Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][N:22]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=2)=[CH:15][CH:14]=1.[C:33]([NH:38][C:39](=[O:44])[O:40][CH:41]([CH3:43])[CH3:42])(=[O:37])/[CH:34]=[CH:35]/[CH3:36]>C(#N)C>[CH3:36][CH:35]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][N:22]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=2)=[CH:15][CH:14]=1)[CH2:34][C:33]([NH:38][C:39]([O:40][CH:41]([CH3:42])[CH3:43])=[O:44])=[O:37]
Reactant: CC(C)(C)OC(=O)CCn1cnc(-c2ccc(N)cc2)c1
Reactant: C/C=C/C(=O)NC(=O)OC(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CC(=O)NC(=O)OC(C)C)Nc1ccc(-c2cn(CCC(=O)OC(C)(C)C)cn2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
DBU (954 mg, 944 μl, 6.26 mmol) was added to a stirred solution of 1,1-dimethylethyl 3-[4-(4-aminophenyl)-1H-imidazol-1-yl]propanoate (for a preparation see Intermediate 96) (1.8 g, 6.26 mmol) and 1-methylethyl (2E)-2-butenoylcarbamate (for a preparation see Intermediate 49) (1.34 g, 7.83 mmol) in acetonitrile (25 mL). The reaction mixture was stirred at 50° C. for 48 h then was cooled to room temperature and most of the solvent was removed in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in AcOEt) gave 1,1-dimethylethyl 3-[4-(4-{[1-methyl-3-({[(1-methylethyl)oxy]carbonyl}amino)-3-oxopropyl]amino}phenyl)-1H-imidazol-1-yl]propanoate (1.53 g, 3.34 mmol, 53%) as an orange oil.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:3][CH:2]1[C:4](O)=[O:5].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[C:7](=[O:9])[CH:1]2[CH:2]([CH2:3]2)[C:4]1=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C1CC1C(=O)O
Product: O=C1C2CC2C(=O)N1Cc1ccccc1

Procedure:
1,2-cyclopropanedicarboxylic acid is treated with benzylamine to form 3-(benzyl)-3-azabicyclo(3.1.0)hexane-2,4-dione (I).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:37][CH3:38])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[CH:9]=[C:8]2[O:21][C@@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])=[O:28])[CH2:23]1.[C:39](N1C=CN=C1)([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)=[O:40]>ClCCl>[Cl:2][C:3]1[C:4]([O:37][CH3:38])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[CH:9]=[C:8]2[O:21][C@@H:22]1[CH2:26][N:25]([C:39]([N:41]2[CH:45]=[CH:44][N:43]=[CH:42]2)=[O:40])[C@H:24]([C:27]([N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])=[O:28])[CH2:23]1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)n1ccnc1
Reaction time: 0.75 h
Yield: 99 %

Procedure:
Compound 135 (10 g) was dissolved in anhydrous dichloromethane (20 mL) under argon. 1,1′-Carbonyldiimidazole (2 eq.) was added at room temperature. The reaction mixture was stirred for 45 min. The mixture was diluted with DCM, washed with water, dried over Na2SO4, and concentrated under vacuum. Compound 136 (9.9 g) was recovered as an off-white foam in 99% yield and in 98% purity (HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].O.[C:14]([OH:18])(=[O:17])[CH:15]=O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])/[CH:11]=[CH:15]/[C:14]([OH:18])=[O:17])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)/C=C/C(=O)c1cc(Br)c(O)c(Br)c1
Yield: 78.5 %

Procedure:
A mixture of 1-(3,5-dibromo-4-hydroxyphenyl)ethanone (5.0 g, 17.01 mmol) and glyoxylic acid monohydrate (1.566 g, 17.01 mmol) in acetic acid (10 mL) was stirred and heated at reflux for 5 days. After this time, the precipitate formed was collected and recrystallised from toluene. This gave the title compound as a brown solid (4.674 g, 78%). 1H NMR δ (ppm) (DMSO-d6): 6.70 (1 H, d, J=15.45 Hz), 7.93 (1 H, d, J=15.46 Hz), 8.24 (2 H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:15]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:20][CH2:21][NH:22][S:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCN1CCCC1
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCN2CCCC2)cc1

Procedure:
Starting from 4-acetylaminobenzenesulfonyl chloride and 2-pyrrolidin-1-ylethylamine, the title compound is prepared analogously to the method described in Example 10, intermediate 2. The crude product thus obtained can be used for further reaction without further purification. (MS-ES+: 312.1; LCMS Rt=1.957 min)
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].[CH:9]1([C:13](OCC)=[O:14])[CH2:12][CH2:11][CH2:10]1.C(#N)C.C(=O)=O>C1COCC1>[CH:9]1([C:13](=[O:14])[CH2:7][C:6]#[N:8])[CH2:12][CH2:11][CH2:10]1
Reactant: CC#N
Reactant: CCOC(=O)C1CCC1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCC1
Reaction time: 2 h

Procedure:
To 800 mL of THF at −78° C. was added n-BuLi (312.0 mL, 780.0 mmol, 2.5 M in hexanes). After the reaction temperature equilibrated (˜15 min), a solution of acetonitrile (40.7 mL, 780.0 mmol in 100 mL of THF) was added dropwise via addition funnel over a 20 min period. The resulting slurry (milky white) was allowed to stir for one hr before a solution of ethyl cyclobutanecarboxylate (53.9 mL, 390.1 mmol in 150 mL of THF) was added down the side of the flask over a 20 min period. After one hr the reaction was warmed to −45° C. (acetonitrile/CO2) and allowed to stir for two hr. The reaction was quenched cold by the dropwise addition of 2 N HCl (˜390 mL, pH=7) and then diluted with EtOAc (1 L). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×600 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield 3-cyclobutyl-3-oxo-propionitrile (quantitative yield) as a yellow oil that was used without further purification. Rf 0.32 (40% EtOAc/hexanes); m/z (APCI+) 138 (M−1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:28][C:26]=2[N:27]=1>CCO>[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:42])[CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:40][CH2:41]3)=[CH:28][C:26]=2[N:27]=1
Reactant: ClCCCCOc1ccccc1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCCCOc4ccccc4)CC3)ccc2s1
Temperature: 88 °C
Reaction time: 14 h

Procedure:
(4-Chlorobutoxy) benzene (320 mg, 1.39 mmol) in EtOH (17 Ml) was treated with DIEA (0.48 Ml, 2.78 mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as prepared in Example 3A (427 mg, 1.39 mmol), then stirred 14 hours at 88° C. Upon cooling, concentrated in vacuo and purified on the Isco™ (10 g Redisep™ columns, 100% EtOAc hold 2 min., 8 min. gradient to 20% MeOH/EtOAc, hold 10 min) to provide (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-phenoxybutyl)piperazinyl]propan-2-ol.
Reaction SMILES: [OH:1][C@H:2]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:27][CH2:26][C:20]4([C:24](=[O:25])[O:23][CH2:22][CH2:21]4)[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[OH:1][C@H:2]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@@H:3]1[NH:4][C@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:18][CH2:19][C:20]4([C:24](=[O:25])[O:23][CH2:22][CH2:21]4)[CH2:26][CH2:27]3)=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCC4(CCOC4=O)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)N1CCC2(CCOC2=O)CC1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 28 mg (0.05 mmol) of the title compound from Step A above in 1 ml anhydrous dichloromethane at ambient temperature was added 0.3 ml trifluoroacetic acid. The solution was stirred for 1 h. It was then evaporated and purified by reverse-phase HPLC (TMC Pro-Pac C18; 5-65% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give 18 mg (80%) of the title compound as a white solid. LC/MS 449.2 (M+1). 1H NMR (DMSO): δ 7.27-7.32 (m, 8H), 7.19-7.22 (m, 1H), δ 5.15 (bs, 1H), δ 4.28 (t, J=6.8 Hz, 2H), δ 4.23 (d, J=7.2 Hz, 1H), δ 4.20 (bs, 1H), δ 3.60 (bs, 1H), δ 3.27 (t, J=7.0 Hz, 1H), δ 3.21 (m, 2H), δ 3.11 (q, J=7.1 Hz, 1H), δ 2.71 (qd, J=13.1, 6.8 Hz, 2H), δ 2.23 (s, 2H), δ 1.52-1.65 (m, 5H), δ 1.38-1.44 (m, 1H), δ 1.28-1.34 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.CCN(CC)CC.CS(Cl)(=O)=O.[F:30][C:31]([F:40])([F:39])[C:32]1[C:33]([OH:38])=[N:34][CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:39])([F:40])[F:30])[C:33]2=[O:38])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: Cc1ccnc(CO)c1COC1CCCCO1
Reactant: Oc1ncccc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1COC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
[4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol (138 mg. 0.58 mmol) was dissolved in DCM (5 mL) and cooled to 0° C. NEt3 (324 μL. 2.33 mmol) and methanesulfonyl chloride (90 μL. 1.16 mmol) were added and the reaction mixture was stirred for 1 h at 0° C. After removal of the solvents in vacuo the residue was dissolved in DMF (10 mL) and CsCO3 (570 mg. 1.75 mmol) and 3-trifluoromethyl-pyridin-2-ol (142 mg. 0.87 mmol) were added. After stirring for 2 h at RT the solvent was removed in vacuo and the residue was partioned between water (20 mL) and DCM (20 mL) extracted with DCM (3×20 mL) and the combined organic fractions were dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 2:1→1:1) to give the title compound. MS (m/z): 382.9 [M+H+].
Reaction SMILES: [NH2:1][C:2](=[N:21][N+:22]([O-:24])=[O:23])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](O)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:21][N+:22]([O-:24])=[O:23])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1)=[O:10])[NH:8][C:32](=[O:33])[CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(CO)cc1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(CO)cc1
Yield: 79 %

Procedure:
Prepared analogously to Example 5f) from (R)-N5 -[amino(nitroimino)methyl]-N-[[4-(hydroxymethyl)phenyl]methyl]-ornithinamide, diphenylacetic acid and TBTU in a yield of 79% of theory.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:21]([O-])=O)=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[C:6]=1[NH2:21])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2)c1N
Temperature: 70 °C
Yield: 61.7 %

Procedure:
A suspension of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(4-iodo-phenyl)-amine (Intermediate 9, 1.1 g, 2.5 mmol) in ethanol (15 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (1.3 g, 7.6 mmol) in water (3.1 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and the organic phase was dried over anhydrous Na2SO4 and concentrated to yield 6-allyloxy-3,4-difluoro-N2-(4-iodo-phenyl)-benzene-1,2-diamine as a brown solid (620 mg). 1H-NMR (400 MHz, CDCl3): δ 4.54 (2H, d, J=4.8), 5.24 (1H, s), 5.32 (1H, d, J=10.8), 5.42 (1H, d, J=17.2), 6.06-6.02 (1H, m), 6.45 (2H, d, J=8.4), 6.57-6.62 (1H, m), 7.47 (2H, d, J=8.4).
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([OH:21])=[O:20])[CH2:14]1.[CH3:22][C:23](O)([CH3:25])[CH3:24]>C(Cl)Cl>[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([O:21][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:20])[CH2:14]1
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Anhydrous MgSO4 (3.4 g, 28 mmol) was suspended in DCM (28.1 mL) and to this vigorously stirred mixture was added concentrated sulfuric acid (0.7 g, 7 mmol). The resulting mixture was allowed to stir at ambient temperature for 30 minutes. 3-Oxocyclohexanecarboxylic acid (1.0 g, 7.0 mmol) was added followed by t-BuOH (2.6 g, 35 mmol). The resulting mixture was allowed to stir for 24 hours before it was filtered and flushed with DCM. The filtrate was washed with water, and the organic layer was again washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the title compound. The residue was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-(4-Fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.103) (0.24 g, 0.68 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.21 g, 0.82 mmol) according to the general procedure VI. Obtained as a light brown solid (0.38 g), which was subsequently deprotected.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=O.[NH:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[N+:18]([C:17]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[CH:1]=[C:27]1[NH:21][C:22](=[O:23])[NH:24][C:25]1=[O:26])([O-:20])=[O:19]
Reactant: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: O=C1CNC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(O)CCCOc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Reaction time: 1 h
Yield: 37 %

Procedure:
A mixture of ethyl 4-[3-formyl-4-nitrophenoxy]butanoate (2.00 g, 7.1 mmol), hydantoin (0.71 g, 7.1 mmol), and anhydrous sodium acetate (0.58 g, 7.1 mmol) and acetic anhydride (20 mL) was heated at reflux for 1 hour. Upon cooling, H2O was added and the mixture extracted with dichloromethane. The organic portion was washed with water, evaporated, and the residue dissolved in a solution of methanol (20 mL) and 4N NaOH (30 mL). After stirring for 1 hour, the mixture was acidified to pH=2 by addition of 2N HCl. The precipitate was collected and triturated with MeOH/CH2Cl2 to afford 4-[[4-nitro-3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]phenyl]oxy]butanoic acid (0.88 g, 37%). An analytical sample was prepared by crystallization from DMF/H2O to give gold plates, m.p. 181°-184° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH:11]=O>CO.[Pd].O>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)CCN
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(CNCCC(C)(C)C)OC
Reaction time: 3 h

Procedure:
A solution of 3,3-dimethylbutan-1-amine (1.33 mL) and 2,2-dimethoxyacetaldehyde (1.5 mL) in MeOH (10 mL) was added to palladium on carbon (0.316 g) in water (0.5 mL) at 25° C. The mixture of was hydrogenated under 5 bar at 25° C. for 3 h. The reaction mixture was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)-3,3-dimethylbutan-1-amine (1.85 g) as a liquid. 1H NMR (300 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.40 (s, 6H), 2.75 (d, J=5.8 Hz, 2H), 2.65-2.57 (m, 2H), 1.45-1.35 (m, 2H), 0.90 (s, 9H)
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:21]([O-])=O)[CH:6]=[CH:7][C:8]=2[N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)[C:3]1=[O:24].[H][H]>CO.[Pd]>[NH2:21][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:16]2)=[C:9]2[C:4]=1[C:3](=[O:24])[N:2]([CH3:1])[CH2:10]2
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Yield: 72 %

Procedure:
A mixture of methyl 1-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)piperidine-4-carboxylate (Compound 256B, 33 mg, 0.099 mmol) and palladium/C in methanol (1.0 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight. The reaction mixture was filtered through celite, concentrated in vacuo and used directly in next step without further purification (20 mg, 72% yield). MS (ES+): m/z 304.20 (100) [MH+]; HPLC: tR=0.58 min (UPLC, Analytical).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:14])[NH:12][N:13]=2)=[C:5]([CH3:15])[CH:4]=1)[CH3:2].Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([S:14][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)=[C:5]([CH3:15])[CH:4]=1)[CH3:2]
Reactant: BrCc1ccccn1
Reactant: CCc1ccc(-c2n[nH]c(=S)[nH]2)c(C)c1
Agent: Br
Product: CCc1ccc(-c2nc(SCc3ccccn3)n[nH]2)c(C)c1
Yield: 39 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4-ethyl-2-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 10a) and 2-(bromomethyl)pyridine hydrobromide. Yield 39%. 1H NMR (300 MHz, dMSO): δ 1.17-1.22 (t, 3H), 2.46 (s, 3H), 2.60-2.64 (dd, 2H), 4.50 (s, 2H), 7.14-7.18 (m, 2H), 7.27-7.29 (m, 1H), 7.47-7.49 (d, 1H), 7.58 (bd, 1H), 7.72-7.77 (m, 1H), 8.50-8,51 (d, 1H). MS(M+H, 311).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br>>[C:1]1([C:12]2[CH:13]=[CH:14][C:9]([OH:15])=[CH:10][CH:11]=2)([C:12]2[CH:13]=[CH:14][C:9]([OH:15])=[CH:10][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCC1
Reactant: Oc1ccccc1
Agent: Br
Product: Oc1ccc(C2(c3ccc(O)cc3)CCCCCC2)cc1

Procedure:
Into a solution of 112.7 parts by weight (1.0 partmole) cycloheptanone and 470 parts by weight (5.0 partmole) phenol there was introduced gaseous hydrobromic acid. The mildly exothermic reaction was moderated by external cooling, keeping the reaction temperature between 30° and 37° C. After ca. 1.5 hours of reaction time, the red colored mixture thickened and solids began to form. After an additional four hour contact with a slow stream of hydrobromic acid, all acid was removed by placing the stirred mixture under water aspirator vacuum and the solid phase removed by vaccum filtration. Washing the solids with hot water and recrystallizing them by charcoaling from aqueous menthol, yielded white crystals of 4,4'-cycloheptylidenediphenol, melting point 208°-209° C., that were 99.1% pure by gas chromatography analysis (retention time: 25.35 min.; p-cumylphenol reference retention time: 16.47 min.).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:31][NH:32][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])[C:15]=2[O:14]1
Reactant: CN
Reactant: COc1ccc(Cl)cc1-c1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cccc(-c3cc(Cl)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.058 g, 79%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.213 mmol) and methylamine (0.045 g, 2.1 mmol). mp 201-203° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:7][C:6]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[C:4](=O)[CH2:3]1.[CH2:17]([NH2:19])[CH3:18].[BH4-].[Na+]>O1CCCC1.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:17]([NH:19][CH:4]1[CH2:3][C:2]([CH3:16])([CH3:1])[S:7][C:6]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:5]1=2)[CH3:18]
Reactant: CC1(C)CC(=O)c2cc(S(N)(=O)=O)sc2S1
Reactant: CCN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCNC1CC(C)(C)Sc2sc(S(N)(=O)=O)cc21
Yield: 77.1 %

Procedure:
A solution of 5,6-dihydro-6,6-dimethyl-4H-thieno[2,3-b]thiopyran-4-one 2-sulfonamide (3.00 g, 0.011 mol) in dry tetrahydrofuran (40 ml) and benzene (40 ml) was cooled to -10° C. and condensed ethylamine (15 ml, 10.8 g, 0.24 mol) was added rapidly with stirring. Titanium tetrachloride 1.14 g, 0.006 mol) was added over 20 minutes while maintaining the temperature below 0° C. The mixture was stirred at ambient temperature for 2.5 hours, filtered, and the solid was washed with tetrahydrofuran. The combined filtrate and washings were evaporated in vacuo and the residue was suspended in absolute methanol (105 ml). With stirring under nitrogen, sodium borohydride (0.53 g, 0.014 mol) was added portionwise over 15 minutes and the mixture was stirred at ambient temperature for 21 hours. After acidification with concentrated hydrochloric acid, the mixture was concentrated in vacuo. The residue was distributed between water (100 ml) and ethyl acetate (100 ml), and the aqueous layer was separated and extracted with ethyl acetate (2×50 ml). The water layer then was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×250 ml). The combined extracts were washed with water (3×), dried over sodium sulfate, and evaporated in vacuo. The residue was crystallized as the hydrochloride salt from ethanolic hydrogen chloride to afford 2.60 g (69%) of pure product.