Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([NH:9][C:10]([NH:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].O.[OH-].[Li+]>C1COCC1.CO.O>[C:13]12([NH:12][C:10](=[O:11])[NH:9][C@@H:4]([C:5]([CH3:7])([CH3:6])[CH3:8])[C:3]([OH:23])=[O:2])[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: COC(=O)[C@@H](NC(=O)NC12CC3CC(CC(C3)C1)C2)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](NC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
To a solution of (S)-2-(3-Adamantan-1-yl-ureido)-3,3-dimethyl-butyric acid methyl ester (265 mg, 0.822 mmol) in THF (4 mL) and MeOH (4 mL) was added a pre-made solution of lithium hydroxide monohydrate (69 mg, 1.644 mmol) in water (4.00 mL). The cloudy white solution was stirred at rt for 5 hrs. The volatiles were removed, and the reaction mixture was diluted with dilute citric acid solution and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, evaporated to obtain white solid (232 mg, 92%) as product. The crude material was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:12]=3[S:11](=[O:30])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1c(O)ccc2c(CCc3ccccc3)csc12
Solvent: ClCCl
Product: CCCc1c(O)ccc2c1S(=O)C=C2CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product of Example 63, Step H (2.017 grams) in CH2Cl2 solution (40 mL) was stirred (0° C.) and treated with solid 75% m-chloroperbenzoic acid (1.567 grams) in portions. The reaction was warmed to ambient temperature after 15 minutes and stirred for 1.5 hours. Partition of the reaction between isopropyl acetate and aqueous sodium bicarbonate was followed by washing of the organic with aqueous sodium bicarbonate, then water. Drying over magnesium sulfate, filtration and evaporation afforded a solid which was chromatographed over silica gel (2 step gradient; 5:1 hex/ethyl acetate; 5:2 hex/ethyl acetate; 5:2:0.35 hex/ethyl acetate/methanol). The title compound was acquired as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C1COCC1.C(Cl)Cl>[N:28]1([C:26]([C:23]2[CH:22]=[CH:21][C:20]([S:17]([N:14]3[CH2:15][CH2:16][CH:11]([NH:10][C:34](=[O:37])[CH:35]=[CH2:36])[CH2:12][CH2:13]3)(=[O:19])=[O:18])=[CH:25][CH:24]=2)=[O:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C=CC(=O)Cl
Reactant: NC1CCN(S(=O)(=O)c2ccc(C(=O)N3CCCCC3)cc2)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)N3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
Diisopropylethylamine (0.33 ml, 1.9 mmol) was added in one portion to a stirred solution of [4-(4-amino-piperidine-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone (0.13 g, 0.39 mmol) in THF (7 ml) followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.43 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 100% EtOAc) to give the title compound (0.09 g, 58% yield) as a white powder.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.O(C1C=CC([B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)=CC=1C#N)C1C=CC=CC=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[O:10]([C:4]1[CH:3]=[CH:2][C:9]([B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)=[CH:8][C:5]=1[CH:6]=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(C#N)c2)OC1(C)C
Reactant: O=Cc1ccc(Br)cc1Oc1ccccc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: CC1(C)OB(c2ccc(Oc3ccccc3)c(C=O)c2)OC1(C)C

Procedure:
The title compound was prepared in a 62% from 4-bromo-2-phenoxybenzaldehyde in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 10.43(s, 1H), 8.14(s, 1H), 7.89(d, 1H), 7.48(t, 2H), 7.27(t, 1H), 7.20(d, 2H), 6.88(d, 1H), 1.30(s, 12H); RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 14.02min.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[CH3:8][O:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[C:23]([O:29][CH3:30])=[C:22](N)[CH:21]=2)=[C:14]([Br:32])[CH:13]=1>ClCCl>[CH3:8][O:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[C:23]([O:29][CH3:30])=[C:22]([F:1])[CH:21]=2)=[C:14]([Br:32])[CH:13]=1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(N)c(OC)c(C(C)C)c2)c(Br)c1
Agent: N#[O+]
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(Oc2cc(F)c(OC)c(C(C)C)c2)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
A solution of nitrosonium tetrafluoroborate (121 mg, 1.03 mmol) in dichloromethane (10 mL) was cooled to 0° C. and methyl[3,5-dibromo-4-(3-amino-5-isopropyl-4-methoxy-phenoxy)phenyl]acetate (457 mg, 0.94 mmol) was added. The reaction mixture was stirred at 0° C. for one hour. Dichloromethane was removed by flushing of nitrogen gas and o-xylene (10 mL) was added to the residue. The reaction mixture was heated at reflux for one hour and the organic phase concentrated in vacuo. The residue was purified on column (silica gel, n-heptane/ethyl acetate, gradient elution from 98:2 to 60:40) to give 205 mg (44%) of methyl[3,5-dibromo-4-(3-fluoro-5-isopropyl-4-methoxyphenoxy)phenyl]acetate.
Reaction SMILES: CC(C)(O[C:5]([NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]1=[O:20])=[O:6])C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:46][C:47]1[CH:56]=[C:55]2[C:50]([C:51]([N:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)=[CH:52][C:53]([NH2:57])=[N:54]2)=[CH:49][CH:48]=1>>[CH2:18]([O:17][C:15]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:8]([NH:7][C:5]([N:61]2[CH2:62][CH2:63][N:58]([C:51]3[C:50]4[C:55](=[CH:56][C:47]([Cl:46])=[CH:48][CH:49]=4)[N:54]=[C:53]([NH2:57])[CH:52]=3)[CH2:59][CH2:60]2)=[O:6])[C:9]1=[O:20])=[O:16])[CH3:19]
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CCOC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid, ethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the title product as a light yellow solid. LC-MS: 489 (M++1). 1H NMR (CDCl3): δ 1.37 (t, 3H), 1.44˜2.02 (m, 5H), 2.12˜2.20 (m, 1H), 3.13 (m, 4H), 3.41 (dd, 1H), 3.67 (m, 4H), 4.35 (m, 2H), 4.42 (m, 1H), 4.74˜4.86 (m, 3H), 6.00 (d, 1H), 6.16 (s, 1H), 7.18 (dd, 1H), 7.62 (d, 1H), 7.73 (d, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH:22]([CH2:30][CH:31]([CH3:41])[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:33])[CH2:21]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH2:8]([N:20]1[CH2:29][CH2:28][C:23]2([O:24][CH2:25][CH2:26][O:27]2)[CH:22]([CH2:30][CH:31]([CH3:41])[C:32]([NH:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:33])[CH2:21]1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CC1CN(C(=O)OCc2ccccc2)CCC12OCCO2)C(=O)Nc1ccccc1
Reactant: O=CCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(CC1CN(CCc2ccccc2)CCC12OCCO2)C(=O)Nc1ccccc1
Yield: 92 %

Procedure:
Phenylacetaldehyde (0.87 mL, 7.40 mmol) was added to a solution of (8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethyl)-N-phenylpropionamide (96) in MeOH (49.4 mL, 0.03M) in a hydrogenation flask. 20% Pd/C (0.53 g) was added, and the mixture was shaken under 40 psi H2 until the consumption of H2 ceased and the reaction was judged complete by TLC (3.5 h). The crude reaction mixture was passed through a column of Celite, concentrated in vacuo, and purified by flash column chromatography (60:38:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain pure (8-phenethyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethyl)-N-phenylpropionamide (97) (0.59 g, 92%). 1H NMR (CDCl3): 7.42–7.12 (10H, m), 4.08 (1H, dd, J=13.4, 9.5 Hz), 3.96–3.77 (4H, m), 3.65 (1H, broad d, J=10.9 Hz), 2.92–2.80 (1H, m), 2.80–2.64 (3H, m), 2.64–2.51 (2H, m), 2.33 (2H, broad t, J=10.3 Hz) 2.20–1.94 (3H, m), 1.72 (1H, dt, J=13.3, 13.2, 3.7 Hz), 1.58 (1H, ddd, J=13.1, 10.9, 4.3 Hz), 1.03 (3H, t, J=7.4 Hz) ppm. LRMS: 408.86.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28]Br)[N:18]3[C:23]=2[C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>CN(C=O)C.[I-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:18]3[C:23]=2[C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(CCCCBr)cc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 55 °C
Yield: 94.5 %

Procedure:
To a solution of 5-[3-(benzyloxy)phenyl]-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (129 mg, 0.29 mmol) in DMF (1.5 mL) was added pyrrolidine (26 μL, 0.31 mmol), triethylamine (120 μl, 0.86 mmol), and sodium iodide (0.4 mg, 0.003 mmol). The reaction was heated (55° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the organic was washed with water (2×20 mL), brine, dried (Na2SO4) and evaporated to afford 121 mg (96%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ7.87 (s, 1 H), 7.46-7.41 (m, 2 H), 7.41-7.28 (m, 4 H), 7.08-7.04 (m, 1 H), 7.02-6.97 (m, 2 H), 6.55 (s, 1 H), 5.14 (s, 2H), 2.87 (t, 2 H), 2.42-2.33 (m, 6 H), 1.76-1.66 (m, 2 H), 1.67-1.60 (m, 4 H), 1.56-1.46 (m, 2 H); ES-MS m/z 442.2 [M+H]+, HPLC RT (min) 2.30.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:32]([O:39][C:40]1[CH:57]=[CH:56][C:43]([C:44]([NH:46][CH2:47][C:48](=[O:55])[N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[O:45])=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:58]1([CH2:64][C:65](O)=[O:66])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>O.CN(C=O)C>[CH2:32]([O:39][C:40]1[CH:57]=[CH:56][C:43]([C:44]([NH:46][CH2:47][C:48](=[O:55])[N:49]2[CH2:50][CH2:51][N:52]([C:65](=[O:66])[CH2:64][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:53][CH2:54]2)=[O:45])=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)Cc2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
EDCI.HCl (122 mg, 0.634 mmol), HOBT (68 mg, 0.51 mmol) and DIPEA (220 μL, 1.27 mmol) were added to a mixture of 4-benzyloxy-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamide (150 mg, 0.42 mmol), DMF (5 mL) and phenyl acetic acid (69 mg, 0.51 mmol). The resulting mixture was allowed to stir at room temperature overnight. Water was then added, and the product was extracted using EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford a crude product, which was purified twice by column chromatography (using silica gel with a mesh size of 60-120, and 80:20 EtOAc:hexane as the eluent) to afford 4-benzyloxy-N-[2-oxo-2-(4-phenylacetyl-piperazin-1-yl)-ethyl]-benzamide in 55% yield. LC-MS purity: 92% 1H NMR (DMSO-D6): δ 8.4 (t, 1H), 7.8 (d, 2H), 7.4 (m, 7H), 7.2 (d, 3H), 7.1 (d, 2H), 5.2 (s, 2H), 4.1 (d, 2H), 3.8 (d, 2H), 3.5 (m, 8H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)N[C@@H](CO)[C@@H](O)c2ccccc2)cc1
Yield: 18.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 5.7 g of (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol, 5 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 250 ml of benzene, 250 ml of absolute methanol and 4.34 g of sodium cyanoborohydride, 1.54 g of the title compound were obtained having an Rf=0.27 (thin layer chromatography over silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O>[CH:24]1([N:23]([CH3:22])[C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CNC1CCCCC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: CS(C)=O
Product: CN(c1cc2nc3c(cc2cc1F)c(=O)c(C(=O)O)cn3C)C1CCCCC1

Procedure:
8-[(Cyclohexyl)(methyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 1, but from 1.5 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.3 cm3 of N-methylcyclohexylamine in 30 cm3 of dimethyl sulphoxide. After washing 2 times with with 15 cm3 of ethanol, 1.7 g of 8-[(cyclohexyl)(methyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 265° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1[N:12]1[CH:17]=[CH:16][N:15]=[C:14](OC2C=CC=CC=2)[C:13]1=[O:25].[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][NH2:35].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C1([Mg]Br)CCCC1>O1CCCC1>[CH:36]1([NH:39][C:6](=[O:8])[C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:35][CH2:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[S:27][CH3:26])[C:13]3=[O:25])[CH:4]=2)[CH2:38][CH2:37]1
Reactant: CSc1ccccc1CN
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(Oc3ccccc3)c2=O)c1
Reactant: NC1CC1
Agent: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Product: CSc1ccccc1CNc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-methyl-3-(2-oxo-3-phenoxy-2H-pyrazin-1-yl)-benzoic acid, methyl ester (Example 128a, 111 mg), 2-(methylthio)-benzenemethanamine (100 mg) and tetrahydrofuran (1 mL) was heated within a microwave for 5 h at 120° C. before being cooled to room temperature. Cyclopropylamine (0.2 mL) was added followed by addition of cyclopentylmagnesium bromide (2M in diethyl ether, 0.8 mL). The mixture was stirred for 10 min., quenched with sat. NH4Cl and extracted into ethyl acetate. The organic phase was concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (39 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH2:12]=O.[C:14]([O:19][CH3:20])(=[O:18])[C:15]([CH3:17])=[CH2:16]>CO>[OH:1][C:2]1[C:7]([CH3:12])=[C:6]2[C:5](=[C:4]([CH3:10])[C:3]=1[CH3:11])[O:9][C:15]([CH3:17])([C:14]([O:19][CH3:20])=[O:18])[CH2:16][CH2:8]2
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=C(C)C(=O)OC
Reactant: C=O
Solvent: CO
Product: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C

Procedure:
Into a 30-mL stainless-steel pressure reactor equipped with a stirrer, 1,4-dihydroxy-2,3,5-trimethylbenzene (1.0 g, 6.6 mmol), an aqueous formalin solution (1.1 g, formaldehyde 37 wt. %, methanol 7 wt. %, and water 56 wt. %), and methyl methacrylate (3.3 g, 32.9 mmol) were placed. The mixture was allowed to react at 180° C. for three hours under stirring, while the reactor was tightly closed. After completion of reaction, the reaction mixture was cooled to room temperature, and methanol was added to the mixture, whereby crystals were precipitated. The crystals were collected through filtration, to thereby yield methyl 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylate in the form of white powder (1.45 g, 5.5 mmol). Reaction scores on the basis of 1,4-dihydroxy-2,3,5-trimethylbenzene and chemical purity which was determined through high-performance liquid chromatography (HPLC) were found to be as follows:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=[C:5](B(O)O)[CH:4]=[C:3]1[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])C)[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>N1C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:30][SiH:28]([CH3:31])[CH2:27][CH2:26][O:25][CH2:24][N:23]1[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=[C:19]1[C:3]1[C:2](=[O:1])[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])[N:6]=[C:5]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:4]=1
Reactant: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Reactant: c1c[nH]cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: C[SiH](C)CCOCn1c(-c2cc(-n3ccnc3)nn(COCC[Si](C)(C)C)c2=O)nc2ccccc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
100 mg of 6-oxo-1-(2-trimethylsilanylethoxymethyl)-5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-yl]-1,6-dihydropyridazine-3-boronic acid (example 55), 35.5 mg of copper(II) acetate and 20 mg of imidazole are dissolved in dry pyridine, and the solution is stirred at 80° C. for 3 hours. For workup, it is diluted with 20 ml of water and extracted several times with ethyl acetate, the organic phases are dried using a silica gel cartridge, and the volatile components are distilled off. The crude product is purified by preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)(O[C:20](=[O:26])OC(Cl)(Cl)Cl)Cl.[CH2:28]([N:30](CC)CC)C.Cl>ClCCl>[CH3:20][O:26][N:30]([CH3:28])[C:13]([C:10]1[CH:11]=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1)=[O:15]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 144.9 %

Procedure:
To an ice-cooled solution (0° C.) consisting of 2-phenylpyrimidine-5-carboxylic acid (prepared according to WO 2007/041634 Al Example 1, 2.10 g, 10.5 mmol) in dichloromethane (40 mL) was added triphosgene (1.55 g, 5.25 mmol) and triethylamine (7.3 mL, 52.45 mmol). Upon addition of triethylamine a yellow precipitate formed in solution. After stirring for five minutes in the ice bath, N,O-dimtheylhydroxylamine hydrochloride (1.02 g, 10.5 mmol) was added and the solution was allowed to slowly warm to room temperature over 30 minutes. The reaction was complete after stirring for three hours at room temperature. The crude solution was filtered and washed with excess dichloromethane. The filtrate was concentrated under reduced pressure to afford an orange solid. The crude product was purified by flash silica column chromatography. Elution through a 40-g Silicylce® flash silica cartridge with 10-30% ethyl acetate in hexanes afforded the title intermediate as a colorless oil (1.85 g, 72% yield); Rf 0.48 with 1:1 v/v hexanes-ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 9.20 (s, 2H), 8.50 (dd, 2H), 7.55 (m, 3H), 3.62 (s, 3H), 3.42 (s, 3H); MS (APCI+) m/z 244.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[S:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2ccc(Cl)cc2C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=S)Nc2ccc(Cl)cc2C1
Yield: 157.1 %

Procedure:
A mixture of 7-chloro-2-oxo-1,2,3,5-tetrahydro-benzo[1,4]diazepine-4-carboxylic acid tert-butyl ester (41.1 g, 0.139 mol) and 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (31.5 g, 0.0763 mol) in tetrahydrofuran (1100 ml) was heated at reflux for 3 h. The solvent was evaporated and the residue was triturated in tert-butyl methyl ether. The precipitate was removed by filtration and the filtrate was concentrated to dryness. The residue was crystallized from hot ethanol to give the title compound (37.5 g, 86.4%) as light yellow solid.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH:6](=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C)C=O.C(N(CC)CC)C>C(O)C>[CH:6](=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16]1([C:14](=[O:15])[CH2:13][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCC=O
Agent: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCC(=O)C(CC(=O)c1ccccc1)c1ccccc1
Reaction time: 36 h

Procedure:
Following the description in Example 1, 18 g (0.25 mol) of n-butyraldehyde, 52 g (0.25 mol) of benzylideneacetophenone and 500 ml of dimethylformamide, 250 ml of ethanol and 13.5 g (0.05 mol) of Cat. 1 are -- after addition of 10.1 g (0.1 mol) of triethylamine -- brought to the reflux temperature for 36 hours. To work up the batch, the solvent mixture is distilled off in a waterpump vacuum, the oily residue, when cold, is taken up in 250 ml of chloroform and the solution is washed successively with water, with dilute sodium bisulphite solution and twice more with water. The organic phase is separated off, the chloroform is distilled off and the residue is distilled in an oil pump vacuum. The fraction of boiling point0.2 = 140° - 170° C which is thus obtained is subsequently fractionated through a 30 cm Vigreux column. After a first running of benzylideneacetophenone, 1,3-diphenylheptane-1,4-dione is isolated as the main fraction.