Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH3:19])[C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])=[O:8])=[O:4].C[SiH](C)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH3:19])[C@@H:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[OH:8])=[O:4]
Reactant: COC(=O)N[C@@H](C)C(=O)c1cc(OC)ccc1OC
Agent: C[SiH](C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@@H](C)[C@H](O)c1cc(OC)ccc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a stirred solution of ketone i.e. (S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanone (20 g, 74.9 mmol) and dimethylphenyl silane (10.7 g, 78.6 mmol) in dry DCM (500 cm3) at 0° C. in an ice bath was added dropwise trithioroacetic acid (TFA) (50 cm3). The solution was stirred at 0° C. for 1 h and then quenched by the addition of sodium hydroxide (500 cm3, 1N). The organic layer was dried and concentrated under reduced pressure to give a yellow oil which solidified on standing. This solid was crystallized from ether/hexane to give the product as a white crystalline solid (15.6 g, 75%). 1H NMR (250 MHz; C2HCl3) 1.03 (3H, d, J7.0, CH3), 3.04 (1H, d, J4.3, OH), 3.68 (3H, s, COCH3), 3.78 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.94-3.99 (1H, m, H-2), 5.05-5.15 (2H, m, H-1 and NH), 6.72-6.85 (2H, m, ArH) 6.97 (1H, d, J 2.0, ArH).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]([F:17])[CH:10]=1)CCC>C1COCC1>[F:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][CH2:6][OH:5])[CH:10]=[C:11]([F:17])[C:12]=1[CH3:16]
Reactant: CCCCOC(=O)CCc1cc(F)c(C)c(F)c1
Solvent: C1CCOC1
Product: Cc1c(F)cc(CCCO)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 3-(3,5-difluoro-4-methyl-phenyl)-propionic acid butyl ester (2.200 g; 8.584 mmol) in anhydrous THF (20 ml) was added dropwise a 1N solution of BH3.THF complex in THF (13 ml; 13 mmol). The resulting solution was stirred at 0° C., under nitrogen, for 1 h, and then at rt overnight. The reaction mixture was quenched by dropwise addition of MeOH (5 ml) followed by water (10 ml). The volatiles were removed under vacuum, and the product was extracted with DCM (3×20 ml). The combined organic layers were then washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=12/1) to give the pure product 3-(3,5-difluoro-4-methyl-phenyl)-propan-1-ol as a pale yellow oil (1.440 g; 90%). LC-MS: tR=0.87 min.; [M+H]+: no ionisation.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16].C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:16][C:15]3[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:13]([OH:12])[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(N)cc1O
Reactant: Clc1ncnc2[nH]c(Br)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(Nc2ncnc3[nH]c(Br)cc23)cc1O
Temperature: 120 °C
Yield: 69.9 %

Procedure:
6-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.41 mmol), prepared as in reference 1, is mixed with 3-hydroxy-4-methoxyaniline (170 mg, 1.22 mmol) and diisopropylethylamine (213 μL, 1.22 mmol) in n-butanol (1.3 mL). The mixture is heated to 120° C. for 18 hours, with stirring. The reaction is then cooled to ambient temperature and the solvent is removed. The resultant crude product is purified by flash column chromatography using a gradient of 3-5% MeOH in DCM to yield 5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methoxy-phenol (96 mg; 66%); 1H NMR (500 MHz, d-methanol) δ 8.17 (s, 1H), 7.16 (s, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H), 6.61 (s, 1H), 3.87 (s, 3H), 3.75 (s, 3H); LC-ESMS observed [M+H]+ 349.0 (calculated for C14H13BrN4O2, 348.0).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To dichloromethane solution (2 ml) of 3-bromo-4-methylbenzoic acid (50 mg, 0.23 mmol), WSCI (67 mg, 0.348 mmol), morpholine (24 μl, 0.278 mmol) and N,N-dimethylaminopyridine (28 mg, 0.232 mmol) were added, followed by stirring at room temperature for 16 hours. To the reaction mixture, saturated aqueous ammonium chloride solution was added, followed by extraction twice with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), and dried over sodium sulfate, followed by distilling off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1), whereby (3-bromo-4-methyl-phenyl)-morpholin-4-yl-methanone was obtained as a yellow brown solid (68 mg, 100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][CH3:23])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:22]([C@@H:2]1[NH:1][C:32](=[O:34])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:23]
Reactant: CC[C@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]1NC(=O)N(c2ccc(Oc3ccc(C)c(OC)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 178.6 %

Procedure:
To a solution of (2S)-2-amino-N-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)butanamide (Intermediate 67, 43 mg) in dry dichloromethane (3 mL), triethylamine (0.095 mL, 0.682 mmol) was added. The reaction mixture was cooled down with an ice bath. A solution of triphosgene (18.21 mg, 0.061 mmol) in dichloromethane (0.750 mL) was then added dropwise and the reaction mixture was stirred during 30 minutes at 0° C. The reaction was quenched with water (10 mL). The organic phase was then separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column SNAP 10 g and cyclohexane/ethyl acetate from 80/20 40/60 as eluent to afford the title compound as a white solid (37.2 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.Cl>C(#N)C>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)[C@@H](CCC(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Product: CCOC(=O)CC[C@@H](Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-ethyl 4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate, 39a, (0.30 g, 0.53 mmol) was in acetonitrile (5 mL) was added HCl (0.70 mL of 4 M solution in dioxane, 2.80 mmol). The reaction mixture was heated at 60° C. for 3 hours and then heated to 80° C. for 6 hours to drive the reaction to completion. After cooling to room temperature, the mixture was then stirred overnight. LCMS showed remaining starting material. Fresh HCl (0.7 mL of 4 M solution in dioxane, 2.80 mmol) was added and the mixture was heated to 80° C. overnight. All volatiles were removed under reduced pressure and the residue was diluted with EtOAc and aqueous saturated NaHCO3 solution. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 144 mg of (R)-ethyl 4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate, 23, and 29 mg of (R)-4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoic acid, 20. Spectral data for 20: 1H NMR (400 MHz, DMSO) δ 12.23 (s, 1H), 11.93 (s, 1H), 8.48 (d, J=9.9 Hz, 1H), 8.33-8.07 (m, 3H), 7.18 (d, J=9.3 Hz, 1H), 4.39 (t, J=10.2 Hz, 1H), 2.38-2.07 (m, 2H), 1.99-1.92 (m, 1H), 1.80-1.64 (m, 1H), 1.00 (d, J=20.2 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.14 minutes (M+H) 390.06.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH2:10](Cl)[C:11]#[CH:12].[OH-].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:12][C:11]#[CH:10]
Reactant: Cc1cccc(C)c1N
Reactant: C#CCCl
Agent: [Na+]
Agent: [OH-]
Product: C#CCNc1c(C)cccc1C

Procedure:
2,6-Dimethylaniline (12.1 g, 0.1 mole) and propargyl chloride (3.8 g, 0.05 mole), were mixed and heated over a steam bath using an efficient reflux condenser for 8 hours, then treated with aqueous caustic soda solution, extracted with ether, the ethereal layer worked up and the residue distilled to give 2,6-dimethylphenyl propargylamine, b.p. 56°-58° C./0.01 mm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:41]1[CH:42]=[CH:43][C:38]([CH:36]=[O:37])=[CH:39][CH:40]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: COC(=O)c1c(-c2ccc(C=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and 4-formylphenylboronic acid.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[O-]CC.[K+].[CH2:15]([O:22][C:23]1[C:24]([N+:31]([O-:33])=[O:32])=[C:25]([CH3:30])[C:26]([Cl:29])=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(OCC)C>[CH2:15]([O:22][C:23]1[C:24]([N+:31]([O-:33])=[O:32])=[C:25]([CH2:30][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:26]([Cl:29])=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c(Cl)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1c(Cl)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
Diethyl oxalate, 1.20 g (7.92 mmol), was added dropwise to a suspension of 0.67 g (7.92 mmol) of potassium ethoxide in diethyl ether (50 ml) at room temperature. Subsequently 2.00 g (7.20 mmol) of 3-benzyloxy-6-chloro-2-nitrotoluene was added to the mixture followed by stirring for 4 hours at room temperature. The reaction solution was poured onto 1N hydrochloric acid and the mixture was extracted twice with diethyl ether. The combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 1.60 g (53.5%) of ethyl (3-benzyloxy-6-chloro-2-nitrophenyl)pyruvate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnn3C)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnn3C)c1)=N2

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M31) (78 mg, 0.14 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (48 mg).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1(N)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)([CH3:17])[CH3:16].C1C=CC2N(O)N=[N:39]C=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([C:31]2[CH:32]=[C:24]([CH:21]3[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]3)[CH:25]=[CH:26][C:27]=2[C:28]([NH2:39])=[O:29])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1
Reactant: On1nnc2ccccc21
Reactant: CC(C)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(c2ccc(C(N)=O)c(C3(C(=O)NCC#N)CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.95 mmol), 4-(1-isopropyl-piperidin-4-yl)-benzoic acid hydrochloride (0.95 mmol), HOBT (0.95 mmol), WSCD (0.95 mmol) and triethylamine (0.95 mmol) are dissolved in DMF (5 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 214-216° C., Rf=0.38 (CH2Cl2/MeOH (with 3N NH3)=9:1) is obtained.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:33][CH3:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:21]>C(O)C>[ClH:1].[CH2:33]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:28]1)[CH3:34]
Reactant: CCN(CC)CCCCC1CCCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CCO
Product: CCN(CC)CCCCC1CCCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Product: Cl
Yield: 90 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[4-(diethylamino)butyl]piperidine in a yield of 90% of theory. Colourless crystals, m.p. 182°-184° C. (ethanol).
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14]([Mg]Br)[CH3:15]>C1COCC1>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([OH:7])[CH2:14][CH3:15])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)cc(OC)c1Br
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cc(OC)c(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
An oven-dried flask under argon was charged with 4-bromo-3,5-dimethoxybenzaldehyde (5.0 g, 20.4 mmol) and anhydrous THF (30 mL). The mixture was cooled over ice then a solution of ethyl magnesium bromide (3.0 M in diethyl ether, 8.2 mL, 24.5 mmol) was added dropwise from an addition funnel over a period of 45 min. After stirring for 20 min, the mixture was allowed to warm to room temperature and stirred for 19 hrs. After quenching with a solution of aqueous NH4Cl, it was diluted with H2O and EtOAc then cooled over an ice bath. After the mixture was cooled, the layers were separated. The organics were washed with H2O and brine then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo again to give 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-ol as a clear oil (5.43 g, 97% yield). The product was used without further purification.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCCCCC>[CH:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C=NC1CCCCC1
Solvent: CCCCCC
Product: O=C(NC1CCCCC1)N1CCCCC1
Yield: 98.3 %

Procedure:
23.8 g of cyclohexyl isocyanate (0.190 mol) are added dropwise to a solution of 18.62 g of piperidine (0.219 mol) in 360 ml of hexane, and then the cloudy mixture is refluxed for 2 h and then cooled and filtered, to give 39.3 g of pure N-cyclohexyl-piperidine-1-carboxamide (yield 98.3%). 12 g of POCl3 (78 mmol) are added, over 1 h, to a suspension of 15.05 g of said N-cyclohexylpiperidine-1-carboxamide (71.6 mmol) in 65 ml of dry toluene, and then, after a few hours at 20° C., 18.1 g of N-butyl-N-ethylamine (0.179 mmol) are added over 2 h, and then, after a further 2 h at 20° C., 50 ml of water are added. 49 g of 35% sodium hydroxide are then added while cooling, and the two-phase medium is then extracted with diisopropyl ether. After drying and evaporation to dryness, the oil obtained, 20 g, is distilled at 185° C. under 1 mbar, to give 17 g of the expected guanidine (yield 81%).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:9]=[CH:10][CH2:11][CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14](=[O:19])[NH:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]>[Pd]>[ClH:1].[NH2:2][CH:3]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14](=[O:19])[NH:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(N)C=CCC1CCCCC(=O)N1
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)C(N)CCCC1CCCCC(=O)N1

Procedure:
The product of EXAMPLE 245 is reduced via hydrogenation using palladium on carbon as catalyst to produce the title material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:25]\[OH:26])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)CC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)CC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-5-methyl-hexanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=391.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@H:13]3[CH2:15][C@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.[F:19][C:20]([F:26])([F:25])[C:21]([CH3:24])([NH2:23])[CH3:22]>>[F:19][C:20]([F:26])([F:25])[C:21]([NH:23][C:16]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:15][C@@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])([CH3:24])[CH3:22]
Reactant: CC(C)(N)C(F)(F)F
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Product: CC(C)(NC(=O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21)C(F)(F)F

Procedure:
The title compound was prepared in a manner similar to that described in Method UU using Intermediate 4 and 1,1,1-trifluoro-2-methylpropan-2-amine. LCMS m/z=352.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.6 and 3.2 Hz, 1H), 1.23-1.29 (m, 1H), 1.71 (s, 6H), 2.27-2.33 (m, 1H), 2.74-2.80 (m, 1H), 2.93 (d, J=17.1 Hz, 1H), 3.00 (dd, J=16.6 and 6.2 Hz, 1H), 6.94 (s, 1H), 8.42 (dd, J=2.5 and 1.5 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[NH:8]2.[C:18](Cl)(=[O:26])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:8]2[C:18]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:26]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)ccc(C)c2n1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
A suspension of 1.2 g (50 mmol) of 60% sodium hydride in 100 ml of anhydrous DMF was prepared. A solution of 9.2 g (45.3 mmol) of methyl 4,7-dimethylindole-2-carboxylate in 150 ml of anhydrous DMF was added dropwise thereto over a period of 1 hour. The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0° C. A solution of 6.25 ml (50.0 mmol) of phenyl chlorocarbonate in 20 ml of anhydrous DMF was added dropwise over a period of 30 minutes. The reaction mixture was stirred at room temperature for 15 hours and then added dropwise to 800 ml of ice water. The reaction mixture was extracted with 200 ml of ethyl acetate three times. The ethyl acetate layers were combined, washed with 300 ml of water twice and dried over anhydrous magnesium sulfate. After the ethyl acetate layers were distilled off under reduced pressure, the residue was recrystallized from acetone to provide 1.50 g of light yellow crystals. Yield: 10%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[NH:14][C:6]=2[CH:12]=1
Reactant: Cc1ccc2c(c1)C(=O)CCS2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)NC(=O)CCS2
Reaction time: 1 h
Yield: 23.7 %

Procedure:
6-Methyl-2,3-dihydro-4H-1-benzothiopyran-4-one (2g, 10.9 mmol) was dissloved in 80% ethanol (73 mL) and to this was added hydroxylamine hydrochloride (840 mg, 12.05 mmol) and sodium acetate (990 mg, 12.03 mmol). This mixture was heated at reflux for 3 hours. Water (150 mL) was added and then extracted with dichloromethane (3×100 mL), washed with brine (75 mL), water (75 mL), dried (sodium sulfate) and concentrated to residue. The residue was taken up in polyphosphoric acid (10 mL) and heated at reflux for 1 hour. Ice chips were added and water was added (100 mL) this was stirred for 1 hour. A solid formed and was filtered and purified by flashcolumn chromatography on 20 g of silica gel, eluting with (50%, 60%, and 70%) ethyl acetate in hexanes to give 7-methyl-2,3,4,5-tetrahydrobenzo[b]1,4-thiazepin-4-one (500 mg, 30%). 1H NMR (CDCl3, 300 MHz): δ7.87 (s-broad, 1H), 7.47 (d, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8.1 Hz), 6.91 (s, 1H), 3.42 (t, 2H, J=6.9 Hz), 2.62 (t, 2H, J=6.9 Hz), 2.35 (s, 3H) ppm.