Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH2:28])[CH3:27])=[C:16]([F:29])[CH:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH:28][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:11])=[O:10])[CH3:27])=[C:16]([F:29])[CH:15]=1
Reactant: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)c1
Yield: 103.3 %

Procedure:
3-Methoxybenzenesulfonyl chloride (331 mg, 1.6 mmol) was added to a solution of 1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethylamine (400 mg, 1.6 mmol) and triethylamine (246 μL, 1.7 mmol) in acetonitrile. The reaction was mixed at room temperature for 24 hours, afterwhich the acetonitrile was removed in vacuo. The remaining solid was dissolved in dichloromethane and purified by preparative liquid chromatogrpahy on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-50% methyl tert-butyl ether in hexane (35 min), to afford the the desired product (694 mg, 99%) as a white solid;
Reaction SMILES: [ClH:1].[CH2:2]([N:9](C)[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13])C1C=CC=CC=1>CO.O.[Pd]>[ClH:1].[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH3:2])=[CH:19][CH:18]=1
Reactant: CN(CCC(=O)c1ccc(F)cc1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CNCCC(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 42.15 g (0.137 mole) of compound VI dissolved in 221 mL of a MeOH-water (1:1) mixture were added 9.68 g of Pd over 5% carbon (56.5% water). The mixture was hydrogenated at atmospheric pressure for 1 hour. The catalyst was filtered and the solvent was evaporated to dryness. The solid formed was recrystallized from AcCN and acetone to give 28.6 g (96%) of compound VII as a white crystalline solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[OH:12][C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.[CH2:26](Br)[CH:27]=[CH2:28]>O>[CH2:28]([O:12][C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)[CH:27]=[CH2:26]
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cccc2[nH]c3ccccc3c12

Procedure:
138 g of potassium carbonate was added to N,N-dimethylformamide (500 mL) solution of 121.9 g of 4-hydroxycarbazole. Under stirring, 88.6 g of allyl bromide was added thereto and the reaction mixture was stirred at 80° C. for 5 hours. The reaction mixture was allowed to cool, 3.5 L of water was added thereto, and extracted twice with 1 L of ethyl acetate. The combined organic layer was washed with 1 L of brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by NH silica gel chromatography (ethyl acetate:n-hexane=1:1), and 129 g of the subject compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][C:22](=[O:24])[CH3:23])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)CCl
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 14.2 g (82 mmole) of 4-chloro-3-nitrophenol, 12.4 g (90 mmole) of ground potassium carbonate, 8.2 g (55 mmole) of sodium iodide, 8.3 g (90 mmole) of chloroacetone and 220 ml of dimethylformamide is stirred for 3 hours at room temperature. The whole is subsequently filtered, the residue is washed with dimethylformamide, the organic phase is concentrated by evaporation in vacuo and the resulting crude product is partitioned between water and methylene chloride. The solid remaining after drying and removal of the methylene chloride is recrystallised from methylene chloride/petroleum ether. 1-(4-chloro-3-nitrophenoxy)-2-propanone is obtained having a melting point of 92°-94°.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:6][C:15](=[O:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: CC/C=C/CO
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC=CCOC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.8 %

Procedure:
Trans-2-penten-1-ol (49.6 ml; 487.6 mmol) and (4-chloro-phenyl)-acetic acid (83.2 g; 487.6 mmol) were dissolved in 1200 ml of dichloromethane. After addition of EDC (140.2 g, 731 mmol) and DMAP (11.9 g, 97.5 mmol), the reaction mixture was stirred for 18 hours at room temperature. After evaporation under reduced pressure, the residue was dissolved with diethyl ether, washed with water, brine and dried over anhydrous sodium sulfate. Evaporation gave 136 g of an yellow oil, which was further purified by flash-chromatography (silica gel; hexane/ethyl acetate 9:1). Yield: 68 g (59%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[CH:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C#CCCCCCC.[I:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[I:27][C:28]1[CH:33]=[CH:32][C:31]([C:17]#[C:16][C:8]2([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]2)=[CH:30][CH:29]=1
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Reactant: Ic1ccc(I)cc1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(I)cc2)COC(C)(C)OC1
Yield: 34 %

Procedure:
When tert-butyl-5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl-carbamate was substituted for 1-octyne and 1,4 diiodobenzene was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 34% yield, as the pale solid. 1H-NMR (CDCl3) 1.43 (s, 3H); 1.46 (s, 9H); 1.48 (s, 3H); 2.40 (s, 1H); 3.99 (d, 2H, J=11.34 Hz); 4.00 (d, 2H, J=11.37 Hz); 5.18 (broad s, 1H); 7.12 (d, 2H, J=8.28 Hz); 7.61 (d, 2H, J=8.28 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](O)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21].CN.C1C=CC2N(O)N=[N:30][C:28]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:30][CH3:28])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1c(-c2ccc(Br)cc2)oc2ccc(O)c(F)c12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(Br)cc2)oc2ccc(O)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-fluoro-2-(4-bromophenyl)-5-hydroxybenzofuran-3-carboxylic acid (0.62 g, 1.77=10, 1 eq), 2M solution of methylamine in THF (5.4 ml, 10.8 mmol, 6.1 eq), HOBT (0.43 g, 3.18 mmol, 1.8 eq), EDCI.HCl (0.61 g, 3.18 mmol, 1.8 eq) in THF at r.t. under an nitrogen atmosphere was added diisopropylethylamine (1.9 ml, 10.9 mmol, 6.2 eq). The clear reaction mixture was stirred at r.t. overnight. The reaction mixture was concentrated and diluted with water, and then the solid precipitate was collected by filtration. The product was washed with petroleum ether and dried under vacuum. Yield: 0.51 g (79.7%). 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.63 (t, J=4.4 Hz, 1H), 7.79-7.72 (m, 4H), 7.33 (d, J=8.8 Hz, 1H), 7.02 (m, 1H), 2.81 (d, J=4.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][CH2:47][C:48]1[C:57](=[O:58])[C:56]2[C:51](=[CH:52][C:53]([Cl:59])=[CH:54][CH:55]=2)[N:50]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:49]=1>C(Cl)Cl>[Cl:59][C:53]1[CH:52]=[C:51]2[C:56]([C:57](=[O:58])[C:48]([CH2:47][NH:46][C:7]([C:4]3[S:3][C:2]([Br:1])=[N:6][CH:5]=3)=[O:9])=[CH:49][N:50]2[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:55][CH:54]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
To a stirred solution of 2-bromothiazole-5-carboxylic acid (241 mg, 1.16 mmol) and N,N-diisopropylethylamine (409 mg, 552 μL, 3.16 mmol) in methylene chloride was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (559 mg, 1.26 mmol). After 15 min., 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (300 mg, 1.05 mmol) was added. The reaction mixture was stirred at room temperature. The mixture was diluted with CH2Cl2 and washed with water followed by 1N aqueous HCl and finally saturated aqueous sodium carbonate solution. The organic layer was dried (Na2SO4), filtered and concentrated. The product 2-bromo-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide (464 mg, 93%) was obtained without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([OH:50])[CH2:47][CH2:46][N:45]([CH3:48])[C:44]2=[O:49])=[N:41][CH:42]=1>>[OH:50][C:43]1([C:40]2[N:41]=[CH:42][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:38][CH:39]=2)[CH2:47][CH2:46][N:45]([CH3:48])[C:44]1=[O:49]
Reactant: CN1CCC(O)(c2ccc(Br)cn2)C1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(O)CCN(C)C3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 14 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 3-(5-bromo-pyridin-2-yl)-3-hydroxy-1-methyl-pyrrolidin-2-one following a procedure analogous to that described in Example 1. Yield: 14% of theory; LC (method 3): tR=2.76 min; Mass spectrum (ESI+): m/z=544 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([CH:25]=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[BH3-]C#N.[Na+]>CCO.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([CH2:25][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C=O)cc32)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(CN4CCOCC4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbaldehyde (Step A, Example 453, 10 mg, 0.020 mmol) in EtOH (2 mL) at rt was added morpholine (10 uL, 0.12 mmol) and NaCNBH3 (100 mg). After stirring at rt overnight, the reaction was diluted with sat. NaHCO3, and product was extracted with EtOAc (3×). The combined extracts were washed with brine, dried with MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the title compound. 1H NMR (500 MHz, (CD3)2CO): δ, 8.31 (s, 1H), 7.71 (d, 1H), 7.46 (s, 1H), 7.27 (s, 2H), 7.20 (d, 2H), 7.12 (d, 1H), 6.97 (d, 2H), 4.82 (br s, 2H), 3.66 (t, 4H), 3.51 (s, 2H), 2.46 (br, 4H), 1.24 (s, 9H). LCMS: m/e 561.1 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH:4]1[C:12]1[N:16]2[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]=3[N:19]=[CH:20][C:15]2=[N:14][N:13]=1)[CH3:2].Cl>C1COCC1>[CH2:1]([CH:3]1[CH:4]([C:12]2[N:16]3[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:18]=4[N:19]=[CH:20][C:15]3=[N:14][N:13]=2)[CH2:5][C:6](=[O:7])[CH2:11]1)[CH3:2]
Reactant: CCC1CC2(CC1c1nnc3cnc4c(ccn4COCC[Si](C)(C)C)n13)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: CCC1CC(=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.5 %

Procedure:
To a solution of 1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (3.87 g, 8.72 mmol) in THF (30 mL), was added aqueous HCl (1N, 26.2 mL) at about 0° C. The ice bath was removed and the reaction was stirred at ambient temperature for about 6 h. THF was removed under reduced pressure. The aqueous phase was neutralized by the addition of saturated aqueous NaHCO3 and was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (60 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 20 to 80% EtOAc in DCM to yield 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (2.84 g, 81%) as a yellow amorphous solid. LC/MS (Table 1, Method a) Rt=2.44 min; MS m/z: 400 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])[CH:8]=2)[N:3]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:31]=1[CH:32]=[O:33].CCN(CC)CC>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:32]([C:31]1[CH:34]=[C:35]([C:2]2[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[O:18])[CH:8]=3)[N:3]=2)[CH:36]=[CH:37][C:30]=1[OH:29])=[O:33]
Reactant: COc1ccc(COC(=O)c2ccc3nc(Br)c(N(C)C(C)C)nc3c2)cc1
Reactant: CC1(C)OB(c2ccc(O)c(C=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: COc1ccc(COC(=O)c2ccc3nc(-c4ccc(O)c(C=O)c4)c(N(C)C(C)C)nc3c2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of (4-methoxyphenyl)methyl 2-bromo-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (400 mg, 0.90 mmol) in 1,2-dimethoxyethane (10 mL) was added 2-hydroxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (444 mg, 2.26 mmol), Et3N (273 mg, 2.7 mmol), Pd(dppf)Cl2 (58 mg, 0.08 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. and maintained under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated in vacuo to give the residue, which was purified by silica gel column chromatography eluting with 1% to 5% ethyl acetate in petroleum to afford (4-methoxyphenyl)methyl 2-(3-formyl-4-hydroxyphenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a yellow solid (190 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=O)[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[NH:29]1[CH2:37][CH2:36][CH2:35][C@H:30]1[C:31]([NH:33][CH3:34])=[O:32]>>[CH3:34][NH:33][C:31]([C@@H:30]1[CH2:35][CH2:36][CH2:37][N:29]1[C:24](=[O:26])[CH2:23][N:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=3)[S:10][CH:11]=2)[CH2:18][CH2:19]1)=[O:32]
Reactant: CNC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Product: CNC(=O)[C@@H]1CCCN1C(=O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1

Procedure:
In analogy to example 22.3, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid (example 22.2) was coupled with H-Pro-NHMe, using general method C, to give (S)-1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylic acid methylamide. White solid. MS 533.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:35][C:36]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl.O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:5]2[CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[N:1]([C:38](=[O:39])[C:37]3[CH:41]=[C:42]([F:45])[CH:43]=[CH:44][C:36]=3[CH3:35])[CH2:11][CH:6]2[C:7]([O:9][CH3:10])=[O:8])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2cc(F)ccc2C)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
To a mixture of 1.5 g (3.80 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.64 ml (18.97 mmol) of triethylamine in 15 ml of CH2Cl2, chilled to 0° C., was added 1.36 g (11.4 mmol) of 2-methyl-5-fluorobenzoyl chloride. The mixture was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 and water and the organic layer separated. The organic layer was washed with 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 2.2 g of a white foam. Anal. for C26H25FN2O6S: Calc'd: C, 60.9; H, 4.9; N, 5.5; Found: C, 60.9; H, 5.0; N, 5.0;
Reaction SMILES: [Cl-].C(=[N:9][N+:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:11]=1[CH2:23][CH3:24])C1C=CC=CC=1.Cl.C(=O)C1C=CC=CC=1>O>[Cl-:22].[NH2:9][N+:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:11]=1[CH2:23][CH3:24]
Reactant: CCc1n(Cc2ccc(Cl)cc2)cc[n+]1N=Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O=Cc1ccccc1
Solvent: O
Product: CCc1n(Cc2ccc(Cl)cc2)cc[n+]1N

Procedure:
500 mg (1.39 mmol) of 1-(benzylideneamino)-3-(p-chlorobenzyl)-2-ethylimidazolium chloride are subjected to a steam distillation in 5 ml of water and 2 ml of 3N hydrochloric acid until benzaldehyde no longer evolves. The mixture is evaporated and the residue is recrystallized from ethanol/ether. There is obtained 1-amino-3-(p-chlorobenzyl)-2-ethylimidazolium chloride of melting point 223°-225°.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20](O)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br.[S:26]1[C:30]2[CH2:31][CH:32]([NH2:35])[CH2:33][CH2:34][C:29]=2[N:28]=[C:27]1[NH2:36]>>[NH2:36][C:27]1[S:26][C:30]2[CH2:31][CH:32]([NH:35][C:20](=[O:21])[CH2:19][N:14]3[C:15]([CH3:18])=[CH:16][CH:17]=[C:12]([NH:11][S:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)(=[O:10])=[O:9])[C:13]3=[O:23])[CH2:33][CH2:34][C:29]=2[N:28]=1
Reactant: Nc1nc2c(s1)CC(N)CC2
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Agent: Br
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NC1CCc2nc(N)sc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6), and was obtained as an off-white solid compound.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][OH:14].[Br:15][C:16]1[C:24]2[C:19](=[N:20][C:21](F)=[CH:22][CH:23]=2)[N:18]([CH3:26])[CH:17]=1.O>CN(C=O)C>[Br:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([O:14][CH2:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=3)=[CH:22][CH:23]=2)[N:18]([CH3:26])[CH:17]=1
Reactant: OCc1ccccn1
Reactant: Cn1cc(Br)c2ccc(F)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ccc(OCc3ccccn3)nc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.7 %

Procedure:
Potassium tert-butoxide (137.4 g; 1.19 mol) and DMF (1.44 L) are charged into a flask, and a solution of 2-pyridylmethanol (145.8 g, 1.34 mol) in DMF (306 mL) is added over 15 min. The flask is cooled as necessary to maintain room temperature. The mixture is stirred at room temperature for 40 minutes. A solution of 3-bromo-6-fluoro-1-methyl-pyrrolo[2,3-b]pyridine (170 g, 742.2 mmol) in DMF (306 mL) is added over 15 min., maintaining the temperature between 20 and 25° C. The mixture is stirred for 2 h. Water (1.7 L) is added slowly to the mixture, cooling as necessary, followed by extraction with EtOAc (4×1.0 L). The combined extracts are washed with water (4×1.0 L), then brine, and dried over sodium sulphate, filtered and concentrated to leave the product as a yellow solid (235.1 g, 0.74 moles). MS (m/z): 318.0/320.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:21]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:28])=O)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:23][C:22](=[N:24][CH:25]([CH3:27])[CH3:26])[C:21]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:28])[C:16]=4[N:15]=3)=[CH:11][C:10]([C:29]([F:30])([F:31])[F:32])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c(=NC(C)C)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Yield: 38.6 %

Procedure:
A stirred solution of the title compound from Step D (1.2 g, 2.6 mmol) in 8 mL of phosphorous oxychloride was heated at reflux for 8 hours. The hot reaction solution was poured onto a large excess of ice and 100 ml of ethyl acetate added almost immediately (before allowing all of the ice to melt). After stirring and allowing the remaining ice to melt, the ethyl acetate layer was separated, washed with water, aqueous saturated sodium bicarbonate and brine. Followed by drying over magnesium sulfate, the solvent was removed in vacuo to give a crude yellow oily solid residue. Purification by flash chromatography on silica gel (4:1 hexane/ethyl acetate as eluant) afforded 450 mg of the title compound, a compound of the invention, isolated as a white solid melting at 175–176° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(C)cc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)cc(CBr)c1
Yield: 67.9 %

Procedure:
A suspension of 3,5-dimethylanisole (13.60 g, 100 mmol), N-bromosuccinimide (18.35 g, 100 mmol) and 2,2′-azobis(2-methylpropionitrile) in CCl4 was heated under reflux for 1 h. The succinimide was filtered off, the filtrate was concentrated and the residue was chromatographed (SiO2, CH2Cl2/hexane 1:4). There were obtained 14.61 g (68%) of 1-bromomethyl-3-methoxy-5-methyl-benzene.