Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13].COC(OC)N(C)C>CN(C)C=O>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[CH:13]=[CH:1][O:2][C:3]2=[O:14])([O-:12])=[O:11]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: O=c1occc2c([N+](=O)[O-])cccc12
Yield: 54.4 %

Procedure:
16.4 g (84.03 mmol) of the 2-methyl-3-nitrobenzoic acid methyl ester that is described under Example 1 is stirred with 26.8 g (225.1 mmol) of N,N-dimethylformamide dimethyl acetal in 85 ml of dimethylformamide for 12 hours at 130° C. The solvent is drawn off in a rotary evaporator, the residue is taken up in methyl tert-butyl ether and washed three times with water. After washing with saturated NaCl solution, the organic phase is dried. After the desiccant is filtered off and the solvent is spun off, the remaining residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 8.73 g (54.4%) of the desired compound is isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6](OCC)([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16].C(OC(=O)CP(OCC)(Cl)=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][PH:6]([O:8][CH2:9][CH2:10][Cl:16])=[O:7])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CCOC(=O)CP(=O)(Cl)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C[PH](=O)OCCCl

Procedure:
Ethyl(diethoxyphosphinyl)acetate (11.2 gm., 0.05 mol.) and phosphorus pentachloride (10.5 gm., 0.05 mol.) are dissolved in 200 ml. of benzene and refluxed overnight. The solvent is removed in vacuo, leaving yellow, oily, ethyl(ethoxychlorophosphinyl)acetate as residue (11.5 gm.).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[C:14]([C:18]#[N:19])=[N:15][NH:16][CH:17]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:25][N:24]=1>CC(O)(C)C>[C:33]1([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([NH:1][C:2]3[CH:21]=[CH:20][C:5]([O:6][C:7]4[C:12]([C:13]5[C:14]([C:18]#[N:19])=[N:15][NH:16][CH:17]=5)=[CH:11][CH:10]=[CH:9][N:8]=4)=[CH:4][CH:3]=3)=[N:24][N:25]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(N)cc1
Solvent: CC(C)(C)O
Product: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
In a 20-mL sealed tube was dissolved 4-(2-(4-aminophenoxy)pyridin-3-yl)-1-H-pyrazole-3-carbonitrile (0.120 g, 0.433 mmol) in t-BuOH (1.0 mL). Then 1-chloro-4-phenylphthalazine (0.104 g, 0.433 mmol) was added and the mixture was stirred at 100° C. for 3 days. The reaction was cooled to RT, concentrated and purified on a Gilson reverse phase chromatography system. The title compound was extracted into CH2Cl2, washed 1× saturated NaHCO3, 1×H2O, dried over Na2SO4, filtered through fritted funnel and concentrated. The title compound was further purified by silica gel chromatography using 10-100% EtOAc/Hexanes to afford 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1-H-pyrazole-3-carbonitrile as light yellow solid. MS m/z=482 [M+1]+. Calc'd for C29H19N7O: 481.51.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].C(C(C)=O)C.[CH3:15][O:16][C:17]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[C:20]([C:27](Cl)=[O:28])=[CH:19][CH:18]=1>O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:27]([C:20]1[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:28])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)c2c1OCCO2
Reactant: CCN1CCCC1CN
Solvent: O
Solvent: CCC(C)=O
Product: CCN1CCCC1CNC(=O)c1ccc(OC)c2c1OCCO2
Yield: 103.4 %

Procedure:
87 g of 1-ethyl-2-aminomethyl pyrrolidine and 775 cm3 of methyl ethyl ketone were introduced into a balloon flask provided with an agitator and a thermometer and then, in portions, 155 g of 8-methoxy-1,4-benzodioxane-5-carbonyl chloride was added, with the temperature being maintained at from 5°-10° C. After agitation the mixture was dissolved with 1,500 cm3 of water and then the methyl ethyl ketone was distilled. The remaining solution was filtered and then treated with sodium hydroxide. The oil was decanted and then extracted with methylene chloride. The solution was dried on potassium carbonate and then the methylene chloride was distilled under vacuum. 224.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide was produced. 197.5 g of the base produced was dissolved in 760 cm3 of absolute alcohol, and then 67 g of oxalic acid in solution in 195 cm3 of absolute alcohol was added. The crystals formed were dried off, washed with absolute alcohol and then dried. 208.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide oxalate was produced (M.P. 129°-130° C.; yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[F:42][C:43]1[C:48](O)=[C:47]([F:50])[C:46]([F:51])=[C:45]([F:52])[C:44]=1[F:53]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:10]=[C:11]([C:13]([O:15][C:48]2[C:47]([F:50])=[C:46]([F:51])[C:45]([F:52])=[C:44]([F:53])[C:43]=2[F:42])=[O:14])[N:12]=1
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Step 1, 2-(2-Chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid (1.5 g, 4.5 mmol) was dissolved in dichloromethane (40 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 946 mg, 4.95 mmol) and triethylamine (500 mg, 4.95 mmol) were added followed by pentafluorophenol (815 mg, 4.37 mmol). The mixture was stirred at rt under argon for one hour before it was washed with 5% HCl, sodium bicarbonate solution, and then brine. The organic layer was dried (MgSO4), filtered, and concentrated to give the crude product (1.26 g) which was chromatographed over silica gel (20% EtOAc in hexanes) to afford pentafluorophenyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (0.73 g, 32% yield): LC-MS m/z 499.0 (MH+), retention time 3.93 min (method 1).
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[NH:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:13][C@H:9]1[C@H:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:11][C:10]1=[O:12]
Reactant: O=C1N[C@@H](Sc2ccccc2)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: N[C@@H]1C(=O)N[C@H]1Sc1ccccc1

Procedure:
To a solution of 2.65 g of (3R,4S)-4-phenylthio-3-tritylamino-2-oxoazetidine in 20 ml of acetone is added under ice-cooling 1.27 g of p-toluenesulfonic acid monohydrate, followed by similar procedure to Reference Example 45B to give 1.9 g of tosyl salt of (3R,4S)-3-amino-4-phenylthio-2-oxoazetidine.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([NH2:17])=[N:11][NH:12]2>N1C=CC=CC=1>[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:11][NH:12]2
Reactant: Nc1n[nH]c2cccc(I)c12
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2cccc(I)c12
Temperature: 5 °C
Reaction time: 50 h

Procedure:
0.20 cm3 of butyryl chloride is added to 500 mg of 4-iodo-1H-indazole-3-amine, described previously, in 15 cm3 of pyridine, and cooled to about 5° C. The reaction medium is allowed to return to about 19° C. over 50 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of ethyl acetate, 15 cm3 of tetrahydrofuran and 15 cm3 of distilled water. The organic phase is dried over magnesium sulphate and then filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of dichloromethane and filtered. The insoluble material is taken up in 10 cm3 of methanol and filtered off and the filtrate is evaporated under reduced pressure, to give after drying (90 Pa; 50° C.), 70 mg of N-[4-iodo-1H-indazol-3-yl]butanamide in the form of an off-white solid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=2)[CH:6]=1
Reactant: Cc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(3,5-dimethylphenylamino)pyridazin-3-ylamino)cyclohexylcarbamate (30 mg, 66.0 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (151 mg, 102 μL, 1.32 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo then diluted with dichloromethane and drops of 25% NH4OH added until the pH was measured to be ˜8. The weakly basic solution was washed with water, then the organic phase was concentrated in vacuo and purified by chromatography (silica, 30 to 100% of a 10:89.5:0.5 MeOH:dichloromethane:NH4OH solution in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(3,5-dimethylphenylamino)pyridazine-3-carboxamide (17 mg, 48.0 mmol, 73%) as a light brown solid. 1H NMR (400 MHz, METHANOL-d6) δ0 ppm 6.90 (s, 2H), 6.88 (s, 1H), 6.50 (s, 1H), 4.32 (s, 1H), 1.63-1.84 (m, 6H), 1.51 (m, 2H); MS (EI/CI) m/z: 355.1 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl-].[Cl:18][C:19]1[S:20][S+:21]=[C:22](Cl)[C:23]=1[Cl:24]>C(Cl)Cl>[Cl:24][C:23]1[C:22](=[N:4][C:3]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=2[CH3:1])[S:21][S:20][C:19]=1[Cl:18]
Reactant: Clc1s[s+]c(Cl)c1Cl
Reactant: Cc1ccc(N)c(C)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N=c2ssc(Cl)c2Cl)c(C)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
14.0 g of 2,4-dimethyl-aniline were dissolved in 300 ml of methylene chloride and 50 ml of triethylamine and 31.0 g of 3,4,5-trichloro-1,2-dithiolium chloride were introduced at 10°-15° C. After stirring for three hours at 20° C., a test for aromatic amine, by diazotizing and coupling, proved negative. The resulting dark solution was then washed three times with 200 ml of water, dried over potassium carbonate and filtered over a column of aluminum oxide, to remove impurities that imparted a color. The filtrate was concentrated and caused to crystallize by adding petroleum ether. Yield, 17.0 g of yellowish crystals; melting point: 72°-74° C. The elementary analysis and NMR spectrum agreed with the assumed structure.
Reaction SMILES: C1(C)C=CC(S([N:10]=[N+:11]=[N-])(=O)=O)=CC=1.[CH3:14][O:15][C:16](=[O:24])[CH2:17][C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22].C(N(CC)CC)C>C(#N)C>[CH3:14][O:15][C:16](=[O:24])[C:17](=[N+:10]=[N-:11])[C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=CCCC(=O)CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCCC(=O)C(=[N+]=[N-])C(=O)OC
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of p-toluenesulfonyl azide (592 mg; 3 mmol) in 1 ml of acetonitrile was added at room temperature to a solution of 3-oxo-6-heptenoic acid methyl ester (468 mg; 3 mmol) and triethylamine (306 mg; 3 mmol) in 5 ml of acetonitrile. The mixture was stirred for about 2 hours and the solvent was distilled off under a reduced pressure and the product was dissolved in 50 ml of ether. The solution was washed with a 5% aqueous solution of potassium hydroxide until no color remained in the aqueous phase and was further washed with a saturated aqueous solution of sodium chloride. The ether solution was dried over anhydrous magnesium sulfate and was filtered and condensed under a reduced pressure to obtain 530 mg of 2-diazo-3-oxo-6-heptenoic acid methyl ester as a yellow oily product. The crude product can be purified by distillation under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:18][CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C1C=CC=CN=1)C.[C:39]1([CH3:49])[C:40]([S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:49][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45]([NH:48][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:18][CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:5]=2)=[CH:10][CH:11]=1)=[O:16])(=[O:47])=[O:46]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1OC(C)CCCc1ccccc1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc2)cc1OC(C)CCCc1ccccc1
Reaction time: 50 h
Yield: 103.4 %

Procedure:
To a solution of acid 4'-methoxy-3'-(1-methyl-4-phenylbutoxy)-(±)[1,1'-biphenyl]-4-carboxylic acid, (0.257 g, 0.658 mmoles) in 10 ml of anhydrous methylene chloride under hydrogen atmosphere was added dimethylamino pyridine (88.46 mg, 0.728 mmoles); o-Toluenesulfonamide (0.122 g, 0.712 mmoles) and dicyclohexylcarbodiimide (0.124 g, 0.6 mmoles) the reaction mixture allowed to stir for 50 hours. The solvent was evaporated and the resulting solid triturated with methylene chloride:ether (~1:1) which lead to precipitation of by-product DCU which was filtered. Concentration of the mother liquor followed by 3 g additional triturations with ethyl acetate/ether (~1:1) caused additional deposit of white solid which was filtered. The clear filtrate was concentrated and purified on a silica gel column using methylene chloride/methanol as eluant (95:5). Concentration of fractions containing desired products gave a total of 0.37 g of white foamy solid. Recrystallization from ethyl acetate/hexane gave 0.208 grams of white solid. M.P.: 97°-100° C.
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].C1(C)C=CC=CC=1.[F:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>CN(C)C=O>[F:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:4](=[O:6])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[NH:1][C:34]1=[O:35]
Reactant: CCOC(=O)C=C(N)c1ccccc1F
Reactant: O=C=Nc1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccccc2F)[nH]c(=O)n1-c1ccc(Cl)cc1F
Temperature: 0 °C
Yield: 72.4 %

Procedure:
2.1 g of this ethyl 3-amino-3-(2-fluorophenyl)-2-propenoate was added dropwise to a solution of 0.5 g of sodium hydride (purity: 55%) in 20 ml of dimethylformamide with stirring at 0° C. The resulting solution was further stirred at room temperature for 15 minutes and then cooled to -30° C. and added dropwise with 20 ml of a toluene solution of 1.7 g of 2-fluoro-4-chlorophenyl isocyanate. The resultant solution was heated to room temperature and stirred at 80° C. for 30 minutes. Then the solvent was distilled away under reduced pressure and 100 ml of water was added to the residue to dissolve it. This aqueous solution was washed twice with diethyl ether and added to a mixed solution of 50 g of ice and 20 ml of concentrated hydrochloric acid. The precipitated crystals were filtered out and dried under the reduced pressure to obtain 3.0 g of a crude product. This crude product was washed with heated diisopropyl ether and then dried to obtain 2.4 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[Br:21]Br>O.[OH-].[Na+]>[Br:21][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: BrBr
Reactant: CC(CO)Nc1ccnc2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(CO)Nc1c(Br)cnc2cc(Cl)ccc12
Yield: 57 %

Procedure:
A mixture of 12 g of 7-chloro-N-(2-hydroxy-1-methylethyl)4-quinolinamine and 112 ml of acetic acid was stirred at room temperature and to it 8 g of bromine was added dropwise over a thirty minute period. The product precipitated from the solution as the hydrobromide salt and it was isolated by filtration, dissolved in water and basified with sodium hydroxide. The free base was extracted into dichloromethane and evaporation of solvents resulted in a solid which was purified by HPLC using 95:5 dichloromethane/methanol as the eluent. Recrystallization from isopropanol yielded 9 g of crystalline solid with a melting point of 145°-147° C.
Reaction SMILES: Cl[CH:2]([Cl:23])[B:3]1[O:7][C:6]([CH2:9][CH2:10][CH:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:8])[C:5]([CH3:22])([CH3:21])[O:4]1.[CH2:24]([Mg]Br)[CH3:25]>O1CCCC1.C(OCC)(=O)C>[Cl:23][CH:2]([B:3]1[O:7][C:6]([CH2:9][CH2:10][CH:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])([CH3:8])[C:5]([CH3:21])([CH3:22])[O:4]1)[CH2:24][CH3:25]
Reactant: CC(CCC1(C)OB(C(Cl)Cl)OC1(C)C)CC(=O)OC(C)(C)C
Reactant: CC[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(Cl)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -78 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
0.86 g (2.3 mmol) of tert-butyl 5-[2-(dichloromethyl)-4(RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved in 5 ml of tetrahydrofuran and the solution was cooled to -78° C. under a nitrogen atmosphere. 2.6 ml (2.6 mmol) of 1 M ethylmagnesium bromide in tetrahydrofuran were added dropwise, the resulting solution wasstirred for 16 hours while slowly warming to room temperature and then diluted with ethyl acetate and extracted with 2M hydrochloric acid and brine. The organic phase was dried over sodium sulphate and then evporatedunder a vacuum to give 0.83 g of tert-butyl 5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in the next step without purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[S:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[S:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.23 g) (Example K27) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH:36]([CH3:38])[CH3:37])[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)Br
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a light yellow foam (33%).
Reaction SMILES: CN(CCN(C)C)C.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN([CH:24]=[O:25])C>CCOCC>[Cl:14][C:15]1[C:16]([CH:24]=[O:25])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: Clc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ncccc1Cl
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of TMEDA (660 μL, 2.58 mmol) in ether (20 mL) at −78° C. was added a solution of n-butyl lithium in ether (2.5 M, 1.76 mL, 4.40 mmol). After 30 minutes at −78° C., 3-chloropyridine (419 μL, 4.40 mmol) was added. After another 2 hours at −78° C., DMF (375 μL, 4.84 mmol) was added. After a further 2 hours at −78° C., the reaction was quenched with saturated aqueous NaHCO3 (20 mL), extracted with ether (4×15mL), dried (Na2SO4), filtered and concentrated in vacuo to give the crude oil. Purification by column chromatography on silica gel (Hexanes:EtOAc 4:1) afforded the title compound as a crystalline solid (168 mg, 27%). 1H NMR (CDCl3) 7.45 (dd, 1H, J=8.3, 4.4 Hz), 7.83 (dd, 1H, J=4.8, 1.4 Hz), 8.70 (dd, 1H, J=4.8, 1.5 Hz), 10.28 (s, 1H).
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C@H:36]([C:37]([O-:39])=O)[CH2:35][C:34](=[O:40])[C:33]2[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=2[N:31]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:30](=[O:52])[C@H:29]1[CH2:53][C:54]12[CH2:63][CH:58]3[CH2:59][CH:60]([CH2:62][CH:56]([CH2:57]3)[CH2:55]1)[CH2:61]2)(=[O:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:75]([O:82][C:83](=[O:86])[CH2:84][NH2:85])[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:25]([N:28]1[C@H:36]([C:37]([NH:85][CH2:84][C:83]([O:82][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:86])=[O:39])[CH2:35][C:34](=[O:40])[C:33]2[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=2[N:31]([CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:30](=[O:52])[C@H:29]1[CH2:53][C:54]12[CH2:63][CH:58]3[CH2:59][CH:60]([CH2:62][CH:56]([CH2:57]3)[CH2:55]1)[CH2:61]2)(=[O:27])[CH3:26]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: NCC(=O)OCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
PyBroP (233 mg, 0.5 mmol) was added to a solution of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate (264 mg, 0.5 mmol), glycine benzyl ester p-toluenesulphonate (170 mg, 0.5 mmol) and diisopropylethylamine (260 μl, 1.5 mmol in dry DCM (5 ml). The reaction mixture was stirred at room temperature for 18 hours, diluted with DCM (20 ml), washed successively with 2N HCl solution (25 ml), brine (25 ml) and dried (MgSO4). Filtration an evaporation of the solvent gave the crude product (350 mg) which was purified by flash chromatography on silica gel with ethyl acetate-DCM (3:7) as eluant, affording the product as a colourless oil. (190 mg, 55%).