Nc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 150 °C

Procedure:
0.10 g (0.34 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 90 mg (0.31 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.87 mmol) DIPEA in 1.5 mL DMF were combined and stirred at 150° C. After the reaction had ended the reaction mixture was diluted with water. The precipitate formed was suction filtered, taken up in DMF and purified by preparative HPLC. The product-containing fractions were combined, evaporated down and the residue dried.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4]1.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:10][C@@H:5]2[CH2:4]1
Reactant: N#Cc1ccc(F)cc1
Reactant: OC[C@H]1C[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCN3C[C@@H](CO)C[C@H]3C2)cc1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
A mixture of 1.5 g (9.6 mmol) of (7S,8aS)-7-hydroxymethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 13, Step A), 1.75 g (14.4 mmol) of 4-fluorobenzonitrile and 2.04 g (19.2 mmol) of sodium carbonate in 10 mL of DMSO was heated at 80° C. for 16 h. The solution was cooled to room temperature, diluted with water and extracted with 1:1 ethyl acetate:diethyl ether (3×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 9:1 chloroform: methanol gave 0.925 g (37%) of the title compound. 13C NMR (CDCl3): δ 31.1, 37.2, 46.7, 51.0, 51.8, 57.6, 62.3, 67.3, 100.1, 114.3, 120.0, 133.5, 153.4. m/z (MH+) 258.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:38]=[CH:37][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:34]([CH3:36])[CH3:35])[N:28]=[C:29]([CH2:31][O:32][CH3:33])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:38]=[CH:37][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:34]([CH3:35])[CH3:36])[N:28]=[C:29]([CH2:31][O:32][CH3:33])[N:30]=2)[N:19]=4)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCc1nc(-c2cn3c(n2)-c2ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Product: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
To a solution of 4-[2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (224 mg, 0.43 mmol) in IMS (3 mL) was added a catalytic amount of palladium on carbon (10% by wt) and the reaction mixture stirred under an atmosphere of hydrogen at 50° C. for 16 h. The reaction mixture was filtered and the solids washed with IMS (10 mL). The filtrate was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 2% MeOH in DCM) to yield 4-[2-(2-Isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (162 mg, 72%). LCMS: RT=5.05 min, [M+H]+=523
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[CH:3][S:4](Cl)(=[O:6])=[O:5].[C:9]([O:13][C:14]([NH:16][CH2:17][C@H:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.O>ClCCl>[C:9]([O:13][C:14]([NH:16][CH2:17][C@H:18]([N:23]1[CH2:24][CH2:25][N:26]([S:4]([CH2:3][CH:2]([CH3:8])[CH3:1])(=[O:6])=[O:5])[CH2:27][CH2:28]1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCNCC1
Reactant: CC(C)=CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(=O)(=O)CC(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
479 mg (3.0 mmol) of 2-methylpropene-1-sulfonyl chloride are added to a solution of 800 mg (2.8 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate (prepared as described in example 23.1) and 775 μl (5.5 mmol) of triethylamine in 8 ml of dichloromethane, cooled beforehand to 0° C. The reaction medium is stirred at ambient temperature for 18 h and then water is added and the medium is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue obtained Is purified by chromatography on silica gel, elution being carried out with a 5/5 heptane/ethyl acetate mixture. 785 mg (71%) of methyl (S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate are obtained in the form of a colorless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)S([O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])(=O)=O.[Br:25][C:26]1[N:30]2[CH:31]=[CH:32][C:33]([C:36](O)([CH3:38])[CH3:37])=[C:34]([F:35])[C:29]2=[N:28][CH:27]=1>C(Cl)Cl>[Br:25][C:26]1[N:30]2[CH:31]=[CH:32][C:33]([C:36]([O:15][Si:16]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:21][CH3:22])([CH3:38])[CH3:37])=[C:34]([F:35])[C:29]2=[N:28][CH:27]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2c1F
Temperature: 25 °C
Yield: 101.7 %

Procedure:
Hünig's base (0.44 ml, 3.8 mmol) and triethylsilyl trifluoromethane-sulfonate (0.57 ml, 2.6 mmol) were added sequentially to a cold (−78° C.), stirred solution of 2-(3-bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (637 mg, 2.3 mmol) in CH2Cl2 (13 ml) and the solution warmed to ambient temperature. The mixture was partitioned between CH2Cl2 (50 ml) and water (50 ml) and the organic phase dried over anhydrous MgSO4, filtered through a short plug of silica (eluent CH2Cl2) and concentrated to afford 3-bromo-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine (906 mg, quant.): δH (360 MHz, CDCl3) 0.70 (6H, q, J 7.8), 0.99 (9H, t, J 7.8), 1.71 (6H, s), 7.32 (1H, t, J 6.9), 7.59 (1H, s), 7.88 (1H, d, J 7.3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[O:35][N:34]=[CH:33][C:32]=1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:32]4[CH:33]=[N:34][O:35][C:31]=4[CH3:30])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1oncc1C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cnoc2C)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-methylisoxazole-4-carboxylic acid (19 mg, 0.15 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2(O)[C:12]1[C:20]([OH:21])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2[C:12]1[C:20]([OH:21])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: O=C1Nc2c(Br)cccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2c(Br)cccc2C1c1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
To a solution of 7-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (9.50 g, 27.3 mmol) in trifluoroacetic acid (24 mL) at 0° C. was added triethyl silane (6.12 g, 52.8 mmol). The mixture was stirred at ambient temperature for 3 h. The reaction was quenched by the addition of hexanes and diethyl ether mixture (2:1, 300 mL). The precipitate was filtered, washed with hexanes and ether mixture (100 mL). The solid was dried under reduced pressure to afford 7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (8.40 g, 93%) as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.26 (s, 1H), 7.33-7.31 (m, 1H), 6.90-6.78 (m, 2H), 6.68 (s, 1H), 6.38 (s, 1H), 5.91 (d, J=1.0 Hz, 2H), 4.75 (s, 1H); MS (ES+) m/z 347.9 (M+1), 349.9 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(CN3CCNCC3)cc2OCc2ccccc2)cc1

Procedure:
Synthesized according to General Procedure A: 3,4-bis(benzyloxy)benzyl chloride (4{10}, 2 g, 5.90 mmol, 1 equiv.), piperazine (3.05 g, 35.4 mmol, 6 equiv.), THF (28 mL). Purification with flash column chromatography on silica gel (gradient, 4:1 to 1:4 EtOAc:MeOH) afforded 5{10} (2.12 g, 92%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 7.46 (d, 4H, J=7.5 Hz), 7.38-7.34 (m, 4H) 7.32-7.28 (m, 2H), 6.96 (d, 1H, J=2.0 Hz), 6.88 (d, 1H, J=8.0 Hz), 6.80 (dd, 1H, J=2.0, 8.0 Hz), 5.18 (s, 2H), 5.15 (s, 2H), 3.38 (s, 2H), 2.84 (t, 4H, J=5.0 Hz), 2.33 (br s, 4H), 1.74 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 148.5, 147.9, 137.4, 137.3, 131.3, 128.4, 128.3, 127.6, 127.6, 127.3, 127.2, 122.0, 116.1, 114.6, 71.3, 71.1, 63.1, 54.3, 46.0.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]([CH3:13])[N:6]=1)[NH2:4].[CH3:14]OC(OC)OC.FC(F)(F)C(O)=O>CO>[CH3:13][N:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:5]([C:3]2[N:4]=[CH:14][O:1][N:2]=2)=[N:6]1
Reactant: COC(OC)OC
Reactant: Cn1nc(C(N)=NO)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1nc(-c2ncon2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of N′-hydroxy-1-methyl-5-nitro-1H-pyrazole-3-carboximidamide (1.66 g, 8.97 mmol) and trimethoxymethane (17.6 mL, 161 mmol) in MeOH (2.8 mL) was added 2,2,2-trifluoroacetic acid (0.35 mL, 4.48 mmol) and the mixture was refluxed for about 1 h. The reaction was cooled to ambient temperature and continued to stir for about 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM (25 mL) and saturated NaHCO3 (10 mL). The aqueous layer was back extracted with DCM (25 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 3-(1-methyl-5-nitro-1H-pyrazol-3-yl)-1,2,4-oxadiazole (1.75 g, 8.97 mmol, 100%, which was used without further purification). LC-MS (Table 1, Method g) Rt=1.56 min, m/z 196 (M+H)+. 1H-NMR (DMSO-d6, Bruker 400 MHz) 9.79 (s, 1H), 7.72 (s, 1H), 4.27 (s, 3H).