Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.[N:12]1C=CC=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH:4]=[N:12][C:13]([CH3:14])=[N:1]2
Reactant: c1ccncc1
Reactant: COc1cccc(N)c1C=O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc2nc(C)ncc12
Yield: 85.4 %

Procedure:
To a stirred solution of 2-amino-6-methoxybenzaldehyde [K. Tsuda et al., Chem. Pharm. Bull. 1962, 10, 856] (1.3 g, 8.6 mmol), pyridine (0.81 g, 10.3 mmol) and toluene (60 mL) was added acetic anhydride (0.97 g, 9.5 mmol). The resulting mixture was heated at reflux for 18 h, cooled, then partitioned between saturated aqueous NaHCO3 (100 mL) and ether (50 mL). The organic phase was dried (Na2SO4) and evaporated in vacuo to give a solid which was purified by chromatography on silica with 0-50% ether in hexane gradient elution to give a colourless solid (1.28 g). The latter was dissolved in 2 M methanolic ammonia (100 mL) and the solution heated at reflux for 3 h, cooled, then evaporated in vacuo. Chromatography of the residue on silica with 0-100% ether in dichloromethane gradient elution gave the title compound (0.92 g, 62%) as a colourless solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2]CC.[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1.[CH2:12](N(CC)CC)[CH3:13]>>[C:9]([O:11][CH2:7][CH2:6][CH2:12][CH3:13])(=[O:10])[CH2:8][C:1]([CH3:2])=[O:5]
Reactant: C=C1CC(=O)O1
Reactant: CCCCO
Reactant: CCN(CC)CC
Product: CCCCOC(=O)CC(C)=O
Temperature: 35 °C

Procedure:
A charge of 5,600 grams of n-butanol was placed in a 22 L, jacketed reaction flask equipped with an overhead stirrer, reflux condenser, thermocouple, and a liquid feed pump. A glycol-water mixture maintained at a set temperature of 70° C. was circulated through the reactor jacket from a bath reservoir to bring the reactor contents to 50° C. When the reactor reached 50° C., 365 mL of triethylamine was added. Diketene, in an amount of 6,049 grams, was then added at a rate of 15 mL/min. The reactor temperature was increased slowly during the addition of diketene. When the reactor reached 55° C., the circulating liquid bath temperature was lowered to cool the reactor and to maintain the reaction temperature in the range of from about 55 to about 57° C. The addition of the entire charge of diketene, (4.1 kg) required 8 hours. The reaction mixture was then allowed to cool slowly to 35° C. with continued agitation. The crude reaction product was then purified by fractional distillation at a pressure of 6 torr and provided pure n-butyl acetoacetate as a clear, colorless liquid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[N:28]1([C:24]2[CH:23]=[C:22]([NH:21][C:19]([C:18]3[CH:34]=[C:35]([C:2]4[CH:7]=[CH:6][C:5]([C:8]5[O:9][C:10]([CH3:13])=[N:11][N:12]=5)=[CH:4][CH:3]=4)[C:15]([CH3:14])=[CH:16][CH:17]=3)=[O:20])[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4cccc(N5CCOCC5)c4)ccc3C)cc2)o1

Procedure:
Example 36 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and 4-methyl-N-(3-morpholin-4-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 5) with propan-2-ol as the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(OC(=O)C)(=[O:17])C.FC(F)F.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:13][OH:17])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)c[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: FC(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Cl)cnc1CO
Reaction time: 72 h
Yield: 20 %

Procedure:
To a solution of ethyl 5-chloro-2-methylnicotinate 1-oxide (step 3, 4.1 g, 19 mmol) in dichloromethane (100 ml) was added trifluoromethane acetic acid anhydride (4 ml) at room temperature and the reaction mixture was stirred for 3 days. The reaction mixture was added 2 N hydrochloric acid solution (30 ml) with stirring. After 30 min, the whole mixture was extracted with dichloromethane. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20/1 to 4/1) to afford 840 mg (20%) of the title compound:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:24])=[O:23]
Reactant: COc1ccc(CCO)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCOS(C)(=O)=O)cc1OC
Reaction time: 4 h
Yield: 102.6 %

Procedure:
A solution of 18.2 g (0.1 mole) of 3,4-dimethoxyphenethyl alcohol in 150 ml of methylene chloride was cooled to -5° C. To the solution was added 13.9 ml (0.1 mole) of triethylamine followed by 7.7 ml (0.1 mole) of methanesulfonyl chloride keeping the temperature below 0° C. The reaction was stirred for 4 hr, poured into water, washed with brine, dried over Na2SO4, and evaporated to give 26.7 g of product as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([NH2:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.Cl.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.CC1(C)C(C)(C)OB([C:46]2[CH:54]=[CH:53][CH:52]=[C:51]3[C:47]=2[CH:48]=[N:49][NH:50]3)O1>C(Cl)Cl>[NH:50]1[C:51]2[C:47](=[C:46]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([C:11]([NH:14][C:29](=[O:36])[C:30]5[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=5)([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:54]=[CH:53][CH:52]=2)[CH:48]=[N:49]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(N)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cccnc1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (150 mg, 0.5 mmol) in CH2Cl2 (10 mL) was added Et3N (450 μL, 3.2 mmol) and nicotinoyl chloride hydrochloric acid (160 mg, 0.9 mmol). The resulting mixture stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. A portion (0.2 mmol) of the resulting crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 to provide 410 after reverse phase HPLC purification (22 mg). MS (Q1) 500 (M)+
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4](O)=[O:5].C1C=[C:26]2[N:28]=N[N:30](O)[C:25]2=CC=1.O.CCN=C=NCCCN(C)C.Cl.NCC#N.CN1CCOCC1>CN(C=O)C>[C:26]([CH2:25][NH:30][C:4](=[O:5])[C@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:2]([CH3:20])([CH3:21])[CH3:1])#[N:28]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](C(=O)NCC#N)N1Cc2ccnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
(R)-3,3-Dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (40.0 mg, 0.139 mmol), HOBt hydrate (25.6 mg, 0.167 mmol), and EDC hydrochloride (40.0 mg, 0.209 mmol) were combined in DMF (2 mL). 2-Aminoacetonitrile (11.71 mg, 0.209 mmol) and 4-methylmorpholine (0.062 mL, 0.557 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-45% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a pale yellow solid (36 mg, 59%). 1H NMR (500 MHz, DMSO-d6) δ 1.09 (s, 9H), 4.01-4.12 (m, 2H), 5.13-5.22 (m, 2H), 5.33 (br s, 1H), 7.10 (d, J=4.5 Hz, 1H), 7.87 (s, 1H), 8.26 (d, J=4.5 Hz, 1H), 8.86 (br s, 1H), 12.25 (br s, 1H). [M+H] calc'd for C17H19N5O2, 326; found, 326.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:43][C@@H:44]([C:50]1[CH:51]=[C:52]2[C:57](=[CH:58][CH:59]=1)[N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:55][CH2:54][CH2:53]2)[CH2:45][C:46]([O:48][CH3:49])=[O:47]>CN(C)C=O>[C:60]([N:56]1[C:57]2[C:52](=[CH:51][C:50]([C@H:44]([NH:43][C:7]([C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[O:9])[CH2:45][C:46]([O:48][CH3:49])=[O:47])=[CH:59][CH:58]=2)[CH2:53][CH2:54][CH2:55]1)([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]
Reactant: Cc1cc(C(=O)O)no1
Reactant: COC(=O)C[C@@H](N)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](NC(=O)c1cc(C)on1)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 5-methyl-isoxazole-3-carboxylic acid (65 mg) in dimethylformamide (30 ml) was treated successively with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg), diisopropylethylamine (1 ml) and methyl (R) 3-amino-3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (200 mg, Reference Example 14). After standing at room temperature overnight the mixture was evaporated to low bulk and the residue partitioned between ethyl acetate and dilute hydrochloric acid. The layers were separated and the organic layer was washed with sodium carbonate solution, dried, and evaporated. The residue was purified by flash chromatography to give the title compound as an orange gum, 310 mg.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[NH:5][C:6]([N:8]([CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH3:9])=[O:7].Cl>O1CCOCC1.O>[CH3:9][N:8]([CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[C:6]([NH:5][C@H:4]([C:3]([OH:24])=[O:2])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)N(C)CC(O)CO
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C[C@H](NC(=O)N(C)CC(O)CO)C(=O)O)cc1

Procedure:
The resultant compound from Example 55 (114 mg, 0.355 mmol) in dioxane (4 ml) and water (2 ml) at 0° C. was treated with LiOH monohydrate (42.0 mg, 1 mmol). After 90 min 2M HCl (0.6 ml, 1.2 mmol) was added and the mixture was evaporated to a foam which was used without further purification, DCI-MS: (M+H)=327.
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1C(=O)c2ccncc2C1=O
Reactant: COc1cccc(N)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)C2C(=O)c3ccncc3C2=O)c1
Temperature: 25 °C

Procedure:
5,7-Dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester (18 g) (see, Robin D. Allan and Joyce Fong, Aust. J. Chem., Vol. 36, pp. 1221-1226, 1983), m-anisidine (17.7 ml) and acetic acid (9 ml) were suspended in toluene (1,000 ml). This mixture was refluxed for 110 minutes under nitrogen. The mixture was cooled to room temperature and the precipitate was collected with suction. The precipitate was washed with toluene and dichloromethane and dried under reduced pressure to give a brown powder (21.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:12][C:11]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]3[C:10]=2[N:9]=[CH:8][N:7]=[C:6]3[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1NC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Yield: 9.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 7-methyl-N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-37, 140 mg, 0.44 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 163 mg, 0.57 mmol), oxalyl chloride (108 mg, 0.86 mmol), DMF (1 drop) and DIPEA (170 mg, 1.32 mmol) in CH2Cl2 (5 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.71 (s, 1H), 10.03 (s, 1H), 8.72 (s, 1H), 8.46 (d, J=8.4 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J=9.3 Hz, 1H), 8.19 (t, 1H), 7.66-7.63 (m, 2H), 7.46 (d, J=6.9 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.31 (t, J=8.1 Hz, 1H), 4.33 (d, J=5.4 Hz, 2H), 2.50 (s, 3H), 1.15 (s, 9H); MS (m/z): 588.23 (M)+.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#N)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[C:13](O)(=[O:15])C.S(=O)(=O)(O)[OH:18]>O>[CH3:13][O:15][C:11]([C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][N:5]=[CH:4]2)=[O:18]
Reactant: CC(=O)O
Reactant: N#Cc1ccc2[nH]ncc2c1F
Reactant: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc2[nH]ncc2c1F
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To 1.65 g of 4-fluoro-1H-indazole-5-carbonitrile obtained in Production Example II-13-b were added 8 ml of glacial acetic acid, 8 ml of water and 16 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 4 hours. After standing to cool, 150 mg of ice-water was added, and the precipitated carboxylic acid was collected by filtration. Under ice-cooling, to a solution of the resulting carboxylic acid in 12 ml dimethylformamide and 40 ml tetrahydrofuran was added an excess amount of a solution of diazomethane in diethyl ether, and the mixture was stirred at the same temperature for 45 minutes. The solvent was evaporated, and the residue was dissolved in 100 ml of ethyl acetate. The mixture was sequentially washed with saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 1.98 g of the title compound as bright yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:19]=1[CH2:20][N:21]([CH3:42])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:17][C:18]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:19]=1[CH2:20][N:21]([CH3:42])[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH2:40][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH2:36][CH2:35]2)(=[O:32])=[O:33])=[CH:29][CH:30]=1)=[O:23]
Reactant: CN(Cc1cc(F)ccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(Cc1cc(F)ccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Yield: 37.4 %

Procedure:
The title compound was prepared from N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.130 g, 0.53 mmol), 1-(2,5-difluoro-benzyl)-3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-1-methyl-urea (0.8 mmol), glacial acetic acid (0.029 mL, 0.5 mmol) and sodium cyanoborohydride (0.031 g, 0.5 mmol) according to the general procedure used for example 84 (Step E) to give the final product (0.135 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].[CH:27](N(CC)C(C)C)(C)C.C[C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4([CH3:27])[CH:37]=[CH:45][CH:44]=[CH:43][CH2:42]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)C1(C)C=CC=CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
A mixture of 1.0 g of 5-(3-methoxy-4-amino-benzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.56 g of 2-methylbenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.27 g of the desired product as a crystalline solid, m.p. 209°-210° C.
Reaction SMILES: O[CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[ClH:20].[Cl:20][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: O=c1cc(CO)[nH]cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=c1cc(CCl)[nH]cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A suspension of 2-(hydroxymethyl)-5-[(phenylmethyl)oxy]-4-oxo-1,4-dihydropyridine (3 g, 12.99 mmole) in chloroform (15 ml) was cooled to 0° C. under argon and treated with thionyl chloride (6.1 ml, 83.62 mmole). Within several minutes, a homogeneous solution was obtained. After stirring an additional 5 minutes, a cream colored solid precipitated. The cooling bath was removed, and the mixture was heated at reflux for 45 minutes. The mixture was cooled to 0° C. and the white suspended material was filtered, washed with chloroform and hexane and dried in vacuo. The yield of the title compound was 3.65 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].Cl>C(OCC)C.C1COCC1.O>[C:16]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)N(C)C
Reactant: Clc1ccc(Br)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)cn1
Reaction time: 1 h

Procedure:
To a suspension of 56 g of 2-bromo-5-chloropyridine in 560 ml of dry diethylether is added a solution of 179 ml of n-butyllithium (15% solution in hexane) at -78° and under argon at such a rate that the temperature never exceeds -72°. Immediately thereafter the solution of 25.7 ml of N,N-dimethylacetamide in dry THF is added. The mixture is stirred for one hour at the same temperature and thereafter decomposed by careful addition of 100 ml of 3N hydrochloric acid, followed by 100 ml of water with vigorous cooling. Working up by process A (see Example 1) and purification by chromatogrphy over silica gel (toluene/ethyl acetate=20/1) yields the compound as white needles; m.p.: 58°-65°.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1I.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C1COCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1ccc(I)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 2.89 ml (20.7 mmol, 5.0 eq.) of triethylamine, 2.99 g (4.1 mmol) of 2-bromo-4-chloro-1-iodobenzene and 489 mg (4.97 mmol, 1.2 eq.) of ethynyl(trimethyl)silane were added successively to a solution of 73 mg (0.10 mmol, 0.025 eq.) of bis(triphenylphosphine)palladium(II) chloride and 20 mg (0.10 mmol, 0.025 eq.) copper(I) iodide in 27 ml of THF, and the mixture was stirred at RT overnight. The reaction mixture was then diluted with ethyl acetate and filtered through Celite, and the filtrate was concentrated under reduced pressure. After addition of ethyl acetate/water and phase separation, the organic phase was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 3.21 g (quant.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:11][S:12][CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C=C(Cl)C=C(C(OO)=[O:30])C=1.[OH-:33].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:10][CH2:11][S:12]([CH3:13])(=[O:30])=[O:33])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [OH-]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 84 %

Procedure:
To a stirred solution of 372 (660 mg, 1.88 mmol) in DCM (20 mL) at 0° C. was added MCPBA (1393 mg, 5.65 mmol) and stirring was continued at RT for 24 h. A dilute solution of NaOH was added and the mixture was twice extracted with DCM, washed with brine, dried (MgSO4), and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford 609 mg (84%) of (R)-tert-butyl 1-(3,4-dichlorophenyl)-3-(methylsulfonyl)propylcarbamate (374) as a white solid.