Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+].[Cl:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].[CH3:31][NH:32][CH3:33]>C(Cl)Cl.C(Cl)Cl.CO>[Cl:25][CH2:26][S:27]([N:5]([CH2:4][CH2:3][CH2:2][N:32]([CH3:33])[CH3:31])[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)CCl
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(NCCCO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCN(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)CCl
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl 4-[(3-hydroxypropyl)amino]piperidine-1-carboxylate (Yokoyama et al., Bioorg. Med. Chem. 2008, 16, 7968) (710 mg, 2.75 mmol) and dry powdered K2CO3 (5.0 g, 36.0 mmol) in CH2Cl2 (20 mL) at 0° C. was added chloromethanesulfonyl chloride (1 mL, excess). The reaction mixture was stirred at 20° C. for 4 hrs, a solution of 40% aqueous dimethylamine (5 mL) was then added, and stirring was continued for a further 20 hrs. The organic layer was separated and the aqueous layer was further extracted with CH2Cl2 (2×20 mL). The combined organic fractions were washed with water (50 mL) and dried (Na2SO4). The solvent was removed to give an oily product. Chromatography on neutral alumina eluting with CH2Cl2/MeOH (98:2) gave tert-butyl 4-{[(chloromethyl)sulfonyl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylate, as an oil (946 mg, 87%): 1H NMR (CDCl3) δ 4.47 (s, 2H), 4.22 (br, 2H), 3.82-3.75 (m, 1H), 3.31-3.27 (m, 2H), 2.28-2.46 (m, 2H), 2.76-2.70 (m, 2H), 2.26 (t, J=6.9 Hz, 2H), 2.23 (s, 6H), 1.87-1.64 (m, 6H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13].[Li]C(C)(C)C.[CH3:26][S:27]SC>CCOCC>[CH3:26][S:27][C:5]1[N:6]([Si:11]([CH:15]([CH3:16])[CH3:17])([CH:12]([CH3:14])[CH3:13])[CH:18]([CH3:20])[CH3:19])[C:7]2[C:3]([CH:4]=1)=[CH:2][CH:10]=[CH:9][CH:8]=2
Reactant: CSSC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CSc1cc2ccccc2n1[Si](C(C)C)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a solution of the indole of Step 2 (2.9 g, 8 mmol) in Et2O (50 mL) at −78° C. was added t-BuLi (11 mL, 18 mmol). The reaction mixture was stirred for 10 minutes at −78° C. and dimethyl disulfide (2.3 g, 25 mmol) was added. The reaction mixture was stirred for 30 minutes and the reaction was quenched with water. The phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 5% EtOAc in Hexanes to provide 2.5 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[C:16](=O)([O-])[O-].[K+].[K+].O>CO>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.2 g, 10.4 mmol) and potassium carbonate (2.9 g, 20.8 mmol) in methanol (100 mL) was added Example 21A (2.0 g, 10.4 mmol) in methanol (20 mL) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate (twice). The combined organic layers were washed with brine and concentrated. Purification by flash chromatography on silica gel (Teledyne CombiFlash Rf, 1:5 ethyl acetate/hexane) gave the title compound. MS (DCI/NH3) m/z 210 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:13][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:10][N:5]2[C:6](=[O:9])[C:7]=1[F:8].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(#N)C>[F:8][C:7]1[C:6](=[O:9])[N:5]2[CH2:10][CH2:11][C@@H:12]([C:14]([F:17])([F:16])[F:15])[NH:13][C:4]2=[N:3][C:2]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: O=c1c(F)c(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Solvent: CC#N
Product: O=c1c(F)c(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reaction time: 8 h

Procedure:
The product can be prepared according to the procedure described in Example 16, stage b, but using 1 g of (8S)-2-chloro-3-fluoro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one in 5 ml of acetonitrile, and 1.6 ml of morpholine. After a period overnight at 65° C., 1.1 g of (8S)-3-fluoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>C(O)(=O)C(C)O>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Agent: CC(O)C(=O)O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 115 °C
Yield: 48.6 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of lactic acid is heated to its boiling point and maintained at this temperature (115° C.) for 2 hours. After completion of the reaction the mixture is cooled down, causing separation of the crystalline product. 5 ml of ethyl acetate are added. After drying, 0.53 g of raw deferasirox is obtained, i.e. 49% of the theory, with an HPLC content of 94% and a melting temperature of 248 to 260° C.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][CH2:21][C:22](O)=[O:23].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)C>[Cl:20][CH2:21][C:22]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: O=C(O)CCl
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCl

Procedure:
A solution of 1-octadecanol 5 (5 0 g, 180 mmol), chloroacetic acid (17.5 g, 180 mmol) and concentrated sulfuric acid (0.1 mL) in 350 mL of toluene was refluxed overnight in a flask equipped with a Dean-Stark trap. The solution was diluted with 500 mL of diethyl ether and extracted twice with a saturated bicarbonate solution (500 mL). The aqueous phase was subsequently extracted with 400 mL of diethyl ether. The combined organic layers were dried with sodium sulfate and evaporated in vacuo yielding a brown solid, which was used without further purification. 1H-NMR (CDCl3) δ=4.20 (t, 2H), 4.07 (s, 2H), 1.68 (q, 2H), 1.30 (m, 30H), 0.89 (t, 3H) ppm. FT-IR: ν=2919, 2851, 1749 (C═O stretch), 1333, 1208 (C—O stretch), 786 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:9]2
Reactant: C=C[Mg]Br
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1ccc(Br)c2cc[nH]c12
Reaction time: 1.5 h
Yield: 16 %

Procedure:
To a solution of 4-bromo-1-methyl-2-nitrobenzene (10 g) in THF (130 mL) was slowly added vinylmagnesium bromide (1 M in THF, 162 mL) at −40° C. under nitrogen atmosphere. The reaction mixture was stirred for 1.5 h and then quenched with sat'd. aq. NH4Cl (50 mL). The mixture was partitioned between EtOAc (500 mL) and water (150 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by SiO2 chromatography eluting with 2.5% EtOAc/petroleum ether to afford 1.54 g (16%) of 4-bromo-7-methyl-1H-indole (306) as brown solid: MS (ESI) m/z=209.9 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])=[CH:4][CH:3]=1.[OH:28]OS([O-])=O.[K+].[OH2:34]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])(=[O:28])=[O:34])=[CH:4][CH:3]=1
Reactant: O
Reactant: O=S([O-])OO
Reactant: O=S(=O)(NCCNCCSc1ccc(Br)cc1)c1cccc2cnccc12
Agent: [K+]
Solvent: CO
Product: O=S(=O)(CCNCCNS(=O)(=O)c1cccc2cnccc12)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of isoquinoline-5-sulfonic acid {2-[2-(4-bromo-phenylsulfanyl)-ethylamino]-ethyl}-amide (73.0 mg, 0.157 mmol) and oxone (289 mg, 0.470 mmol) in CH3OH (5 mL)/H2O (1.3 mL) is allowed to stir at ambient temperature for 30 minutes to form a suspension. After filtration, the white solid is sonicated in H2O (10 mL), then filtered to give a tan solid of the title compound. ESIMS: m/z 498 [(M+H)+, 79Br], 500 [(M+H)+, 81Br].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.Cl.Cl.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:5](=[O:7])[C:4]2[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[C@H:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1C
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(Cl)cc(Cl)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a mixture of 3,5-dichlorobenzoic acid (2.6 g), (3R)-1-benzyl-3-(3,4-dimethylbenzyl)piperazine dihydrochloride (5.0 g) and triethylamine (8.54 ml) in dichloromethane (80 ml) was added 2-chloro-1-methylpyridinium iodide (3.83 g) under ice-cooling, and then the mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure, and the resulting residue was dissolved into ethyl acetate. The ethyl acetate solution was filtrated and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using hexane-ethyl acetate (10:1) as eluent to give (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazine (5.58 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][CH2:13][O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([C:30]([O:32][CH3:33])=[O:31])=[C:20]([CH3:34])[NH:19][C:18]=1[CH2:35][O:36][CH2:37][CH2:38][NH2:39])=[O:16]>CO>[CH3:12][CH2:13][O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([C:30]([O:32][CH3:33])=[O:31])=[C:20]([CH3:34])[NH:19][C:18]=1[CH2:35][O:36][CH2:37][CH2:38][NH2:39])=[O:16].[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
In 100 ml of methanol was dissolved 20 g of para-toluenesulfonic acid. A solution of 40 g of the amlodipine prepared in Reference Example 1 in 500 ml of methanol was added dropwise to the methanol solution, followed by stirring at 23° C. for 3 hours.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>C([O-])(O)=O.[Na+].CCOC(C)=O>[CH:24]1([NH:29][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCCC3)n2n1)c1cccnc1
Yield: 23 %

Procedure:
N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) in cyclopentylamine (1.0 mL) was stirred at rt overnight. The reaction mixture was diluted with a saturated solution of NaHCO3 (10 mL) and EtOAc (5 mL). The two phases were separated and the organic phase was washed four times with a saturated solution of NaHCO3, after which the product precipitated in the organic phase. It was filtered, washed with a saturated solution of NaHCO3 and EtOAc, dried under vacuum and isolated as a white solid (13 mg, 23%). HPLC, Rt: 3.54 min. (purity 100%). LC/MS, M+(ESI): 391.3, M−(ESI): 389.3.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:36][S:37][C:38]2[N:39]=[N:40][NH:41][CH:42]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:28]1([CH2:27][C:26]([NH:25][C@@H:24]2[C:23](=[O:35])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:36][S:37][C:38]4[N:39]=[N:40][NH:41][CH:42]=4)[CH2:19][S:20][C@H:21]23)=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CSc3c[nH]nn3)CS[C@H]12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(O)=S)=C(CSc3c[nH]nn3)CS[C@H]12
Reaction time: 0.67 h
Yield: 50.6 %

Procedure:
To a suspension of 7β-phenylacetylamino-3-(1,2,3-triazol -4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (186 mg : 0.296 mMol ) in dichloromethane (3 ml) under ice cooling is added anisole (0.45 ml) and trifluoroacetic acid (0.45 ml), and the mixture is stirred for 1 hour 40 minutes. The reaction mixture is concentrated, triturated with hexane, and washed with ethyl acetate to give 7β- phenylacetylamino-3-(1,2,3-triazol-4-yl) thiomethylthio-3-cephem-4- carboxylic acid as white solid (67 mg). Yield : 49%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:13][N:14]([O:15][CH3:16])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[NH2:1]
Reactant: CNOC
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1N
Temperature: 25 °C

Procedure:
2-Amino-4-chlorobenzoic acid (3 g) and N,O-dimethylhydroxylamine hydrochloride (1.9 g) were dissolved in a mixture of methylene chloride (40 ml) and N,N-dimethylformamide (4 ml). To the solution were added, while stirring at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-hydrochloride (3.6 g) and triethylamine (1.4 g). The mixture was stirred for 90 minutes, which was then concentrated under reduced pressure. To the concentrate were added ethyl acetate (100 ml) and-water (100 ml). The mixture was shaken, The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was purified by means of a silica gel chromatography to give N-methyl-N-methyloxy-2-amino-4-chlorobenzamide as a yellow oily product (3.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6](N)=[CH:5]2.[FH:13].N1C=CC=CC=1.N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([F:13])=[CH:5]2
Reactant: Nc1cc2cc(Br)ccc2cn1
Reactant: F
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1cc2cc(Br)ccc2cn1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
To a mixture of 6-bromoisoquinolin-3-amine (0.71 g, 3.18 mmol) in pyridine hydrofluoride (10 mL, 3.18 mmol) at −78° C. was carefully added sodium nitrite (0.26 g, 3.82 mmol). The reaction mixture was stirred at −78° C. for 5 minutes. The reaction mixture was then warmed to room temperature over 40 minutes. The mixture was poured into an ice bath and the pH was adjusted to >9 with Na2CO3. The mixture was filtered to recover a yellow-purple solid. The solid was dissolved in EtOAc and water with stirring. The mixture was extracted with EtOAc (3×200 mL). The EtOAc was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was taken up in DCM-MeOH and adsorbed onto silica gel. Purification by chromatography on silica gel eluting with EtOAc 0-7% in hexanes provided the product (500 mg, 70%). LCMS (API-ES) m/z: 226, 228 (M+H+).
Reaction SMILES: [F:1][C:2]([F:27])([C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][CH:14]=1)=O)[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:28][C:29]([S:32]([NH2:34])=[O:33])([CH3:31])[CH3:30]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[F:1][C:2]([F:27])([C:3](=[O:4])[N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:11](=[N:34][S:32]([C:29]([CH3:31])([CH3:30])[CH3:28])=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)C(=O)N1CCCCC1
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a solution of Intermediate 103B (1.97 g, 5.01 mmol) and 2-methylpropane-2-sulfinamide (1.821 g, 15.02 mmol) in anhydrous THF (25.04 mL) was added Ti(OEt)4 (5.19 mL, 25.04 mmol). The reaction was heated at refluxed temperature overnight. The reaction was cooled to rt, poured into brine, diluted with EtOAc, and stirred for 30 min. The titanium oxide was removed by filtering through a plug of Celite®. The filtrate layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (80 g silica gel, eluted with EtOAc in hexanes to yield the desired product (1.62 g, 59%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=8.80 Hz, 2H), 6.95 (d, J=9.08 Hz, 2H), 4.07 (t, J=6.05 Hz, 2H), 3.62-3.69 (m, 1H), 3.52-3.58 (m, 1H), 3.39 (t, J=5.09 Hz, 2H), 2.26-2.37 (m, 2H), 2.05-2.11 (m, 2H), 1.53-1.70 (m, 7H), 1.25 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.C(N(CC)CC)C.[N:44]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.O>CN(C)C=O>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:47]2[CH2:48][CH2:49][N:44]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45][CH2:46]2)=[O:29])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (4.6 g) in N,N-dimethylformamide (32 ml) were added triethylamine (1.08 g) and tertbutyl 1-piperazinecarboxylate (1.99 g). The reaction mixture was stirred for 3 hours and poured into water. The mixture was extracted with ethyl acetate, and the organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate→ethyl acetate:ethanol=20:1) to give tert-butyl 4-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-1-piperazinecarboxylate (4.7 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][C:28](O)([CH3:30])[CH3:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 40 °C
Reaction time: 48 h

Procedure:
3-Chloro-4-methoxycarbonylbenzoic acid (0.24 g) was dissolved in DMF (2.5 mL) under N2 then CDI (0.36 g) was added and the resulting mixture was stirred at 40° C. for 2 h. t-BuOH (0.54 mL) and DBU (0.33 mL) were added and the resulting mixture was stirred at 40° C. for 2 days. The mixture was evaporated and the residue was taken up with AcOEt, washed with 1N HCl and sat. NaHCO3, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: toluene) to give 2-chloro-4-(tert-butoxycarbonyl)benzoic acid methyl ester (216 mg).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]([N:7]=[C:8]=[O:9])[CH3:6]>C1COCC1>[CH:1]#[C:2][CH3:3].[CH2:5]([NH:7][C:8](=[O:9])[NH2:4])[CH3:6]
Reactant: C#CCN
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: C#CC
Product: CCNC(N)=O
Reaction time: 1 h

Procedure:
1-propyn-3-ethylurea was prepared in the following manner: To a 500 mL flask fitted with a stirrer, thermometer, N2 flow tube, and a dropping funnel, 75 mL THF and 5.5 g (0.1 mole, 6.9 mL) monopropargylamine was added followed by the dropwise addition of 7.1 g (0.1 mole) ethylisocyanate in 10 mL THF; the temperature was initially moderated with a water bath and continued for 1 hour at room temperature.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 70 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 70% of theory, Rf value: 0.16 (silica gel; dichloromethane/ethanol=4:1) C26H27N7O3 (485.6) ##EQU27##