Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Ge:1](Cl)([Cl:4])([Cl:3])[Cl:2].C[SiH2]O[Si](C)(C)C.[C:13]([OH:17])(=[O:16])[CH:14]=[CH2:15]>>[C:13]([OH:17])(=[O:16])[CH2:14][CH3:15].[Cl:2][GeH:1]([Cl:4])[Cl:3]
Reactant: Cl[Ge](Cl)(Cl)Cl
Reactant: C=CC(=O)O
Agent: C[SiH2]O[Si](C)(C)C
Product: CCC(=O)O
Product: Cl[GeH](Cl)Cl
Reaction time: 120 h

Procedure:
An example of this alternative process follows. To a 50 L glass reactor was added successively: 7.2 Kg germanium tetrachloride, 5.3 Kg tetramethyl disiloxane, and 2.32 Kg of acrylic acid. The resulting mixture was stirred for 5 days forming TPA (trichlorogermane propionic acid) as a product. Volatile components were removed via vacuum distillation while the TPA product was heated to an internal temperature of 75° C.-80° C., where it was a homogeneous, clear and colorless viscous melt. Distillation is continued until no more distillate appears. The product was then cooled to ambient temperature yielding a white amorphous solid of TPA. To this was added 35 L of concentrated HC1. The resulting heterogeneous mixture was warmed to an internal temperature of 60° C.-70° C., and stirred for four hours and allowed to cool. The cooled mixture was extracted 3 times with 25 L of dichloromethane. The dichloromethane was removed with vacuum distillation at 40° C. to give a white amorphous solid. The white amorphous solid, crude TPA, was then hydrolyzed to carboxyethyl germanium sesquioxide. To this end the crude TPA was immediately taken up (vigorous reaction), with careful addition of 30 L of ammonium hydroxide (29% ammonia). The resulting mixture was stirred for 4 days at ambient temperature. To this, 14.4 L of concentrated sulfuric acid was added dropwise over two hours through a reflux condenser producing a white solid of carboxyethyl germanium sesquioxide. The white solid was isolated via suction filtration, washed successively with 2×5.4 L acetone, and 2×5.4 L of diethyl ether, then the resulting brilliant white solid was air dried overnight, and then taken up with 9 L of hot water, then cooled and filtered to yield carboxyethyl germanium sesquioxide.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:19]=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([Mg]Br)#[CH:22].O.CCOCC>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:19]([OH:20])[C:21]#[CH:22])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: COc1cccc(-c2nc3c(Cl)cccn3c2C=O)c1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)c1c(-c2cccc(OC)c2)nc2c(Cl)cccn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a cold (−78° C.) solution of 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (1.06 g, 3.70 mmol) in tetrahydrofuran (20 mL) was added ethynyl magnesium bromide (18.53 mL, 0.5 M in tetrahydrofuran, 9.26 mmol). After 15 minutes, the resulting mixture was allowed to warm to room temperature and stirred an additional 30 minutes. Water was added and then ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes-ethyl acetate to 100% ethyl acetate) provided 1-[8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-ol (910 mg, 79%) as a white solid. 1H NMR (CDCl3): δ 8.61 (d, 1 H), 7.33–7.26 (m, 2 H), 7.16–7.11 (m, 2 H), 6.88 (m, 1 H), 6.79 (m, 1 H), 6.14 (m, 1 H), 3.85 (s, 3 H), 3.27 (broad, 1 H), 2.64 (d, 1 H); 13C NMR (CDCl3): δ 159.64, 144.46, 134.12, 129.56, 124.99, 124.51, 123.03, 121.37, 119.43, 114.54, 114.13, 111.81, 111.27, 79.96, 75.03, 55.88, 55.38; MS m/z 313 (M+1); Anal. Calcd. for C17H13ClN2O2: C, 65.29; H, 4.19; N, 8.96. Found: C, 65.23; H, 4.34; N, 8.81.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:4][CH:3]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([NH2:28])=[O:27])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(-c2ocnc2-c2ccc(F)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)Nc1cc(-c2ocnc2-c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 61 %

Procedure:
4-[4-(4-Fluoro-phenyl)-oxazol-5-yl]-pyridin-2-ylamine (57 mg, 0.22 mmol) and benzoyl isocynate (39 mg, 0.27 mmol) are mixed in DCM (2.0 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (2.0 mL) and potassium carbonate (46 mg, 0.34 mmol). The mixture is then heated at 80° C. for 55 min. The solvent is removed and the residue is partitioned between water (25 mL) and EtOAc (35 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. EtOAc (2 mL) is added into the crude and a solid is formed. The solid is filtered, rinsed with more EtOAc and dried to give 40 mg of the titled product.
Reaction SMILES: [CH2:1]1[C:11]2[C:12]3[C:3](=[CH:4][CH:5]=[C:6]4[C:16](=[O:17])[O:15][C:13](=[O:14])[C:8](=[CH:9][CH:10]=2)[C:7]4=3)[CH2:2]1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>CC(N(C)C)=O>[CH:18]1([N:24]=[C:16]([C:6]2[C:7]3=[C:12]4[C:3]([CH2:2][CH2:1][C:11]4=[CH:10][CH:9]=[C:8]3[C:13]([OH:15])=[O:14])=[CH:4][CH:5]=2)[OH:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1OC(=O)c2ccc3c4c(ccc1c24)CC3
Reactant: NC1CCCCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)c1ccc2c3c(ccc(C(O)=NC4CCCCC4)c13)CC2
Temperature: 157.5 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
A slurry of 5,6-acenaphthenedicarboxylic acid anhydride (33.6 g, 0.150 mol) (B. M. Trost, G. Michael Bright, Charles Frihart, and David Brittelli, Journal of the American Chemical Society, 93(3), 737-45 (1971); James J. Jordan, Jr; U.S. Pat. No. 3,935,226) in 175 ml of DMAc was treated with cyclohexylamine (34.2 ml, 0.300 mol) over one minute and a thick paste formed. This mixture was heated at 155-160° C. for 2 hours. The resulting deep green solution was poured into 2 liters of water. The mixture was stirred for 10 minutes and then was filtered. The accumulated solid was washed with water and air-dried to provide a yellow solid (45.1 g, 98.5%), mp 264-265° C. A portion (2.00 g) of this material was recrystallized from a mixture of n-propyl acetate and heptanes (200 ml, 1:1 v/v) to provide fine yellow needles (1.42 g, 70%), mp 266-267° C. Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found C, 78.39; H, 6.15; N, 4.83.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[C:20](=[O:26])[CH2:19][CH2:18]4)[CH:11]=[N:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35].O>C(Cl)Cl>[CH3:25][N:21]1[C:22]2[C:17](=[CH:16][C:15]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]4[C:9]=3[CH2:8][CH2:7][CH2:6][N:5]4[CH2:4][CH2:3][NH:2][S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:24][CH:23]=2)[CH2:18][CH2:19][C:20]1=[O:26]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4CCN)ccc21
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)NCCN1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.8 %

Procedure:
To a solution of 6-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro-[1,7]naphthyridin-5-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 12, 0.03 g, 0.081 mmol) in DCM (1 mL) were added triethylamine (0.020 g, 0.201 mmol) and ethanesulfonylchloride (0.011 g, 0.089 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was diluted with DCM, poured into H2O (5 mL) and extracted with DCM (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.01 g, 29%) as a yellow oil. MS: 429.2 (M+H+).
Reaction SMILES: N[C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(#[N:47])C>C(N(CC)CC)C>[CH2:27]([O:26][C:24]([C@@H:23]([C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH:3]1[NH2:47])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CC#N
Reactant: CCOC(=O)C(Br)CCCCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)[C@@H]1C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2OC1N
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2 g), ethyl 2-bromo-7-phthalimidoheptanoate (3.9 g), acetonitrile (100 ml) and triethylamine (0.9 g) is heated at 80° C. for 3 days. After evaporation of acetonitrile, water (150 ml) and ethyl acetate (200 ml) is added to the residue, and the mixture is agitated thoroughly. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is dissolved in a mixture of ethyl acetate (10 ml) and oxalic acid (2 g). The resulting solution is diluted with petroleum ether (200 ml) and agitated thoroughly. The supernatant layer is removed by decantation. To the precipitate are added water (150 ml), ethyl acetate (200 ml) and sodium bicarbonate with stirring. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is chromatographed graphed on silica gel using hexane-ethyl acetate (2:1-1:1) as an eluent. Evaporation of the first fraction affords tert-butyl 3(S)-[1(R)ethoxycarbonyl-6-phthalimidohexyl]-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g) as a colorless oil.
Reaction SMILES: [Cl:1]C1SC2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=CC=CC=4)[N:14](CCOC)[C:13]3=O)=[O:10])=[CH:8]C=2C=1.[ClH:28]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:28].[NH2:6][CH:7]1[CH2:8][C:13]2[C:12](=[CH:21][CH:20]=[CH:15][N:14]=2)[NH:11][C:9]1=[O:10]
Reactant: COCCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1Cc2ncccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-yl)carbamate (Method 26, 263 mg, 1 mmol) was dissolved in DCM (10 mL) and treated with 4M HCl in dioxan (10 mL). After stirring at ambient temperature for 30 mins. the reaction mixture was evaporated under reduced pressure and the residue triturated with ether (20 mL), to give a white solid which was collected by filtration, washed with ether and dried. (234 mg, 100%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:30](=[O:33])[NH:31][CH3:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[C:12]([O:24][C:25](=[O:29])[NH:26][CH2:27][CH3:28])[CH:11]=1)(C)(C)C.CCOCC.[ClH:40].O1CCOCC1>CO.[Pd]>[Cl-:40].[CH2:27]([NH:26][C:25]([O:24][C:12]1[CH:11]=[C:10]([CH2:9][C@H:8]([NH3+:7])[C:30](=[O:33])[NH:31][CH3:32])[CH:15]=[CH:14][C:13]=1[OH:16])=[O:29])[CH3:28]
Reactant: Cl
Reactant: CCNC(=O)Oc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NC)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CCNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)NC)ccc1O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[(S)-2-(4-Benzyloxy-3-ethylcarbamoyloxy-phenyl)-1-methylcarbamoyl-ethyl]-carbamic acid tert-butyl ester (243 mg) was suspended in 4M HCl-dioxane (5 ml) and stirred at room temperature for 1 hour. The clear solution was evaporated to dryness giving an oil which was redissolved in methanol (5 ml). 5% Pd—C (50 mg) was added and the mixture stirred under an atmosphere of hydrogen gas at room temperature for 2 hours. The catalyst was removed by filtration and washed with methanol. Evaporation of the filtrate gave the crude product as an oil. Trituration with ether gave (S)-2-(3-ethylcarbamoyloxy-4-hydroxy-phenyl)-1-methylcarbamoyl-ethyl-ammonium chloride as a grey solid, 150 mg; NMR (500 MHz, d6 DMSO) 1.07 (3H, t J 7), 2.59 (3H, d J 4.5 collapse to s with D2O), 2.82-2.95 (2H, m), 3.03-3.10 (2H, m), 3.83 (1H, t J 7), 6.81-6.85 (3H, m), 7.55 (1H, t J 5.5), 8.19 (3H, br exch D2O), 8.37 (1H, br q exch D2O), 9.5 (1H, s, exch D2O); HPLC/MS Retention time 2.9 min, m/z 282 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[CH:17]=[C:16]([C:18](O)=[O:19])[S:15][C:6]=3[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:8]=2)[CH2:3][CH2:2]1.Cl.[NH:22]1[C:26]([C:27]2[CH:28]=[C:29]3[C:39](=[CH:40][CH:41]=2)[O:38][C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][C:30]3=[O:42])=[N:25][N:24]=[N:23]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C=O)C>[CH:1]1([C:4]2[C:5]3[CH:17]=[C:16]([C:18]([N:35]4[CH2:36][CH2:37][C:32]5([CH2:31][C:30](=[O:42])[C:29]6[C:39](=[CH:40][CH:41]=[C:27]([C:26]7[NH:25][N:24]=[N:23][N:22]=7)[CH:28]=6)[O:38]5)[CH2:33][CH2:34]4)=[O:19])[S:15][C:6]=3[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: O=C(O)c1cc2c(C3CC3)nn(-c3ccccn3)c2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC2(CCN(C(=O)c3cc4c(C5CC5)nn(-c5ccccn5)c4s3)CC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
DMF (5 mL) and TEA (0.2 mL) were added to 3-cyclopropyl-1-pyridin-2-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (143 mg), 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (177 mg), EDCI (119 mg) and HOBT (90 mg), heated at 80° C. and stirred for 2 hours. This was cooled to room temperature, iced water was added to it, and its pH was adjusted at 2.5 with 1 N HCl added thereto. The formed crystal was taken out through filtration, washed with water, washed with Et2O and dried in vacuum at 70° C. to obtain the title compound as a pale brown powder. 1H-NMR (400 MHz, DMSO-d6) δ: 8.54-8.51 (1H, br m), 8.43 (1H, d, J=2.2 Hz), 8.25 (1H, dd, J=8.3, 2.2 Hz), 8.03-7.97 (1H, m), 7.88 (1H, d, J=8.3 Hz), 7.51 (1H, s), 7.36-7.27 (2H, m), 4.24-4.14 (2H, br m), 3.4-3.6 (2H, br m), 3.00 (2H, s), 2.31-2.22 (1H, m), 2.10-2.02 (2H, br m), 1.93-1.81 (2H, br m), 1.11-1.04 (4H, m). MS [M+H]+=553.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C:9]2([CH2:21][NH2:22])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:2][C:3]1[C:4]([C:9]2([CH2:21][NH:22][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:33]=3[Cl:32])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:16])=[O:17])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCS(=O)(=O)N1CCC(CN)(c2ncccc2Br)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2Br)CC1

Procedure:
{[4-(3-Bromopyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}amine hydrochloride salt (100 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL) with N,N-diisopropylethylamine (0.13 mL, 0.72 mmol). 2,4-dichlorobenzoyl chloride (34 μL, 0.24 mmol) was added and the mixture stirred over night. The mixture was poured into aqueous sodium carbonate (10 mL, 2 M) and extracted with dichloromethane (10 mL x 2). The combined organic phases were dried over magnesium sulphate (anhydrous), filtered and evaporated. The reside was purified by flash column chromatography on silica gel using dichloromethane containing 10% ethyl acetate as eluent to afford the desired product: N-{[4-(3-bromopyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}-2,4-dichlorobenzamide: 1H NMR δ (ppm)(CDCl3): 8.50 (1 H, dd, J=1.4, 4.5 Hz), 7.94 (1 H, dd, J=1.4, 7.9 Hz), 7.58 (1 H, d, J=8.3 Hz), 7.36(1 H, d, J=1.9 Hz), 7.29 (1 H, dd, J=8.3, 1.9 Hz), 7.10 (1 H, dd, J=4.5, 7.9 Hz), 6.87 (1 H, m), 5.30 (1 H, s), 4.15 (2 H, d, J=6.2 Hz), 3.46-3.44 (4 H, m), 3.14-3.08 (2 H, m), 2.90-2.88 (2 H, m), 1.90-1.76 (4 H, m), 1.06 (3 H, t, J=7.4 Hz); m/z (ES) 548, 550 (M+H).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:18]([NH2:20])[CH3:19].CCN(C(C)C)C(C)C>C(#N)C>[CH2:18]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:19]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Yield: 89.2 %

Procedure:
2-(2,6-Difluoro-3-nitrophenyl)pyridine (1.00 g, 4.29 mmol), ethylamine (2.24 mL, 4.29 mmol) and then DIPEA (0.75 mL, 4.29 mmol) were added to acetonitrile (10 mL) and the resultant mixture stirred at 20° C. for 40 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to give the title compound as yellow oil (1.00 g, 90%). 1H NMR (CDCl3) δ: 8.73 (1H, ddd, J=6.6, 2.4, 1.3 Hz), 8.28 (1H, dd, J=12.6, 8.1 Hz), 7.80 (1H, td, J=10.3, 2.4 Hz), 7.45 (1H, dq, J=10.4, 1.6 Hz), 7.33 (1H, ddd, J=10.1, 6.5, 1.6 Hz), 6.51 (1H, dd, J=12.7, 10.9 Hz), 2.54-2.44 (2H, m), 1.03 (3H, t, J=9.6 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](OC)=[N:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-:17].[NH4+:18]>C(O)C>[ClH:17].[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[NH:18])[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1=NCCN(C(=O)OC(C)(C)C)CC1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCNC(=N)CC1
Product: Cl
Yield: 92.9 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-5-methoxy-(1H)-1,4-diazepine (170 mg, 0.75 mmol) and ammonium chloride (40.1 mg, 0.75 mmol) in 2.0 mL of anhydrous ethanol was refluxed for 3 h. The solvent was then removed in vacuo and residue was triturated with 3×10 mL of ether to give 174 mg of 1-(tert-butoxycarbonyl)-hexahydro-5-imino-(1H)-1,4-diazepine hydrochloride as a light yellow solid.
Reaction SMILES: N[C@H:2]([C:7](O)=[O:8])[CH2:3]C(C)C.[NH2:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15]NC(=N)N>>[NH2:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13]1[CH:3]=[CH:2][C:7]([OH:8])=[CH:15][CH:14]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N=C(N)NCCCC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
0.98 Leu: 1.00 Har: 0.97 Pro: 0.96:
Reaction SMILES: [O:1]1[C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[N:28]=[CH:27][N:26](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:25]=5)[CH:22]=4)[N:17](C4CCCCO4)[N:16]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=[N:2]1>Cl.O1CCOCC1>[NH:26]1[CH:27]=[N:28][C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:11]2[CH:10]=[C:9]([NH:8][C:6]([C:5]3[O:1][N:2]=[CH:3][CH:4]=3)=[O:7])[CH:14]=[CH:13][CH:12]=2)=[N:25]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccno1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccno1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
Isoxazol-5-yl-N-(3-{1-perhydro-2H-pyran-2-yl-5[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.005 g, 5% yield over 2 steps): 1H NMR (CD3OD) 8.65 (t, 1H), 8.73 (s, 1H), 8.45 (s, 1H), 8.38 (br s, <1H), 8.10 (d, 1H), 7.92 (d, 1H), 7.82 (d, 1H) 7.58 (t, 1H), 7.32 (d, 1H); ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1)([CH3:3])[CH3:2].CN(CCN(C)C)C.C([Li])CCC.CCCCCC.CN([CH:37]=[O:38])C>CC(OC)(C)C>[OH:38][CH:37]1[C:7]2[C:8]([O:12][CH3:13])=[N:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:14])[N:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)NC(C)C)ccn1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: COc1nccc2c1C(O)N(C(C)C)C2=O
Reaction time: 3 h
Yield: 169.8 %

Procedure:
To a stirred suspension of 10.00 g N-isopropyl-2-methoxy-isonicotinamide (51.40 mmol), as obtainable from example 13, in 300 mL TBME were added at room temperature 17.2 mL TMEDA (113.3 mmol, 2.2 eq) resulting in the formation of a clear solution, which was then cooled to −780 C. Subsequently 102.8 mL n-butyllithium in hexane (1.5 M, 154.4 mmol, 3.0 eq) were then added over 35 min and stirring was continued at the same temperature for additional 3 h min and subsequently at −22° C. for another 3 h. To the slightly brown suspension, 13.9 mL DMF (180.0 mmol, 3.5 eq) were added at −28° C. The resulting suspension was quenched after 16 h 45 min by addition of 200 mL saturated aqueous NH4Cl. The mixture was extracted three times with 150 mL, in total 450 mL dichloromethane. The combined organic phases were dried over 20 g Na2SO4 (30 min) and filtered. The filter cake was washed with 40 mL dichloromethane. After evaporation of solvent in a rotary evaporator (40° C./20 mbar), the crude product (19.400 g, 170% w/w, regioselectivity: 11.68:1, as determined by 1H-NMR) was obtained as a brown oil (HPLC purity 77.6%).
Reaction SMILES: [CH2:1]([O:10][CH2:11][C:12]([CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:15][CH3:16])[CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CN(C)C1C=CC=CC=1.O1CCCC1.[C:42](Cl)(=[O:52])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>O>[CH2:19]([O:18][CH2:17][C:12]([CH2:11][O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([CH2:15][CH3:16])[CH2:13][O:14][C:42](=[O:52])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCOCC(CC)(CO)COCCCCCCCCC
Reactant: CCCCCCCCCC(=O)Cl
Solvent: O
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCOCC(CC)(COCCCCCCCCC)COC(=O)CCCCCCCCC
Temperature: 25 °C
Yield: 60 %

Procedure:
To a 1-L three-neck flask provided with a stirrer, thermometer, condenser and dropping funnel with a gas inlet tube, 73.4 g (0.19 mol) of 2,2-bis(nonyloxymethyl)butane-1-ol, 26.7 g (0.22 mol) of N,N-dimethylaniline and 150 mL of tetrahydrofuran were put, to which 38.1 g (0.2 mol) of decanoyl chloride was dropped and stirred at the room temperature under nitrogen stream. After the dropping, the mixture was heated to 45 degrees C. and stirred for five hours. After the reaction, a small amount of distilled water was added to the mixture to dissolve the generated white solid. The mixture was transferred to a separating funnel. After an aqueous layer was separated while an organic layer was added with 50 mL of tetrahydrofuran, washed with 200 mL of saturated saline and with 20 mL of dilute sulfuric acid and then washed with distilled water until the organic layer became neutral. The obtained organic layer was dried with magnesium sulfate. After the solvent was removed by an evaporator, 100 g of the mixture was subjected to vacuum distillation to be fractioned. The obtained fraction was subjected to mass analysis, NMR analysis and IR analysis, whereby the fraction was confirmed to be an ester (target compound) (mass analysis result: m/z=540). The obtained amount was 61.8 g (0.114 mol) (a yield of 60%).