Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:53][O:54][C:55]([C:57]1[S:58][C:59]([C:62](=[O:73])[NH:63][C@@H:64]([C:66]2[CH:71]=[CH:70][C:69](Br)=[CH:68][CH:67]=2)[CH3:65])=[CH:60][CH:61]=1)=[O:56].[NH:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][O:54][C:55]([C:57]1[S:58][C:59]([C:62](=[O:73])[NH:63][C@@H:64]([C:66]2[CH:71]=[CH:70][C:69]([N:74]3[CH2:79][CH2:78][O:77][CH2:76][CH2:75]3)=[CH:68][CH:67]=2)[CH3:65])=[CH:60][CH:61]=1)=[O:56]
Reactant: COC(=O)c1ccc(C(=O)N[C@H](C)c2ccc(Br)cc2)s1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)N[C@H](C)c2ccc(N3CCOCC3)cc2)s1
Temperature: 160 °C
Yield: 7.7 %

Procedure:
To a suspension of 1.0 mg (0.0045 mmol) palladium(II) acetate, 4.06 mg (0.0065 mmol) 2,2′-bis-(diphenylphosphino)-1,1′-binaphtyl (BINAP) and 125 mg (0.384 mmol) cesium carbonate in 1 ml dry toluene, 100 mg (0.272 mmol) (R)-5-[1-(4-Bromo-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester (see example 1, step 1) and 30.0 mg (0.344 mmol) morpholine were added under an argon atmosphere. The mixture was heated in the microwave oven (Emrys Optimizer) at 160° C. for 15 min. After cooling to room temperature, the reaction mixture was filtered and the solid was washed with toluene. The solvent of the combined filtrates was evaporated and the crude product purified by preparative HPLC to yield 7.9 mg (0.021 mmol) (R)-5-[1-(4-Morpholin-4-yl-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: C(OC(N([CH2:13][C:14]([NH:16][C:17]1([C:31](OCC)=[O:32])[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[CH2:18]1)=[O:15])C)=O)C1C=CC=CC=1.[CH2:36](O)[CH3:37]>[Pd].[C]>[CH3:28][O:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:29][CH3:30])[CH2:18][C:17]1([C:31](=[O:32])[CH:36]([CH3:37])[CH2:13][C:14](=[O:15])[NH:16]1)[CH2:26][CH2:25]2
Reactant: CCOC(=O)C1(NC(=O)CN(C)C(=O)OCc2ccccc2)CCc2cc(OC)c(OC)cc2C1
Reactant: CCO
Agent: [Pd]
Product: COc1cc2c(cc1OC)CC1(CC2)NC(=O)CC(C)C1=O
Temperature: 80 °C

Procedure:
A solution of ethyl 2-[(N-benzyloxycarbonyl-N-methylamino)acetylamino]-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalene-2-carboxylate (550 mg, 1.1 mmol) in ethanol (20 ml) was hydrogenated in the presence of 10% Pd-carbon (250 mg) for 6 hr. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in 1N sodium hydroxide (2 ml) and THF (10 ml) and heated at 80° C. for 17 hr. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with water, and sat. sodium chloride, dried, and concentrated in vacuo. The residue was recrystallized from chloroform-isopropylether to give the titled compound (150 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]3[N:14]=[C:13](O)[N:12]([CH3:16])[C:7]=3[CH:8]=[CH:9][C:10]=2[CH:11]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18].O=P(Cl)(Cl)Cl.[OH-].[Na+]>>[Cl:18][C:13]1[N:12]([CH3:16])[C:7]2[CH:8]=[CH:9][C:10]3[CH:11]=[C:2]([Cl:1])[CH:3]=[N:4][C:5]=3[C:6]=2[N:14]=1
Reactant: Cn1c(O)nc2c3ncc(Cl)cc3ccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc2c3ncc(Cl)cc3ccc21
Temperature: 25 °C
Yield: 37 %

Procedure:
7 g (30 mmol) of 7-chloro-2-hydroxy-3-methylimidazo[4,5-h]quinoline are mixed with 7 g (33.6 mmol) of phosphorus pentachloride and 35 ml (0.38 mol) of phosphorus oxytrichloride. The mixture is refluxed for 15 h, then allowed to cool to room temperature and poured into 500 g of ice, the mixture is neutralized with concentrated sodium hydroxide solution, and the precipitate is filtered off with suction. Drying and recrystallization from ethanol result in 2.8 g (37%) of product; melting point 211° to 213° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 95 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After 1.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow solid foam was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 137 mg (94%) of a white solid. MS (ISP) 479.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[CH:4][N:3]=1.CN(C=O)C.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:3]=[CH:4][N:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(Cl)ncnc1NCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of methyl 2-(4,6-dichloropyrimidin-5-yl)acetate (1.00 equiv; 65.10 mmol; 14.39 g) in DMF (0.5 M; 1.68 mol; 130.20 mL), add 4-methoxybenzylamine (1.10 equiv; 71.61 mmol; 9.36 mL) and DIPEA (1.20 equiv; 78.12 mmol; 13.62 mL) and stir the mixture at 60° C. for 1 h. Quench with ice-water, extract with EA, and wash the organic layer with 1N HCl, water and brine, dry over MgSO4, filter and concentrate in vacuo to the title compound (54.98 mmol; 17.69 g; 84.45%) as a yellow solid and use without further purification. 1H NMR (300 MHz, DMSO): 8.20 (s, 1H), 7.21-7.18 (m, 2H), 6.89-6.85 (m, 2H), 4.53 (d, J=5.8 Hz, 2H), 3.76 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:9][CH:10]([CH3:15])[CH2:11][C:12]([OH:14])=O)(=[O:4])=[O:3]>C(OCC)(=O)C>[CH3:15][CH:10]1[CH2:11][C:12](=[O:14])[C:16]2[CH:17]=[C:18]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=2[O:9]1
Reactant: CC(CC(=O)O)Oc1ccc(Oc2ccccc2)c(NS(C)(=O)=O)c1
Solvent: CCOC(C)=O
Product: CC1CC(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2O1
Temperature: 65 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
100 g of polyphosphoric acid was added to 5.69 g of 3-(3-methylsulfonylamino-4-phenoxyphenoxy)-3-methylpropionic acid. The mixture was stirred for 1 hour at 65° C. The reaction mixture was introduced into 400 ml of ice water, and 150 ml of ethyl acetate was added thereto. The organic layer was separated and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 150 ml of 1N aqueous sodium hydroxide solution. The solution was washed with diethyl ether and adjusted to pH 4 with 4N hydrochloric acid. 150 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 25:1 mixture of toluene and ethyl acetate) and recrystallized from ethanol to obtain 2.16 g (yield: 40%) of 2,3-dihydro-2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To an acetic acid (4.1 mL) and dimethyl sulfoxide (70 mL) solution of 1-((E)-2-nitro-vinyl)-4-phenoxymethyl-benzene (4.1 g, 16.2 mmol) described in Manufacturing Example 86-1-3 was added sodium borohydride (981 mg, 25.9 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1 hour at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (2.11 g, 51%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8](OC)=[O:9])=[CH:6][CH:5]=1)[CH3:3].O.[NH2:15][NH2:16].C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>CO>[CH3:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:15][NH2:16])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)C)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(C(=O)NN)cc1
Temperature: 120 °C
Yield: 92.2 %

Procedure:
A mixture of methyl 4-(1-methylethyl)benzoate (10 g) and hydrazine monohydrate (5.62 g) in methanol (50 mL) was heated under reflux overnight. To the reaction mixture was added toluene (50 mL), and the mixture was heated at 120° C. overnight. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane and diisopropyl ether to give the title compound (9.22 g) as a white solid.
Reaction SMILES: O.C[CH2:3][CH2:4][CH:5]1[O:25][C@:24]2([C:26]([CH2:28][OH:29])=[O:27])[C@@H:7]([CH2:8][C@@H:9]3[C@:23]2([CH3:30])[CH2:22][C@H:21]([OH:31])[C@H:20]2[C@H:10]3[CH2:11][CH2:12][C:13]3[C@:19]2([CH3:32])[CH:18]=[CH:17][C:15](=[O:16])[CH:14]=3)[O:6]1>ClCCl>[CH3:3][CH2:4][CH:5]1[O:25][C@:24]2([C:26]([CH2:28][OH:29])=[O:27])[C@@H:7]([CH2:8][C@@H:9]3[C@:23]2([CH3:30])[CH2:22][C@H:21]([OH:31])[C@H:20]2[C@H:10]3[CH2:11][CH2:12][C:13]3[C@:19]2([CH3:32])[CH:18]=[CH:17][C:15](=[O:16])[CH:14]=3)[O:6]1
Reactant: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Solvent: O
Solvent: ClCCl
Product: CCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1

Procedure:
Water (800 mL) was charged to a 1 L stirred crystallizer fitted with a thermo-regulation jacket. The temperature was adjusted to 45° C. Water was pumped around a recirculation loop using a diaphragm pump (operating at 20 L/h) and a 250 ml thermo-regulated glass ultrasonic flow-cell fitted with a 30 mm diameter 20 kHz ultrasonic probe. The probe was held at the highest position in the flow-cell and sealed/clamped at a point of zero vibration (null point). The flow-cell was thermo-regulated at 45° C. Continuous ultrasound was applied at 15 W power, 5 micron amplitude. Budesonide (0.8 g) was dissolved in dichloromethane (80 mL). The solution was dispersed in an aqueous phase held at 45° C. consisting of 800 ml of a 0.2% (w/v) solution of Tween 80. The dichloromethane solution was pumped into the ultrasonic flow-cell using a second inlet on the underside of the flow-cell at a rate of 20 ml/h. The resulting suspension was stirred for 30 minutes at 300 rpm with sonication. Product was collected as aqueous suspension.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:23]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.[Cl:34][C:35]1[C:36]([OH:46])=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1.CCN(CC)CC>C1COCC1>[Cl:34][C:35]1[C:36]([OH:46])=[C:37]([S:42]([N:7]([CH2:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:23]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=2)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(CNCc2ccc(F)cc2)cc(Oc2ccc(F)cc2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a solution of tert-butyl 3-((4-fluorobenzylamino)methyl)-5-(4-fluorophenoxy)benzylcarbamate (0.72 g, 1.58 mmol) in THF (15 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (0.41 g, 1.58 mmol) and Et3N (0.66 mL, 4.75 mmol). The reaction mixture was stirred at rt for 1.5 h. The mixture was concentrated. The sample was purified by flash chromatography. Elution with 0 to 35% of ethyl acetate in dichloromethane gave the product as a white solid (0.65 g, 61%). 1H NMR (CDCl3): δ 9.01 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.45 (s, 1H), 7.15-7.06 (m, 4H), 7.01-6.92 (m, 4H), 6.76 (s, 2H), 6.54 (s, 1H), 4.41 (s, 2H), 4.32 (s, 2H), 4.21 (d, J=5.6 Hz, 2H), 1.49 (s, 9H); MS (ESI): (M−H)−=677.1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C@H:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH2:17].[BH4-].[Na+]>O>[CH2:1]([NH:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N[C@H]1CCCC[C@@H]1NCc1ccccc1
Temperature: 25 °C
Yield: 48 %

Procedure:
Benzaldehyde (3.05 mL, 30.0 mmol) was added to a methanol (300 mL) solution of (1S,2S)-cyclohexane-1,2-diamine (3.43 g, 30.0 mmol) with stirring at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was cooled to 0° C. Sodium borohydride (2.27 g, 60.0 mmol) was added thereto, and the mixture was stirred at 0° C. for 2 hours. To the reaction mixture, water (30 mL) was added, and the product was extracted twice with methylene chloride (50 mL). The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to obtain (1S,2S)-N-benzylcyclohexane-1,2-diamine (cas no. 207450-11-1) (2.95 g, yield: 48%) in a pale yellow oil form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(N)n1
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Nc1cccc(N)n1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a solution of 2,6-diaminopyridine (50.0 g, 0.46 mol) in dioxane (250 mL) was added slowly (1 h) pivaloylchloride (27.9 g, 0.23 mol), dissolved in dioxane (50 mL). The resulting mixture was stirred for 2 h and the white precipitate (2,6-diaminopyridine hydrochloride) filtered off. The organic phase was evaporated to dryness in vacuo, and the crude product recrystalized from n-hexane/ethyl acetate to give the desired product (32.83 g, 74%) as colorless crystals (mp 140-141° C.). 1H NMR (DMSO-d6): δ 8.93 (s, 1H), 7.34 (t, 7.9 Hz, 1H), 7.19 (d, 7.6 Hz, 1H), 6.18 (d, 7.6 Hz, 1H), 5.75 (br. s, 2H), 1.19 (s, 9H). 13C NMR (DMSO-d6): δ 176.5, 158.5, 150.4, 138.4, 103.6, 101.5, 39.4, 27.1. FAB+ MS (m/z): 193.88 M+H+, calc. for C10H15N3O+H+ 194.1293.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:8]1C[CH2:9]1)[C:4]([O:6][CH3:7])=[O:5].NC(CC)C(O)=O>>[ClH:1].[NH2:2][CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(N)C1CC1
Agent: CCC(N)C(=O)O
Agent: Cl
Product: CCC(N)C(=O)OC

Procedure:
Following the procedure for the preparation of methyl amino(cyclopropyl)acetate hydrochloride but substituting alpha-aminobutyric acid and making non-critical variations provided the title compound as a solid: MS (ESI+) for C5H11NO2 m/z 235 (2M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12](C3CCCCO3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[N:27]([Sn](CCCC)(CCCC)CCCC)=[N+:28]=[N-:29].O1CCOCC1.Cl>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:20]=[N:27][NH:28][N:29]=4)[CH:17]=3)[NH:12][N:11]=2)=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(C)c1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)c1ccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1
Yield: 80 %

Procedure:
The title compound was prepared from 3-[4-(methylethyl)phenyl]-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.095 g, 0.307 mmol), azidotributyl tin (0.744 g, 0.689 mL, 2.33 mmol) in toluene (10 mL) as described for the preparation of compound 167. Deprotection was effected by treating a dioxane solution (5 mL) with 5 mL of 6.0 N aqueous solution of hydrogen chloride. The solid obtained upon completion of the reaction was partially dissolved in 2.0 N aqueous sodium hydroxide and was extracted in ethyl acetate (4×15 mL). (0.260 g, 0.85 mmol, 80% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.7 (s, 1H), 8.1 (d, 1H), 7.9 (d, 2H), 7.8 (d, 1H), 7.4 (d, 2H), 3.0 (septet, 1H), 1.3 (d, 6H); ES-MS (m/z) 305 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[C:4]1[CH2:19][CH2:18][CH2:17][C:5]=13.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]1[CH2:19][CH2:18][CH2:17][CH:5]13
Reactant: CN1CCc2ccc(F)c3c4c(n(c23)CC1)CCC4
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2ccc(F)c3c2N(CC1)C1CCCC31
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 8-fluoro-3-methyl-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (0.23 g, 0.89 mmole) in acetic acid (50 mL) was added sodium cyanoborohydride (95 wt. %, 0.20 g, 3.02 mmole) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% methanol in methylene chloride) provided 0.11 g of the title compound as a colorless oil. The oil was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 180-182° C. MS (ES) m/z 261.13 ([M+H]+).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[NH:15][NH:14][C:13]1=[O:18]>C(Cl)Cl>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13](=[O:18])[N:14]=[N:15][C:16]1=[O:17]
Reactant: O=C1C=CC(=O)N1CCCCn1c(=O)[nH][nH]c1=O
Solvent: ClCCl
Product: O=C1C=CC(=O)N1CCCCN1C(=O)N=NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To 4-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl)-1,2,4-triazolidine-3,5-dione (I-14b: 6 mg, 0.024 mmol) in CH2Cl2 (0.95 mL) was added SiO2-HNO3 (50 mg). The mixture was stirred at room temperature for 15 minutes, then filtered, concentrated in vacuo and dried giving 4-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl)-3H-1,2,4-triazole-3,5(4 H)-dione (I-14c: 6 mg, quantitative) as a pink solid. 1H NMR (400 MHz, CD3CN) δ ppm 1.52-1.71 (m, 4 H) 3.49 (t, J=6.44 Hz, 2 H) 3.59 (t, J=6.69 Hz, 2 H) 6.77 (s, 2H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15]CC1C=CC=CC=1)[CH:11]=[CH:10][CH:9]=2)=[O:5].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
103 (46.2 g, 116.8 mmol) is dissolved in ethanol (300 ml) and after addition of ammonium formiate (8.3 g, 128.5 mmol) and 10% Pd—C (5 g) the mixture is stirred at room temperature for 1 h. Then the mixture is filtered off. Evaporation under reduced pressure gave 6.89 g of a white solid, which is further purified by recrystallisation from ether/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:18][C:17]=3[CH:34]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[N:18][C:17]=3[CH:34]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)c(F)c4)ccc3o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2ccc3oc(C4CCNCC4)nc3c2)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (120 mg, 0.26 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (0.5 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (120 mg). 5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (120 mg, 0.25 mmol) was dissolved in DCM (15 ml) and added TEA (0.27 ml, 2 mmol). This mixture stirred at rt for 30 mins and added isopropyl chloroformate in toluene (61 mg, 0.34 mmol). After 1 h, reaction mass diluted with water and extracted with DCM. Removal of DCM afforded crude. Crude was purified by combiflash using a mixture of EtOAc and Petether (35:65) as eluent to afford the titled compound (20 mg) as an off-white solid. M.P.: 187-191° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.14 (d, J 2.6, 1H), 8.02 (t, J 8.2, 1H), 7.90 (d, J 1.4, 1H), 7.63-7.55 (m, 4H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.2, 2H), 3.22-3.14 (m, 1H), 3.04 (t, J 11.4, 2H), 2.18 (d, J 10.8, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).