Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17](I)=[C:18](C)[N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.C(NC([C:31]1N=[CH:33][N:34]2[C:40]3[CH:41]=CC(F)=C[C:39]=3C(=O)N(C)[CH2:36][C:35]=12)=O)C#C.IN1C(=O)CCC1=O.C(NC(C)C)(C)C>C(O)(=O)C.C1COCC1>[CH:35]([N:34]([CH2:33][C:17]1[O:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=23)=[N:19][CH:18]=1)[CH:40]([CH3:41])[CH3:39])([CH3:36])[CH3:31]
Reactant: Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)oc1I
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: CC(C)N(Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1)C(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 6 %

Procedure:
125 ml of a crude THF solution of 8-fluoro-3-(5-iodo-methyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one (prepared from 15.6 g (0.050 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid prop-2-ynylamide and 16.9 g (0.075 mol) of N-iodosuccinimide in 300 ml of acetic acid, subsequently completely freed from the solvents, dried azeotropically several times with toluene and dissolved in 500 ml of THF) were treated with 15.4 ml (0.109 mol) of diisopropylamine and stirred at room temperature for 42 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the brownish product was chromatographed over silica gel with dichloromethane/methanol 39:1 as the eluent. There was obtained 0.83 g (1 6%) of 3-(5-diisopropylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 176°-178°.
Reaction SMILES: [CH3:1][C@@H:2]1[O:9]C(=O)[C@H](C)[O:5][C:3]1=[O:4].[C:11]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCCCC(C([O-])=[O:27])CC.CCCCC(C([O-])=O)CC.[Sn+2].C(O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[C:3]([OH:5])(=[O:4])[CH:2]([CH3:1])[OH:9].[OH:27][CH:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:11]([OH:17])=[O:18]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: O=C1CCCCCO1
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: [Sn+2]
Solvent: CCCCCCCCCCCCO
Solvent: Cc1ccccc1
Product: CC(O)C(=O)O
Product: CCCCC(O)C(=O)O
Reaction time: 10 h

Procedure:
The same procedure as in Preparation Example 3 was effected except that 1441 g (10 mols) of L-lactide, 1140 g (10 mols) of ε-caprolactone and 10 ml of a toluene solution containing 0.26 g of stannous octoate, and 5 g of lauryl alcohol were used and that reaction was carried out at 160° C. for 10 hours, thereby obtaining a lactic acid-hydroxycaproic acid copolymer (hereinafter referred to as "PCLA1").
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.[OH-].[Na+].Cl[CH2:35][CH:36]([OH:39])[CH2:37][OH:38]>O.CCOCC>[O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:35][CH:36]([OH:39])[CH2:37][OH:38])=[O:17])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(O)CCl
Reactant: O=C(O)c1ccc(NCCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: O=C(OCC(O)CO)c1ccc(NCCCOc2ccccc2)cc1

Procedure:
A solution of 5.5 g. of 4-(3-phenoxypropylamino)benzoic acid in 50 ml. of hexamethylphosphoramide is treated with 4.80 g. of 25% aqueous sodium hydroxide followed by 11.0 g. of 3-chloro-1,2-propanediol and then is heated at 140° C. for 6 hours. The mixture is diluted with water and ether and filtered to yield a white solid. Recrystallization from acetonitrile affords pure 2,3-dihydroxypropyl 4-(3-phenoxypropylamino)benzoate as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([O:17][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][C:13]=1[CH:14]=[O:15])([CH3:26])[CH3:25])[CH3:24]
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Yield: 88.8 %

Procedure:
5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch. Pharm., 1975, 308 (5), 339–346) (2.28 g, 10.0 mmol), ethyl bromoisobutyrate (2.2 mL, 15 mmol), and cesium carbonate (3.26 g, 10.0 mmol) in dry DMF (25 mL) are heated at 80° C. for 18 h. The reaction mixture is cooled and partitioned between water (30 mL) and ether (75 mL). The organic layer is washed with brine (15 mL). The aqueous layers are back-extracted with ethyl acetate (30 mL), and the organic layer is washed with brine (20 mL). The combined organic layers are dried (Na2SO4) and concentrated to a brown oil. The crude product is purified by flash chromatography using hexanes:ethyl acetate (2.5:1) to give a pale yellow solid (3.04 g, 89%): mp 65° C.; 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 2H, J=7.1 Hz), 6.81 (d, 1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30–7.43 (m, 6H); MS (ES) m/e 343.1 [M+1].
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:23][C:24]([C:26]1([CH2:31][CH2:32][N:33]=[N+:34]=[N-:35])[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[N:33]([CH2:32][CH2:31][C:26]1([C:24]([NH:23][C@@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:22])[C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])=[CH:10][CH:11]=2)[C:3]([OH:36])=[O:2])=[O:25])[CH2:30][CH2:29][CH2:28][CH2:27]1)=[N+:34]=[N-:35]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCN=[N+]=[N-])CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: [N-]=[N+]=NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.1 %

Procedure:
To a suspension of (S)-2-[[1-(2-azidoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (14.77 g, 27.7 mmol) in THF (200 mL) and ethanol (200 mL) was added aqueous 1.0N sodium hydroxide (150 mL) at room temperature. The mixture was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, it was diluted with water (20 mL) and the THF and ethanol were removed by rotary evaporation and diluted with 100 mL of water and extracted with ether (200 mL) to remove any neutral impurities. The aqueous layer was neutralized with 1N HCl and the resulting white solids were collected by filtration and washed with water and hexanes. After air-drying, 13.37 g (93% yield) of (S)-2-[[1-(2-azidoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid was obtained as a white solid. ES(+)-HRMS m/e calcd. for C24H25Cl2N5O4 (M+Na)+ 540.1176, obsd. 540.1177.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:6][C:5]2=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:6][C:5]2=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3c(F)cc(Br)cc3c2C1
Product: CC(C)C(=O)NC1CCc2c(c3cc(Br)cc(F)c3n2Cc2cccc(F)c2)C1
Yield: 36 %

Procedure:
Prepare the title compound by essentially following the procedure as described in Example 96 with N-(6-bromo-8-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 19) and 3-fluorobenzyl bromide, to obtain the title compound as a white solid in 36% yield. MS (ES): m/z 461,463 (M+1), 459, 461 (M−1); HPLC (Method A): Rt=4.60 (92%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=[CH:3][C:1]#[N:2])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of diethyl cyanomethylphosphonate (2.06 g, 11.62 mmol) and anhydrous potassium carbonate (1.6 g, 11.62 mmol) in dry THF (10 mL) was stirred at room temperature for 15 min and then refluxed for 20 min. After cooling to room temperature, benzyl-piperidin-4-one (compound of Example 25; 2 g, 10.56 mmol) was added and the mixture was heated at reflux for 16 h (˜70° C.). The reaction mixture was cooled to room temperature, filtered and quenched with ice water (25 mL). The resulting mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with water (2×15 mL) followed by brine (20 mL). The organic phase obtained was dried over anhydrous sodium sulphate and concentrated to obtain a crude product, which was purified by crystallisation using 2% ethyl acetate in hexane to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].CCN(CC)CC>C(OCC)C>[Cl:10][CH2:11][C:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: C=Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=Cc1ccc(OC(=O)CCl)cc1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 4-hydroxystyrene (1.22 g, 10 mmol) in ethyl ether 140 mL was added chloroacetic chloride (2.26 g, 20 mmol) and Et3N (1.62 g, 16 mmol). After it was stirred for 2 h, the mixture was washed with brine and water. The ether solution was dried over Na2SO4 and concentrated. After purification by flash column, the 4-chloroacetoxystyrene (1.8 g, 92%) was obtained. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.46 (d, 2H, J=1.8 Hz), 7.11 (d, 2H, J=8.4 Hz), 6.73 (dd, 1H, J=17.7 Hz), 5.74 (d, 1H, J=18 Hz), 5.29 (d, J=11.1 Hz), 4.31 (s, 2H). 13C NMR (CDCl3, 75 MHz) δ166.0, 150.0, 136.0, 135.8, 127.4, 121.3, 114.6, 41.0.
Reaction SMILES: Cl.[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11]([NH:13][CH:14](O)[C:15]([OH:17])=[O:16])=[O:12]>C(O)(=O)C>[Cl:9][CH2:10][C:11]([N:13]([C:5]1[CH:6]=[CH:7][C:2]([OH:8])=[CH:3][CH:4]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:12]
Reactant: O=C(CCl)NC(O)C(=O)O
Reactant: Oc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CN(C(=O)CCl)c1ccc(O)cc1
Reaction time: 8 h
Yield: 52.5 %

Procedure:
18 g of gaseous hydrochloric acid at 5° C are dissolved in a solution of 94 g (1 mole) of phenol and 83.8 g (0.5 mole) of chloracetamidoglycolic acid in 120 g of glacial acetic acid. After 8 hours at this temperature and then 16 hours at ambient temperature, the hydrochloric and acetic acids are distilled off at 25 mm of mercury, then the excess phenol at 2 mm of mercury at a temperature below 50° C, 200 ml of nitromethane are added, it is filtered, washed with ethyl ether and dried. 64 g of product are obtained (yield 53% with respect to the chloracetamidoglycolic acid). The product recrystallised in water melts at 187° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18]([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)[N:17]=3)[CH2:9]1)[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([C@@H:8]1[N:13]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][N:10]([C:14]2[N:15]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=[C:18]([C:29]2[CH:34]=[N:33][C:32]([NH2:35])=[N:31][CH:30]=2)[N:17]=3)[CH2:9]1)[CH3:7]
Reactant: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1S(C)(=O)=O
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Methanesulfonyl chloride (0.022 ml, 0.28 mmol) was added dropwise to a methylene chloride solution (6 ml) of 5-{8-[(3S)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (107 mg, 0.22 mmol) and triethylamine (0.061 ml, 0.44 mmol) with ice cooling and the resulting mixture was stirred at the same temperature for 2 hours. The resulting mixture was partitioned with ethyl acetate and saturated aqueous ammonium chloride solution and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=95:5) to give the title compound (86 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]([CH2:28][C:29]#[C:30][CH3:31])([S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[C:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH2:34][C@@H:35]([C:37]1[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=1)[OH:36]>>[C:1]([O:5][C:6](=[O:32])[C:7]([CH2:8][C:9]#[C:10][CH3:11])([S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][CH:24]([NH:33][CH2:34][C@H:35]([OH:36])[C:37]3[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])[CH2:28][C:29]#[C:30][CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 from 0.37 g (0.8 mmol) of Reference Example 27, 2-But-2-ynyl-2-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-hex-4-ynoic acid tert-butyl ester, and 0.24 g (1.0 mmol) of (R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide, yielding 0.54 g of an off-white solid; m.p. 93-95° C.; MS (ES) m/z 688.2 (MH+); HRMS (ES) Calcd. for C34H46N3O8S2 (MH+): 688.2721, Found: 688.2722.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1.O>O1CCCC1>[N+:11]([C:9]1[CH:8]=[CH:7][C:4]2[CH2:5][NH:6][C:19](=[O:20])[NH:1][CH2:2][C:3]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc([N+](=O)[O-])cc1CN
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCc2ccc([N+](=O)[O-])cc2CN1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-aminomethyl-4-nitrobenzylamine (3.10 g, 17.1 mmol) was dissolved in tetrahydrofuran (300 mL) and a solution of N,N-carbonyldiimidazole (2.78 g, 17.1 mmol) in THF (40 mL) was added dropwise at room temperature over 30 minutes. The reaction was allowed to stir at room temperature for 72 hours. The solution was then poured over water (150 mL) and organics were extracted with ethyl acetate (3×100 mL). Combined organic extracts were dried over Na2SO4, filtered and reduced to afford 7-nitro-1,2,4,5-tetrahydro-benzo(e)(1,3)diazepin-3-one as a crude brown solid. Purification by flash column chromatography (0% MeOH/DCM-10% MeOH/DCM) afforded 2.5 grams of 7-nitro-1,2,4,5-tetrahydro-benzo(e)(1,3)diazepin-3-one as a yellow solid. LC/MS (ESI)=208.42 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12].[Cu][C:14]#[N:15].O>CS(C)=O>[CH3:12][C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:14]#[N:15]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: N#C[Cu]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(Cl)ccc([N+](=O)[O-])c1C#N
Yield: 60 %

Procedure:
1 mol of 2,6-dichloro-3-nitrotoluene in 1 l of dimethyl sulfoxide was stirred at 150° for 5 hours with 1 mol of copper (I) cyanide. The mixture was then cooled, poured into water and extracted with ethyl acetate. The organic phase was evaporated and the residue was purified by chromatography on silica gel. There was obtained 2-methyl-3-chloro-6-nitrobenzonitrile (yield 60%), m.p. 97°-98°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:18]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:26][CH2:25]3)[N:18]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3cnccn3c2-c2ccnc(NC3CCNCC3)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3c(-c4ccc(F)cc4)nc4cnccn34)n2)CC1
Reaction time: 144 h

Procedure:
To a mixture of 4-[2-(4-fluorophenyl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylpiperidin-4-ylamine (Example # H.1; 0.200 g, 0.514 mmol) and DIEA (0.18 mL, 1.0 mmol) in DCM (3 mL) at ambient temperature was added methanesulfonyl chloride (0.062 g, 0.539 mmol). After about six days, the mixture was treated with saturated aqueous NaHCO3 and the layers were separated. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was triturated with EtOAc and filtered to yield the title compound after drying (0.090 g, 37%): LC/MS (Table 1, Method b) Rt=1.7 min; MS m/z: 468.6 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[NH:14][C:15](=[O:17])[CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:21]=[CH:20][C:19]([Br:24])=[CH:18][C:13]=3[NH:14][C:15](=[O:17])[CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CN(Cc3ccccc3)CCN2c2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=C1CC2CN(Cc3ccccc3)CCN2c2ccc(Br)cc2N1
Reaction time: 16 h

Procedure:
To a solution of Example 112A (1.30 g, 4.23 mmol) in acetic acid (20 mL) was added N-bromosuccinimide (0.828, 4.65 mmol). The reaction stirred for 16 hours. The reaction solution was concentrated, then partitioned between NaOH (1M) and dichloromethane. The dichloromethane layer was separated and concentrated onto silica gel. Purification via flash chromatography (30-100% ethyl acetate/hexanes) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.22-7.38 (m, 6H) 7.07 (d, J=2.37 Hz, 1H), 7.01 (d, J=8.81 Hz, 1H), 3.50-3.58 (m, 2H), 3.24-3.30 (m, 1H), 3.05-3.17 (m, 1H), 2.91-3.01 (m, 1H), 2.71-2.86 (m, 2H), 2.52-2.61 (m, 1H), 2.05-2.25 (m, 2H), 1.90 (d, J=13.22 Hz, 1H); MS (APCI+) m/z 386, 388 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:28])[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:27])[NH2:26])[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:28])[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:27])[NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ccnc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(N)=O)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2ccnc3ccccc23)CC1

Procedure:
This was prepared from 4-chloroquinoline (0.49 g) and amide (a) (0.73 g) according to the procedure of Example (1l) affording a white solid (0.66 g, 60%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([S:35][C:36]1[N:37]([CH3:43])[C:38]([C:41]#[CH:42])=[CH:39][N:40]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:42]=[C:41]([C:38]4[N:37]([CH3:43])[C:36]([S:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:40][CH:39]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cnc(SC(C)(C)C)n1C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(SC(C)(C)C)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 30 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 2-tert-butylsulfanyl-5-ethynyl-1-methyl-1H-imidazole in the same manner as Example 15. ESI MS m/z 626 [C30H39N7O4S2+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH2:12](O)[CH2:13][OH:14].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]2[O:14][CH2:13][CH2:12][O:8]2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccc(C2OCCO2)c1
Reaction time: 4 h
Yield: 101.2 %

Procedure:
A mixture of 3-nitrobenzaldehyde (100 g, 0.66 mole), ethylene glycol (49.3 g, 0.7 mole) and p-toluenesulfonic acid (0.8 g) and benzene (1 L) was heated at reflux with continuous removal of water via a Dean and Stark trap. After 4 hours, the mixture was cooled, filtered through a pad of neutral alumina and concentrated in vacuo to afford 2-(3-nitrophenyl)-1,3-dioxolane (130.4 g, 100%) as an amber oil used without further purification below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5](C)[CH2:6][CH:7]([C:9]1[N:10]([CH:25]([CH3:27])[CH3:26])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)C.C(N(CC)CC)C.[OH-:37].[NH4+].[Cl-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5](=[O:37])/[CH:6]=[CH:7]/[C:9]1[N:10]([CH:25]([CH3:26])[CH3:27])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COC(=O)C=C(C)CC(C)c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reactant: [OH-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 2 liter round-bottomed flask equipped with a magnetic stirrer and nitrogen delivery line, 30.5 g of crude 5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-methylhex-2-enoic acid methyl ester are dissolved in 250 ml of THF, 13.49 g (133.3 mmol) of triethylamine are added and the yellow solution is heated under reflux for 2 hours. The reaction mixture is then cooled to room temperature, 53 ml (212 mmol) of 4N ammonium hydroxide solution are added and the mixture is stirred vigorously for 3 hours. The reaction mixture is then poured into 1 liter of saturated sodium chloride solution and extracted three times with 250 ml of ethyl acetate. The combined organic phases are washed once with 100 ml of 1N hydrochloric acid and three times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. The crude product (22.78 g of an orange resin) is purified by means of flash chromatography (hexane/ethyl acetate=9:1). A resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.