Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28]([NH:1][C@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([F:18])[C:12]([C:13]#[N:14])=[C:15]([F:17])[CH:16]=3)=[N:5]2)=[O:29])[CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)no1
Reactant: C[C@@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Product: CC(=O)c1cc(C(=O)N[C@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)no1

Procedure:
The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.214 g, 0.81 mmol) and 5-acetylisoxazole-3-carboxylic acid (0.127 g, 0.81 mmol) using the method of Example 34(d). Yield 0.166 g. 1H NMR (400 MHz; MeOD): δ 1.28 (d, 3H), 2.59 (s, 3H), 4.37 (m, 2H), 4.60 (m, 1H), 6.80 (d, 1H), 7.27 (s, 1H), 7.64 (m, 2H), 7.72 (d, 1H).
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[O:10]=[C:2]1[N:1]([C:22]([O:24][CH3:25])=[O:23])[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of methyl (S)-(+)-2-pyrrolidone-5-carboxylate (4.80 grams, 33.5 mmol) in tetrahydrofuran (90 mL) was added a solution of lithium bis(trimethylsilyl) amide (1 M solution in hexanes, 40.0 mL, 40.0 mmol) dropwise via syringe over 15 minutes; then methyl chloroformate (2.90 mL, 36.9 mmol) was added dropwise via syringe over 5 minutes. The resulting slurry was stirred at −78° C. for 1 hour after which the reaction was quenched with 1 M HCl (50 mL). The mixture was allowed to come to room temperature, concentrated under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and 1 M HCl (200 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic layers were dried (sodium sulfate), filtered, and concentrated to provide the titled compound. MS (DCI/NH3) m/e 202 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 4.70 (dd, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 2.74-2.30 (m, 3H), 2.15-2.05 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][NH2:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45](O)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][NH:44][C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: O=C(O)c1ccccc1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCNC(=O)c4ccccc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 50.0 mg of (2S,4R,5R)-2-(2-amino-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester are reacted with benzoic acid to afford the title compound after flash chromatography (SiO2 60 F) as a colourless oil. Rf=0.50 (dichlormethane-methanol 10:1); Rt=5.33.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:26]([C:33]1[S:34][C:35]([CH3:39])=[C:36]([CH3:38])[CH:37]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:26]([C:33]1[S:34][C:35]([CH3:39])=[C:36]([CH3:38])[C:37]=1[C:7]([C:6]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(Cc2ccccc2)sc1C
Reactant: COc1ccc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
At ambient temperature, to a stirred solution containing 3-isopropyl-4-methoxybenzoic acid (27.00 g, 0.139 mol, RN-33537-78-9) and oxalyl chloride (13.3 mL, 0.153 mol) in CH2Cl2 (460 mL) was added N,N-DMF (5 drops). After 2 h, the reaction was cooled to -78° C. To the reaction was added tin (IV) chloride (17.89 mL, 0.153 mol) followed by a solution of 2-benzyl-4,5-dimethylthiophene (28.12 g, 0.139 mol) in CH2Cl2 (120 mL) that had been previously cooled to -78° C. After the addition was complete, the dry ice/acetone bath was removed and the reaction was stirred for 18 h, eventually warming to ambient temperature. The reaction was quenched into H2O (2 L) and extracted with ether. The combined ethereal extracts were sequentially washed with 1N HCl (3×500 mL), H2O (2×500 mL), NaHCO3 (2×500 mL), brine (1×500 mL), dried (MgSO4) and concentrated. Purification on silica gel, eluting with 5% EtOAc/pet. ether, gave 43.65 g (83%) of the title compound as an oil. 1H NMR (DMSO-d6) δ 1.13 (s, 3 H), 1.15 (s, 3 H), 1.81 (s, 3 H), 2.26 (s, 3 H), 3.23 (q, 1 H), 3.85 (s, 2 H), 3.88 (s, 3 H), 7.04-7.24 (m, 6 H), 7.55 (dd, 1 H), 7.63 (d, 1 H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[S-:12][C:13]#[N:14].[K+]>Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:13]([NH2:14])=[S:12])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Product: NC(=S)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
4-Trifluoromethylaniline (2.00 g; 12.4 mmol) and potassium thiocyanate (4.82 g; 49.7 mmol) was suspended in 1N aqueous HCl (20 ml). A clear solution was obtained upon heating to reflux (after 1 hour, a precipitate started to form). The mixture was refluxed overnight, then cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with brine and dried with anhydrous sodium sulphate. Solvent was removed, and the residual oil was striped twice from acetonitril, to give a quantitative yield of (4-trifluoromethylphenyl)thiourea.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][C@@H:20]([NH:26][C@@H:27]2[C:33](=[O:34])[N:32]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:31]3[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=3[S:29][CH2:28]2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:47].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:47].[BrH:47].[CH2:24]([O:23][C:21]([C@H:20]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([OH:38])=[O:37])[C:31]2[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=2[S:29][CH2:28]1)[CH2:19][CH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 1.5 h

Procedure:
In 2 ml of acetic acid is dissolved 0.4 g of tert-butyl 3(R)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (50 ml) is added to the reaction solution, which is then allowed to stand. The supernatant is decanted, and the precipitate is washed with ethyl ether and dried to give 0.4 g of 3(R)-[1(R)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide as a colorless powder.
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:25])[CH2:23][CH3:24])=[CH:18][CH:17]=1.[C:26]1(O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH3:24])=[CH:20][CH:21]=1
Reactant: CCC(O)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
Azodicarboxylic acid diisopropyl ester (2.8 g, 14.0 mmol) was added to the mixture of 1-(4-bromophenyl)propan-1-ol (2.0 g, 9.3 mmol), phenol (1.05 g, 11.2 mmol), triphenylphosphine (3.7 g, 14.0 mmol) and tetrahydrofuran (40 mL) at room temperature. Then the mixture was stirred at room temperature for 12 hours. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give 1-bromo-4-(1-phenoxypropyl)benzene as a colorless oil (2.0 g, 4%). 1H NMR (300 MHz, CDCl3): δ 7.44 (d, J=8.4 Hz, 2H), 7.25-7.15 (m, 4H), 6.89-6.80 (m, 3H), 4.98 (t, J=6.5 Hz, 1H), 2.00-1.72 (m, 2H), 0.99 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)CCC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C(=O)CCC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-butanoyl)-n-pentyl-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C1(S([O-])=O)C=CC=CC=1.C1(C)C=CC=CC=1.[Cl:27]Cl>O>[C:1]1([S:7]([Cl:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: ClCl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1ccccc1
Yield: 133.1 %

Procedure:
A reactor was charged with 29.3 g of sodium benzenesulfinate (0.14 mole) obtained by the fourth step, and the benzenesulfinate was dissolved in 65 mL of water. Then, 105 mL of toluene was charged, and 10.3 g (0.1456 mole, 1.04 times moles) of chlorine was, little by little, blown into the reactor at a temperature of 18 to 20° C. The reaction solution was aged at the same temperature of 18 to 20° C. with stirring, and separated into an organic layer and an aqueous layer. The organic layer was washed with 90 g of a 3% aqueous sodium chloride solution and then concentrated at a reduced pressure and 45° C. or less to obtain 32.9 g of a benzenesulfonyl chloride solution. Gas chromatographic quantitative analysis revealed that the concentration of benzenesulfonyl chloride in the organic layer was 70.7% (weight; 24.21 g, 0.1371 mole), and the yield was 93.9%
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH:21]=2)=[C:8]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])[CH:9]=1)(=[O:3])[CH3:2].[CH3:28][Mg]Cl.[NH4+].[Cl-]>C1COCC1.[Cl-].[Na+].O>[CH3:26][C:23]1([CH3:27])[CH2:24][CH2:25][C:20]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:28])[CH3:2])=[CH:9][C:8]=2[NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[CH:21][CH2:22]1
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)c[nH]2)c1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2ccc(C(C)(C)O)cc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [5-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 31, step (d), 30.0 mg, 0.0828 mmol) in 2 mL of THF at −78° C. under Ar was added methyl magnesium chloride (58 μL, 0.17 mmol, 3.0 M in THF). The resulting mixture was warmed to RT and stirred for 0.5 h. Treated with 10 mL of saturated NH4Cl aqueous solution followed by 10 mL of brine, the mixture was extracted with EtOAc (2×20 mL). The combined organic layers were dried with Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (2-3% MeOH/DCM) to give 29.0 mg (93%) of the title compound as a white solid. 1H-NMR (DMSO-d6; 400 MHz): δ 14.22 (s, 1H), 9.76 (s, 1H), 8.32 (s, 1H), 8.12 (d, 1H, J=1.8 Hz), 7.25 (dd, 1H, J=8.1, 1.8 Hz), 7.14 (d, 1H, J=8.1 Hz), 5.65 (m, 1H), 2.16-2.29 (m, 2H), 1.87-1.98 (m, 2H), 1.47 (t, 2H, J=6.2 Hz), 1.43 (s, 6H), 0.99 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H26N4O2, 379.2 (M+H), found 379.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:32])=[C:18]([CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:32])=[C:18]([CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=3)[N:19]=2)=[CH:13][CH:14]=1
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Cc1oc(-c2ccc(O)cc2)nc1CCOc1ccc(N)cc1
Yield: 80.9 %

Procedure:
A solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-4-oxazolyl]ethoxy}nitrobenzene (10.65 g) in methanol (200 ml) was subjected to a catalytic hydrogenation over 10% Pd-C (50% wet, 4.0 g). After the catalyst was filtered off, the filtrate was concentrated to give 4-{2-[2-(4-hydroxyphenyl)-5-methyl-4-oxazolyl]ethoxy}aniline (6.21 g, 78.2%). Recrystallization from methanol afforded brownish prisms, m.p. 184°-185° C. Elemental analysis for C18H18N2O3 ; Calcd.: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.69; H, 5.87; N, 9.01.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].[O:14]1[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([CH3:13])=[C:2]([N:21]2[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)[CH:7]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Product: COc1cc(N2CCC3(CC2)OCCO3)c(C)cc1[N+](=O)[O-]

Procedure:
Starting Materials: 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (INTERMEDIATE 7) and 1,4-dioxa-8-azaspiro[4.5]decane. m/z 309.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:27]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:28])=[CH:17][N:16]2[CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Reactant: O=C(O)C1CCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)C3CCC3)ccc2n1
Yield: 30 %

Procedure:
As described for Example 56, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (96 mg, 0.33 mmol) was converted, using cyclobutanecarboxylic acid instead of cyclopropylacetic acid, to the title compound (33 mg, 30%) which was obtained as a light brown foam. MS: m/e=373.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([CH3:28])[C:3]=1[CH2:29]O.[Cl-:31].O>CN(C)C=O>[CH3:1][C:2]1[C:7]([N:8]([C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)[CH3:27])=[CH:6][CH:5]=[C:4]([CH3:28])[C:3]=1[CH2:29][Cl:31]
Reactant: [Cl-]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CO)c2C)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CCl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 2,6-dimethyl-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzene (2.00 g) in N,N-dimethylformamide (100 ml) was added mezhanesulfonyl chloride (784 mg) under ice-cooling, and the mixture was stirred for 2 hours at the same temperature and overnight at ambient temperature. To the mixture was added water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was pulverized with diethyl ether to give 2,6-dimethyl-3-[N-[4-(methylcarbamoyl)-cinnamoylglycyl]-N-methylamino]benzyl chloride (2.00 g) as white powder.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]([NH:16][C:17]3[CH:18]=[N:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=3[CH3:23])[N:12]([CH2:26][CH2:27][CH2:28]O)[C:11]=2[C:10]([C:30]([O:32][CH3:33])=[O:31])=[CH:9][CH:8]=1.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.C(=O)([O-])O.[Na+].C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:30]([O:32][CH3:33])=[O:31])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:17]3[CH:18]=[N:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=3[CH3:23])[CH2:28][CH2:27][CH2:26][N:12]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3cnc(OC)cc3C)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(OC)cc1C
Temperature: 25 °C
Reaction time: 13 h
Yield: 37.5 %

Procedure:
Methanesulfonyl chloride (7.8 mL, 35.5 mmol) was added to a stirred solution of methyl 4-chloro-1-(3-hydroxypropyl)-2-[(6-methoxy-4-methylpyridin-3-yl)amino]-1H-benzimidazole-7-carboxylate (Reference example 120, 3.60 g, 8.89 mmol) and triethylamine (6.2 mL) in tetrahydrofuran (44 mL) at 0° C. The mixture was stirred at room temperature for 13 hr, and concentrated in vacuo. A mixture of the resulting mesylate and potassium carbonate (3.67 g, 26.7 mmol) in N,N-dimethylformamide (40 mL) was stirred at 80° C. for 4 hr. The mixture was diluted with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (1.29 g, 3.33 mmol, 37% in 2 steps).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:9]([NH2:10])=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][C:5]=1[S:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15].[H][H]>O.C(O)C.[Ni]>[NH2:11][C:7]1[CH:8]=[C:9]([NH2:10])[C:4]([CH2:3][CH2:2][NH2:1])=[C:5]([S:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15])[CH:6]=1
Reactant: [H][H]
Reactant: NCCc1c(N)cc([N+](=O)[O-])cc1S(=O)(=O)CCC(=O)O
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: NCCc1c(N)cc(N)cc1S(=O)(=O)CCC(=O)O
Temperature: 60 °C

Procedure:
27.0 g of 3-[2-(2-aminoethyl)-amino-5-nitrophenylsulphonyl]-propionic acid are suspended in 150 ml of water and 150 ml of ethanol. In an autoclave 1 g of nickel is added to the suspension, 60-70 bar of hydrogen are injected, and the temperature is raised to 60° C. Stirring is continued for some time until no further hydrogen is absorbed. After letting down, the resultant solution is clarified at 70° C. with 1 g of activated charcoal, the clarification residue is washed with 20 ml of hot water, and the combined filtrates are reacted as per Example 10.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[O:3][SiH:4]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20].C([Si]1(C)O[Si](C=C)(C)O[Si](C=C)(C)O[Si](C=C)(C)O1)=C>>[NH2:21][CH2:18][CH2:19][CH2:20][Si:4]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([O:3][Si:2]([CH3:17])([CH3:16])[CH3:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CCN
Reactant: C[Si](C)(C)O[SiH](O[Si](C)(C)C)c1ccccc1
Agent: C=C[Si]1(C)O[Si](C)(C=C)O[Si](C)(C=C)O[Si](C)(C=C)O1
Product: C[Si](C)(C)O[Si](CCCN)(O[Si](C)(C)C)c1ccccc1
Temperature: 79 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A 100 ml flask was equipped with a magnetic stirrer, reflux condenser, pot thermometer, and a sampling port. The flask was loaded with 30 g (0.105 mole ) of bis(trimethylsiloxy)phenylsilane and 6 g (0.105 ) mole of allylamine and heated to reflux (79° C.). 180 μl of 3% Pt complexed with tetravinyltetramethylcyclotetrasiloxane were added. The mixture was heated to 125° C. and held for one hour. Thirty one grams (86%) of 3-aminopropyl-bis(trimethylsiloxy)phenylsilane were produced. None of the isomeric 2-aminopropyl-bis(trimethylsiloxy)phenylsilane was formed.
Reaction SMILES: [CH3:1][C@@H:2]1[N:8]2[C:9]3[CH:10]=[C:11]([C:16]([O:18]CC)=[O:17])[CH:12]=[CH:13][C:14]=3[CH:15]=[C:7]2[C:6](=[O:21])[NH:5][CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C>[CH3:1][C@@H:2]1[N:8]2[C:9]3[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=[CH:13][C:14]=3[CH:15]=[C:7]2[C:6](=[O:21])[NH:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)[C@@H](C)CCNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1CCNC(=O)c2cc3ccc(C(=O)O)cc3n21
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of ethyl (5S)-5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (1.9 g, 6.7 mmol) in ethanol (75 mL) is added 1N NaOH solution (16 mL, 16 mmol). The reaction mixture is refluxed for 1.5 h and cooled to room temperature. The ethanol is removed under vacuum and the residue is diluted with water. The mixture is acidified with aqueous 1N HCl solution the resulting solid is collected by filtration, rinsed with water and dried to afford the title compound (1.7 g, 99%).