Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:16]=[C:17]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=4[O:30][CH3:31])[N:18]=[CH:19][C:14]=3[N:13]([CH3:32])[C:12](=[O:33])[CH:11]3[CH:7]2[CH2:8][CH2:9][CH2:10]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[NH2:80][CH:81]1[CH2:86][CH2:85][N:84]([CH3:87])[CH2:83][CH2:82]1>O.CN(C)C=O>[CH:7]1([N:6]2[C:15]3[N:16]=[C:17]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:80][CH:81]5[CH2:86][CH2:85][N:84]([CH3:87])[CH2:83][CH2:82]5)=[O:27])=[CH:23][C:22]=4[O:30][CH3:31])[N:18]=[CH:19][C:14]=3[N:13]([CH3:32])[C:12](=[O:33])[CH:2]3[CH:1]2[CH2:5][CH2:4][CH2:3]3)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C1CCCC1C(=O)N2C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)C1CCCC1C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a mixture of 0.277 g (0.00061 mole) of (rac)-4-(4-cyclopentyl-9-methyl-10-oxo-1,2,3,3a,4,9,10,10a-octahydro-4,5,7,9-tetraaza-benzo[f]azulen-6-ylamino)-3-methoxy-benzoic acid, 0.129 g (0.00092 mole) of 1-hydroxy-1H-benzotriazole, 0.505 g (0.00092 mole) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 0.404 g (0.00306 mole) of ethyldiisopropylamine and 40 mL of dimethylformamide was added 0.150 g (0.00092 mole) of 4-amino-1-methyl piperidine. The mixture was stirred overnight at room temperature, then diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed successively with water and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Waters X-terra column), eluting with a gradient of acetonitrile −0.004 M aqueous ammonium acetate to give 0.070 g of (rac)-4-(4-cyclopentyl-9-methyl-10-oxo-1,2,3,3a,4,9,10,10a-octahydro-4,5,7,9-tetraaza-benzo[f]azulen-6-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-68) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)=[O:8])=[CH:5][CH:4]=1.CC(C)=O.C(=O)=O.[NH3:35]>>[OH:8][C:7]1([C:6]2[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)=[N:35]1
Reactant: COc1ccc(C(=O)c2ccccc2C(=O)c2ccc3c(c2)OCO3)cc1
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Product: COc1ccc(C2(O)N=C(c3ccc4c(c3)OCO4)c3ccccc32)cc1
Temperature: 70 °C
Yield: 90 %

Procedure:
A bomb was charged 1-(4-methoxybenzoyl)-2-(3,4-methylenedioxybenzoyl)benzene (1.0 g, 2.8 mmol) was cooled to -78° C. (acetone/dry ice bath), and liquid ammonia (20 ml) was added and the vessel was sealed. The reaction was heated at 70° C. reaching a steady pressure of 300 psi for 24 h. The pressure was slowly released after the mixture had cooled to room temperature, and the brown residue was partitioned between ethyl acetate and water. The organic extract was acidified with 3N HCl. The resulting aqueous layer (containing the hydrochloride salt) was washed with ethyl acetate, then basified by treatment with concentrated ammonium hydroxide and extracted with ethyl acetate. The combined organic extract was successively washed with water brine and dried (MgSO4). Removal of the solvent under reduced pressure gave an isomeric mixture of the title compound as a brown foam (0.900 g, 90%).
Reaction SMILES: [OH:1][CH:2]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.[OH-].[Na+].[C:42]([OH:54])(=[O:53])[CH2:43][C:44]([CH2:49][C:50]([OH:52])=[O:51])([C:46]([OH:48])=[O:47])[OH:45]>CC(C)=O.C(Cl)(Cl)Cl.O>[C:42]([OH:54])(=[O:53])[CH2:43][C:44]([CH2:49][C:50]([OH:52])=[O:51])([C:46]([OH:48])=[O:47])[OH:45].[CH3:15][N:12]1[CH2:13][CH2:14][C:9]2([C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2](=[O:1])[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:11]1
Reactant: CN1CCC2(CC1)c1ccccc1C(O)c1ccccc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CN1CCC2(CC1)c1ccccc1C(=O)c1ccccc12

Procedure:
To 10-hydroxy-1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine (whose preparation is described in Example 2) (11.5 g.) in acetone (1250 ml.) is added, dropwise with stirring, a solution of oxidising agent (32 ml.), made from sodium dichromate dihydrate (10 g.), water (30 ml.) and concentrated sulphuric acid (7.4 ml.), made up to 50 ml. with water. After addition is complete, the reaction mixture is stirred for 1 hour and is then poured into water (3 l.) basified with 2N sodium hydroxide, and extracted three times with ether. The ether extracts are combined, washed with water and with brine and evaporated to give a brown oil which is dissolved in the minimum volume of chloroform and treated with an excess of saturated ethereal citric acid. The resulting precipitate is crystallised from methanol-ether to give 1'-methyl-10-oxo-9,10-dihydroanthracene-9-spiro-4'-piperidine citrate m.p. 172°-173°C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8]O)=[O:7])=[C:4]([OH:12])[CH:3]=1.N#N.O=S(Cl)Cl.Cl>O1CCOCC1.CCN(CC)CC.O1CCCC1>[OH:7][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[O:12][N:8]=1
Reactant: O=C(NO)c1ccc(Cl)cc1O
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Oc1noc2cc(Cl)ccc12
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
4-chloro-N,2-dihydroxy-benzamide (8 g, 42.7 mmol) is added to 10 ml of tetrahydrofuran under coverage of N2, while maintaining the temperature inside vessel lower than 30° C. and thereto is drop-added slowly 10 ml of SOCl2. After completion of drop-addition, the reaction is stirred for 30 minutes and evaporated to dryness. The residual SOCl2 is removed by azeotropic distillation with anhydrous benzene. The reaction is evaporated to dryness to obtain a yellow powder, which is dissolved in 10 ml of dioxane, while maintaining the temperature inside vessel at lower than 30° C., and thereto is drop-added slowly 5 ml of Et3N and stirred for 30 minutes, then thereto is drop-added 10% hydrochloric acid to pH=2. Under stirred, a large amount of light yellow deposit precipitates and is filtered out and recrystallized in methanol to obtain 6.50 g of 3-hydroxy-6-chloro-benzisoxazole, with a yield of 89%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH:21]=O)=[CH:15][N:14]=1)(=[O:11])=[O:10].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH2:21][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:15][N:14]=1)(=[O:10])=[O:11]
Reactant: COc1nc(C=O)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: C1COCCN1
Product: COc1nc(CN2CCOCC2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 107b using 2,3-dichloro-N-(5-formyl-3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 186a) (0.26 g) and morpholine (3.7 mL). Yield 0.057 g.
Reaction SMILES: [OH:1][C:2](=[CH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[O:9])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>C(O)C>[OH:1][C:2](=[CH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[O:9])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(O)=CC(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(O)=CC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
To an ice cooled solution of Methyl 2-hydroxy-4-(3',4'-dichlorophenyl)-4-oxo-2-butenoate (1 g, 3.6 mmol) in 95% ethanol (120 mL), 1N sodium hydroxide (7.2 mL, 7.2 mmol) were added on stirring, the resulting mixture was stirred at 0° C. for 2 hours and at room temperature for further 3 hours. The most of solvent was removed under reduced pressure and the residue taken up with 2 N HCl, the resulting suspension was stirred for 5 minutes and then filtered. The solid was washed with water, dried and recrystallized from methanol to provide the pure acid as colourless prisms (845 mg, 90%), mp.180-181° C.
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1>N.CO.[Ni]>[O:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[CH:4]([NH2:3])[CH2:5]1
Reactant: CON=C1COc2ncccc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: NC1COc2ncccc21
Reaction time: 8 h

Procedure:
To a solution of furo[2,3-b]pyridin-3(2H)-one O-methyl-oxime (22.2 mmol) in 25 mL 7N NH3 in MeOH was added Actimet M Raney-Nickel (3 g) and the reaction mixture was stirred under a H2 atmosphere at 5 bar overnight. The mixture was then filtered over Celite, washed with 100 mL MeOH and concentrated in vacuo to give the title compound as brown solid;
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)[C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[CH3:18][C:19]1[N:20]=[CH:21][O:22][C:23]=1[C:24](Cl)=[O:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.CCCCCC>C1(C)C=CC=CC=1.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.CCOC(C)=O>[CH3:18][C:19]1[N:20]=[CH:21][O:22][C:23]=1[C:24]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:2]([CH3:1])[C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6])=[O:25]
Reactant: Cc1ncoc1C(=O)Cl
Reactant: CC(C#C[Si](C)(C)C)c1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ncoc1C(=O)c1ccccc1C(C)C#C[Si](C)(C)C
Temperature: 60 °C
Yield: 78.4 %

Procedure:
A solution of 840 mg (1.2 mmol, 0.05 eq) of PdCl2(PPh3)2 in 60 mL of dry toluene was stirred in a 200 mL 3-necked flask equipped with a mechanical stirrer at room temperature under argon. To this mixture was sequentially added 5.90 grams (23.96 mmol, 1.0 eq) of boronic acid 10 and 3.81 grams (26.36 mmol, 1.1 eq) of 4-Methyl-oxazole-5-carbonyl chloride 8. Lastly, 11.0 grams (47.92 mmol, 2.0 eq) of finely powdered K3PO4.H2O was added to the flask. The heterogenous mixture was stirred vigorously with the mechanical stirrer and warmed to 60° C. The solution was stirred at this temperature until complete by TLC (1:1 hexane:EtOAc). The reaction rate was highly dependent on the rate of stirring. Upon completion (˜2 hours) the reaction was cooled to room temperature and the dark mixture was passed through a pad of CELITE. The CELITE was washed with EtOAc and the combined organic fractions were then washed with water and the aqueous layer was back extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over MgSO4. After concentration, silica gel chromatography (hexane/EtOAc) gave 5.85 grams (78%) of 11a as a brown oil, Rf 0.56 (1:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 7.91 (1H, s), 7.75 (1H, d, J=7.8 Hz), 7.53 (1H, m), 7.37 (2H, m), 4.14 (1H, q, J=7.1 Hz), 2.36 (3H, s), 1.50 (3H, d, J=7.1 Hz), 0.11 (9H, s). 13C-NMR (500 MHz, CDCl3): 185.52, 152.11, 146.91, 145.45, 142.46, 136.31, 131.69, 128.54, 128.24, 126.55, 109.40, 86.21, 29.60, 24.72, 14.18, 0.22. IR (cm−1): 2957 (m), 2164 (m), 1655 (s), 1579 (s), 1354 (m), 1248 (s), 904 (s), 843 (s), 760 (s). HRMS (EI) calcd. for C18H21NO2Si: 311.1342. found 311.1356.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]=O)[CH2:11][CH2:10]1.[CH2:19]([NH:22][CH:23]1[CH2:31][CH2:30][C:26]2[N:27]=[CH:28][S:29][C:25]=2[CH2:24]1)[CH2:20]C>>[CH2:19]([N:22]([CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[CH:23]1[CH2:31][CH2:30][C:26]2[N:27]=[CH:28][S:29][C:25]=2[CH2:24]1)[CH3:20]
Reactant: CCCNC1CCc2ncsc2C1
Reactant: COc1ccccc1N1CCN(CCC=O)CC1
Product: CCN(CCCN1CCN(c2ccccc2OC)CC1)C1CCc2ncsc2C1
Yield: 10 %

Procedure:
Compound 29 is prepared from 29B and 1C as described for 1. The salt of maleic acid is crystallized from ethanol/diethylether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[NH:77]1[CH:81]=[C:80](B2OC(C)(C)C(C)(C)O2)[CH:79]=[N:78]1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:80]5[CH:81]=[N:77][NH:78][CH:79]=5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)cccc4c3=O)cc2)CCC1
Yield: 74 %

Procedure:
Following the procedure used to prepare (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 4-pyrazoleboronic acid pinacol ester to give the title compound as a colourless oil (108 mg, 74%). LCMS (Method G): RT=3.86 min, [M+H]+=534.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[CH3:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]2([C:35](O)=[O:36])[CH2:34][CH2:33]2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([C:32]2([N:29]3[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]3)[CH2:33][CH2:34]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CC1CCN(C2(C(=O)O)CC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: CC1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Yield: 39 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(4-methylpiperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16I carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(4-methylpiperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as an off-white solid (39%). MS ISP (m/e): 519.2 (100) [(M+H)]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[S:17])=[CH:14][CH:13]=1>C(O)C>[C:5]1([C:3]2[N:18]=[C:16]([C:15]3[CH:19]=[CH:20][C:12]([OH:11])=[CH:13][CH:14]=3)[S:17][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)c1ccc(O)cc1
Solvent: CCO
Product: Oc1ccc(-c2nc(-c3ccccc3)cs2)cc1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask, 2-bromoacetophenone (520 mg, 2.61 mmol) and 4-hydroxy-thiobenzamide (400 mg, 2.61 mmol) were dissolved in ethanol (10 ml), and the resulting solution was heated to reflux. After about one hour, the reaction was cooled to about 35° C. and was allowed to stir for about an additional twelve hours. The reaction mixture was then concentrated in vacuo to an oil, the residue redissolved in ethyl acetate and methylene chloride, and extracted with saturated aqueous sodium bicarbonate. The combined extracts were then extracted with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride). The title product was isolated as a white solid (516 mg, 78% yield). LRMS ([M+H]+)=254.1.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11]O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C.I[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]1([S:7]([CH:10]=[CH:11][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(CCO)c1ccccc1
Reactant: CCOc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1ccc(C=CS(=O)(=O)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 54.8 %

Procedure:
To 0.186 g (1.0 mmol) of 2-(phenylsulfonyl)ethanol, 3 ml of acetonitrile was added, followed by 0.19 g (1.1 mmol) of methanesulfonic anhydride and 0.56 ml (4.0 mmol) of triethylamine, and the mixture was stirred for 5 hours at the internal temperature of 50° C. Subsequently, 0.37 g (1.5 mmol) of p-iodophenetole, 0.011g (0.05 mmol) of palladium acetate, and 0.067 g (0.22 mmol) of tri(o-tolyl)phosphine were added thereto, and the mixture was then refluxed for 17 hours. After cooled to room temperature, the reaction mixture was concentrated and purified by column chromatography (hexane/ethyl acetate=80/20) to obtain 0.158 g of [2-(phenylsulfonyl)ethenyl]-4-ethoxybenzene. Yield: 55%.
Reaction SMILES: O.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1)=[O:5].BrBr.C(=O)(O)[O-:27].[Na+]>C(Cl)Cl>[C:18]1([CH:17]2[C:15](=[O:16])[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=3)=[C:13]([NH2:14])[O:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(C(C#N)C(=O)Cc2ccccc2)c1
Reactant: O=C([O-])O
Agent: BrBr
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(C2=C(N)OC(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In this example 0.4 g of water was admixed with 6.5 g of (3-methoxycarbonylphenyl)-benzylcarbonyl-acetonitrile in about 40 ml of methylene chloride at room temperature. 1.1 ml of bromine in about 10 ml of methylene chloride was added dropwise at room temperature. After addition of the bromine, the reaction mixture was mixed with saturated aqueous sodium bicarbonate and stirred for about 1/2 hour at room temperature, resulting in a two-phase liquid mixture. The phases were separated. The aqueous phase was extracted three times with methylene chloride. The combined extracts and methylene chloride phase were washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated by evaporation affording an oily residue. The residue was triturated with a mixture of ethyl ether and petroleum ethers affording 5.0 g of the title compound as a solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].[Br:21][CH:22]([CH2:24]Br)[CH3:23].O>ClCCl>[Br:21][C:22](=[CH2:23])[CH2:24][NH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=1[O:10][CH3:9]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC(Br)CBr
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(Br)CNCc1ccc(OC)cc1OC
Reaction time: 18 h
Yield: 50.3 %

Procedure:
Triethylamine (16.0 mL, 114 mmol) was added to a solution of 2,4-dimethoxybenzylamine hydrochloride (11.1 g, 54.5 mmol) and 2,3-dibromopropane (10.9 g, 54.5 mmol) in dichloromethane (200 mL). After 18 h, water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (7.85 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C(N(CC)CC)C.[Cl:17][C:18]1[CH:37]=[CH:36][C:21]2[O:22][C:23]3[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=3[C@@H:25]3[C@H:30]([NH2:31])[CH2:29][CH2:28][CH2:27][N:26]3[C:20]=2[CH:19]=1>CO>[Cl:17][C:18]1[CH:37]=[CH:36][C:21]2[O:22][C:23]3[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=3[C@@H:25]3[C@H:30]([NH:31][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:29][CH2:28][CH2:27][N:26]3[C:20]=2[CH:19]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
Successively, ethyl trifluoroacetate (1.41 mL, 11.8 mmol) and triethylamine (628 μL, 4.5 mmol) were added to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (291 mg, 0.97 mmol) in 11.8 mL of methanol. The resulting mixture was heated to 50° C. for 18 h. A precipitate was formed. The mixture was evaporated under reduced pressure to remove volatile reagents and 5 mL of methanol was added. After 30 min. stirring the precipitate was filtered off, washed with diethyl ether and dried to give trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide as an off-white solid (330 mg, 86%). Data: 1H-NMR (400 MHz, CDCl3) 1.85 (m, 2H), 2.26 (m, 1H), 3.12 (m, 1H), 3.20 (m, 1H), 3.62 (dt, J=12.0, 4.0, 1H), 4.38 (d, J=8.0, 1H), 4.68 (m, 1H), 6.76 (dd, J=8.0, 3.0, 1H), 6.93 (d, J=3.0, 1H), 7.04 (d, J=8.0, 1H), 7.08 (dt, J=8.0, 2.0, 1H), 7.17 (dd, J=8.0, 2.0, 2H), 7.29 (dt, J=8.0, 2.0, 1H). (m/z)=397 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:45])[C@H:4]([NH:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][C:35]2=[O:44])[CH2:30][CH2:29]1)=[O:27])[CH2:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10](S(CC[Si](C)(C)C)(=O)=O)[C:11]([CH3:13])=[N:12][C:8]=2[CH:7]=1.COC(=O)[C@H](NC(N1CCC(N2CC3C(=CC=CC=3)NC2=O)CC1)=O)CC1C=CC2N=C(C)N(S(CC[Si](C)(C)C)(=O)=O)C=2C=1.O=C1N(C2CCN(C(N[C@H](CC3C=C4C(=CC=3)N(S(CC[Si](C)(C)C)(=O)=O)N=C4)C(O)=O)=O)CC2)CC2C(=CC=CC=2)N1.[OH-].[Li+].CO.O1CCCC1.O>>[CH3:13][C:11]1[NH:10][C:9]2[CH:23]=[CH:24][C:6]([CH2:5][C@@H:4]([NH:25][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][C:35]4=[O:44])[CH2:32][CH2:33]3)=[O:27])[C:3]([OH:45])=[O:2])=[CH:7][C:8]=2[N:12]=1
Reactant: COC(=O)[C@@H](Cc1ccc2c(c1)nc(C)n2S(=O)(=O)CC[Si](C)(C)C)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: COC(=O)[C@@H](Cc1ccc2nc(C)n(S(=O)(=O)CC[Si](C)(C)C)c2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: C[Si](C)(C)CCS(=O)(=O)n1ncc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)O)ccc21
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)O)ccc2[nH]1

Procedure:
The 1:1 mixture of (R)-3-[2-Methyl-1-(2-trimethylsilanyl -ethanesulfonyl)-1H-benzoimidazol-5-yl]-2-{[4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester and (R)-3-[2-Methyl-3-(2-trimethylsilanyl-ethanesulfonyl)-3H-benzoimidazol-5-yl]-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester was treated as described above for (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid. The hydrolysis conditions (lithium hydroxide/methanol-tetrahydrofuran-water (1:1:1) at −15° C. overnight were used. The title compound was obtained as a white solid (25%). Mass spec.: 477.24 (MH)+.