Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1>C(O)CCC>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:2]3[N:3]=[C:4]([NH:12][C:13]4[CH:21]=[C:20]5[C:16]([CH:17]=[N:18][NH:19]5)=[CH:15][CH:14]=4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:21]=2)[CH:17]=[N:18]1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCCCO
Product: c1cc2c(Nc3ccc4cn[nH]c4c3)nc(Nc3ccc4cn[nH]c4c3)nc2[nH]1
Temperature: 116 °C
Reaction time: 8 h
Yield: 8.3 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 0.48 mmol) and 6-aminoindazole (127 mg, 0.95 mmol) in n-butyl alcohol (n-BuOH) (4 mL) was stirred at 116° C. overnight. The mixture was purified by reverse phase HPLC using a gradient of 7-50% CH3CN in water over 10 min. The title compound was recovered to give a powder (15 mg). MS 382.4 (M+H) (Compound 4-1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.CO>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCOCC3)ccc2C(=O)O)CC1
Yield: 93.1 %

Procedure:
Using methods substantially equivalent to those described in Example 21-D, methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoate (2.40 g, 5.71 mmol), lithium hydroxide monohydrate (605 mg, 15.1 mmol), and 2:1 (10% water in tetrahydrofuran):methanol (75 mL) afforded 2.16 g (93%) of the title compound; which was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C@:14]([CH2:16][OH:17])([CH3:15])[C@@H:13]3[CH2:18][CH2:19][C@@:20]4([CH3:40])[C@:25]5([CH3:39])[CH2:26][C@@H:27]([OH:38])[C@:28]67[CH2:36][O:37][C@:24]5([C@@H:29]6[CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][CH2:33]7)[CH:23]=[CH:22][C@@H:21]4[C@@:12]3([CH3:41])[CH2:11][CH2:10]2)[C@H:5]([OH:42])[C@@H:4]([O:43][C@@H:44]2[O:49][C@H:48]([CH2:50][OH:51])[C@@H:47]([OH:52])[C@H:46]([OH:53])[C@H:45]2[OH:54])[C@H:3]1[OH:55].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C@:14]([CH2:16][OH:17])([CH3:15])[C@@H:13]3[CH2:18][CH2:19][C@@:20]4([CH3:40])[C@@:25]5([CH3:39])[C:24](=[C:29]6[C@@:28]([CH2:36][OH:37])([C@H:27]([OH:38])[CH2:26]5)[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30]6)[CH:23]=[CH:22][C@@H:21]4[C@@:12]3([CH3:41])[CH2:11][CH2:10]2)[C@H:5]([OH:42])[C@@H:4]([O:43][C@@H:44]2[O:49][C@H:48]([CH2:50][OH:51])[C@@H:47]([OH:52])[C@H:46]([OH:53])[C@H:45]2[OH:54])[C@H:3]1[OH:55]
Reactant: C[C@H]1O[C@@H](O[C@H]2CC[C@@]3(C)[C@@H](CC[C@]4(C)[C@@H]3C=C[C@]35OC[C@@]6(CCC(C)(C)C[C@H]63)[C@H](O)C[C@]54C)[C@]2(C)CO)[C@H](O)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C[C@H]1O[C@@H](O[C@H]2CC[C@@]3(C)[C@@H](CC[C@]4(C)[C@@H]3C=CC3=C5CC(C)(C)CC[C@]5(CO)[C@H](O)C[C@]34C)[C@]2(C)CO)[C@H](O)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O
Reaction time: 9.5 h

Procedure:
By way of example, the fully acetylated saikosaponin d can be obtained by adding 10 to 20 ml of acetic anhydride to a solution of saikosaponin d in 10 to 20 ml/g of pyridine and allowing the mixture to stand at 10° C. to 50° C. for 3 to 16 hours. When this reaction mixture is stirred with a 1 to 40% (w/w) aqueous solution of ferric chloride at 10° C. to 40° C. for 1 to 10 hours for cleavage of the ether ring, there is obtained the acetylated saikosaponin b2 in which only the hydroxy group in the 28 position is free. This product is subjected to the above-described phosphorylation reaction with DPC and, then, to hydrolysis of the acetyl groups under alkaline conditions (pH 9-14, preferably pH 10-13), whereby the salt of saikosaponin b2 -28-(dihydrogen phosphate) is obtained. In the same manner as above, a salt of saikosaponin b1 -28-(dihydrogen phosphate) can be obtained from saikosaponin a, and a salt of saikosaponin h-28-(dihydrogen phosphate) from saikosaponin c.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CCN
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(CC)CCN=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirring, refluxing suspension of 84.4 g (0.4) of 6-nitroveratraldehyde and 1.0 ml glacial acetic acid in 750 ml ethanol was aded gradually a solution of 2-diethylaminoethylamine in 50 ml ethanol. The solution was refluxed and stirred for 1 hr; the solvents were then removed in vacuo. The residue was taken up in 300 ml chloroform; the solution was washed with three 150-ml portions of water, dried over magnesium sulfate, and concentrated to dryness in vacuo to give 123 g (100%) of the product.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][CH2:8]1)=[O:6]>C1COCC1.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]2)(=[O:14])=[O:15])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
Lithium hydroxide (1.45 g, 60.9 mmol) was added in one portion to a stirred solution of 1-(4-nitro-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (10.0 g, 30.4 mmol) in THF/H2O (1:1,100 ml) and the reaction mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was partitioned between ethyl acetate (100 ml) and HCl (2M, 20 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to afford the title compound (5.1 g, 54% yield) as a colourless oil. δH (250 MHz, DMSO) 12.33 (1H, br s), 8.42 (2H, d), 7.99 (2H, d), 3.56-3.44 (2H, m), 2.51 (2H, obscured), 2.32-2.20 (1H, m), 1.90-1.81 (2H, m), 1.62-1.45 (2H, m). Tr=1.71 min m/z (ES+) (M+H+) 315.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:8]=1)#[N:2].[F:17][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC#N>[C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[C:7]([F:17])[CH:8]=1)#[N:2]
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(C)c1nc(N=CN(C)C)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.2 %

Procedure:
To a solution of N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine (3.0 g, 14 mmol) in dry CH3CN (139 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [SELECTFLUOR™] (5.4 g, 15 mmol) at room temperature. The mixture was stirred at room temperature for 18 hours under N2, then concentrated. The residue was diluted with ethyl acetate (100 mL), washed with water (5×40 mL) and brine, dried over MgSO4, and concentrated. The oily residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate=3/1) to give the title compound as colorless crystals (0.63 g, 19%). 1H-NMR (300 MHz, CDCl3) δ ppm: 1.26 (d, J=7.0 Hz, 6H), 3.15 (s, 3H), 3.16 (s, 3H), 3.29 (septet-d, J=7.0, 1.9 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 8.55 (s, 1H). MS ESI+ m/z: 235 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C=Nc1ccccc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)Nc1ccccc1
Yield: 32 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with phenyl isocyanate (660 mg, 5.51 mmol). Recrystallization from acetonitrile provided 670 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl)-N′-phenylurea as light orange needles, m.p. ˜40° C. Analysis: Calculated for C23H26N6O2. 1.0 C2H3N: % C, 65.34; % H, 6.36; % N, 21.34; Found: % C, 65.13; % H, 6.26; % N, 21.35.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:14][C:13]2=[O:28])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:61][C@@H:62]([CH2:92]O)[CH2:63][N:64]1[CH:68]=[CH:67][C:66]([NH:69]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:65]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)=[CH:14][C:13]2=[O:28])[C:9]([NH:69][C:66]2[CH:67]=[CH:68][N:64]([CH2:63][C:62]([OH:61])([CH3:92])[CH3:30])[N:65]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3cccc(C(F)(F)F)c3)=CC2=O)n1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 16.8 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (180 mg, 0.5 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (259 mg, 1.2 mmol) and N,N-diisopropylethylamine (292 mg, 2.3 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (208 mg, 1.41 mol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 70 mg, 0.5 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide (45 mg, 19%) as an off-white sticky solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.78-1.04 (m, 2H), 1.13 (br. s., 6H), 1.15-1.31 (m, 3H), 1.56-1.93 (m, 8H), 2.66 (br. s., 1H), 3.92 (br. s., 2H), 4.10 (d, J=18.1 Hz, 1H), 4.40 (d, J=18.1 Hz, 1H), 4.94 (br. s., 1H), 5.00 (br. s., 1H), 6.64 (br. s., 1H), 7.27 (br. s., 1H), 7.39 (br. s., 1H), 7.45 (br. s., 1H), 7.54 (br. s., 2H), 9.02 (br. s., 1H).
Reaction SMILES: CC(O[CH2:5][C:6]1[C:11]2=[CH:12][CH:13]=[C:14](C=O)[C:10]2=COC=1)=O.[CH2:17]([NH2:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[CH:36](Cl)(Cl)Cl>>[CH2:18]([C:17]1[NH:35][CH:5]=[CH:6][C:11]2[C:10]=1[CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:36]
Reactant: CC(=O)OCc1cocc2c(C=O)ccc1-2
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCc1[nH]ccc2cccc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Baldrinal (2) (1.1 g) was reacted with octadecylamine (2.58 g) in 20 ml of chloroform. After stirring for 15 minutes at room temperature, the solution turned into thick red liquid. When all the baldrinal was reacted, an orange product (7) (53.4 mg) was collected after column chromatography on silica using 8:2 hexanes:ethyl acetate as a solvent.
Reaction SMILES: C([Li])CCC.CCCCCC.[I-].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[C:23]([CH3:25])[N:24]=2)=[CH:16][CH:15]=1.[CH2:46]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH2:59][CH:58]([CH:62]=O)[CH2:57]1)=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1.O>[CH2:46]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH2:59][CH:58]([CH:62]=[CH:26][C:22]2[S:21][C:20]([C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)=[N:24][C:23]=2[CH3:25])[CH2:57]1)=[O:55])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C=CC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
In an argon atmosphere, a solution of 1.59 mol/Ln-butyl lithium in hexane (2.03 mL, 3.23 mmol), chilled to −78° C., was added to a suspension of [2-(4-chlorophenyl)-4-methylthiazol-5-yl]methyltriphenylphosphonium iodide (1.80 g, 2.94 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred for 1 hour as it warmed from −78° C. to room temperature. Subsequently, the mixture was chilled again to −78° C. and 1-benzyloxycarbonyl-3-formylpiperidine (727 mg, 2.94 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred at −78° C. for 1 hour and at room temperature for the subsequent 6 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate and washed with brine. The washed product was dried over magnesium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 1.16 g (87%) of the desired compound as a yellow oil.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:18][CH:19]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH3:20])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:18][CH:19]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH3:20])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)OC(C)OC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CCCCC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (1.1 g, 7.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl pentanoate (800 mg, 2.8 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 12 (150 mg, 16% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.88-0.97 (m, 5H), 1.22-1.38 (br. m, 5H), 1.42 (d, J=5.2 Hz, 3H), 1.44-1.56 (m, 2H), 1.72-1.74 (m, 2H), 1.90-1.93 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.30 (t, J=7.2 Hz, 2H), 2.85 (t, J=6.4 Hz, 2H), 6.68 (q, J=5.6 Hz, 1H), 7.47 (t, J=6.0 Hz, 1H), 12.01 (br. s, 1H). MS (ESI) m/z 352.18 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[C:6](O)=[C:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8])[CH3:2].S(Br)(Br)=O.[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])/[CH:6]=[C:7](\[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH2:8][P:25]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:32])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)C(NC=O)C(O)=C(C)Cc1ccccc1
Agent: O=S(Br)Br
Solvent: CCOC(C)=O
Product: CCOC(=O)C(/C=C(\Cc1ccccc1)CP(=O)(OCC)OCC)NC=O

Procedure:
By reaction of 2-formylamino-3-hydroxy-4-benzyl-3-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite at 100° in a manner analogous to that described in Example 1, and after chromatography (silica gel; ethyl acetate), E-2-formylamino-4-benzyl-5-diethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a colourless oil, 1H-NMR (CDCl3) 2.45 (d, 2H, C(5)-H); 3.80 (s, 1H, CH2); 5.51 (m, 1H, C(3)-H).
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=1)[C:3]([O:5]CC)=O.[NH2:20][C:21](N)=[S:22].S1(CCCC1)(=O)=[O:25].COC(O)C.Cl>C(OCC)(=O)C.O>[O:19]=[C:17]([CH3:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:2]2[S:22][C:21](=[O:25])[NH:20][C:3]2=[O:5])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC(C)=O)cc1
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Agent: COC(C)O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 90 °C

Procedure:
A mixture comprising 12 g of ethyl 2-chloro-3-[4-(2-oxopropoxy)phenyl]propionate [prepared as described in step (b) above], 5 g of thiourea and 30 ml of sulfolane was heated at 90° C. for 3 hours, and then 100 ml of methoxyethanol were added to the mixture, which was then heated for a further 4 hours. At the end of this time, 40 ml of water and 20 ml of concentrated aqueous hydrochloric acid were added to the reaction mixture, and the resulting mixture was heated for 4.5 hours in an oil bath kept at 100° C. After this, the reaction mixture was mixed with water and ethyl acetate, and then the ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 3:2 to 2:3 by volume as the eluent, followed by crystallization from a mixture of ethyl acetate and hexane, to give the title compound as crystals, melting at 158°-159° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:14]=2[CH:15]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.C(O)C.C(O)(=O)C.[N+:32]([CH3:35])([O-:34])=[O:33]>CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH:15]=[CH:35][N+:32]([O-:34])=[O:33])=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C=O)c1OCCCCCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CN
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(C=C[N+](=O)[O-])c1OCCCCCc1ccccc1
Yield: 49 %

Procedure:
Operating analogously to example 2 using 2-(5-phenylpentyloxy)-3-methoxy-benzaldehyde (1 g, 3.35 mmoles), obtained as described in example 12, 8.03M methylamine in ethanol (0.088 ml, 0.7035 mmoles), acetic acid (0.04 ml, 0.7035 mmoles) and nitromethane (0.198 ml, 3.685 mmoles) in methanol (5 ml), 0.56 g of the title product was obtained (yield: 49%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].OC1C2N=NNC=2C=CC=1.Cl.Cl.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:1](=[O:5])[CH2:2][OH:3])[CH2:30][CH2:31]1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C(O)CO
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CO)N1CCN(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a screw-cap vial was added glycolic acid (100 mg, 1.31 mmol), 1-(3-dimthylaminopropyl)-3-ethylcarbodiimide hydrochloride (277.3 mg, 1.45 mmol), hydroxybenzotriazole (195.5 mg, 1.45 mmol), 1-(2,4-dichlorophenyl)-piperazine dihydrochloride (439.8 mg, 1.45 mmol), triethylamine (0.55 mL, 3.94 mmol) and N,N-dimethylformamide (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (8 mL), successively washed with water (8 mL), saturated aqueous sodium bicarbonate (2×8 mL) and water (8 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified on silica gel using hexanes:ethyl acetate=4:1 to 100% ethyl acetate in a gradient fashion, to isolate the desired product as yellow solid (171.1 mg, 45%). 1H NMR (300 MHz, CDCl3): δ 7.28 (d, 1H), 7.11 (dd, 1H), 6.85 (dd, 1H), 4.11 (br, 2H), 3.74 (t, 2H), 3.72 (br, 1H, OH), 3.36 (t, 2H), 2.92 (t, 4H)
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccnc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and nicotinoyl chloride: ESMS m/e: 485.3 (M+H)+.
Reaction SMILES: ClC1C=CC(C2C3C(OC)=NC=CC=3C3C(C)=N[O:15][C:12]=3CN=2)=CC=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[C:30]3[C:46]([CH3:47])=[N:45][O:44][C:31]=3[CH2:32][N:33]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[C:35]=2[N:36]=1.ClC1C=CC(C2C3C(F)=NC=CC=3C3C(C)=NOC=3CN=2)=CC=1>>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C:34]2[C:35]3[N:36]=[C:26]([O:15][CH3:12])[CH:27]=[CH:28][C:29]=3[C:30]3[C:46]([CH3:47])=[N:45][O:44][C:31]=3[CH2:32][N:33]=2)=[CH:38][CH:39]=1
Reactant: COc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Reactant: Cc1noc2c1-c1ccc(Cl)nc1C(c1ccc(Cl)cc1)=NC2
Agent: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Product: COc1ccc2c(n1)C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2

Procedure:
A procedure similar to 6-(4-Chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine (Compound 170) was followed, except that 8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine (Compound 240) was used as starting material instead of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine. LC/MS m/z 340 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.31 Hz, 1H), 7.83 (d, J=8.31 Hz, 1H), 7.43 (td, J=2.30, 8.70 Hz, 2H), 7.35 (td, J=2.30, 8.70 Hz, 2H), 4.79 (br. s, 2H), 3.34 (s, 3H), 2.53 (s, 3H).