Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:25]=1[NH2:26]>C(O)C>[ClH:23].[Cl:23][C:24]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:25]=1[NH:26][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Cl)c(Nc2cc(C)nc3ccc4nc[nH]c4c23)c1
Reaction time: 8 h

Procedure:
A mixture of 40 g. (0.184 m.) of the compound of Example I, C., 26.1 g. (0.184 m.) of 2-chloro-5-methylaniline and 500 ml. of ethanol was refluxed with stirring overnight. The reaction mixture was concentrated to dryness in vacuo, and the residue dissolved in 700 m. of MeOH. The insolubles were removed by filtration and the MeOh filtrate concentrated in vacuo to give 24 g. m.p. decomposes 315°-400°C. The crude product was triturated in 500 ml. of MeOH, then oven-dried (100°C) to give m.p. 332°-335°C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=S)Oc1ccccc1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc(C(C)=O)c(C)nc3OC)CC2)c1
Yield: 77 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6]Br.C(=O)([O-])[O-].[Na+].[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].O>C(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[Cl:1]
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Reactant: NCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cccc(CNCCOc2ccc(Cl)cc2Cl)c1

Procedure:
2.70 Grams (10.0 mmol) of 2-(2,4-dichlorophenoxy)ethyl bromide was dissolved in 30 ml of ethanol, followed by the addition of 1.06 g (10.0 mmol) of anhydrous sodium carbonate and 4.25 g (30.0 mmol) of 3-chlorobenzylamine. The mixture was refluxed for 6 hours on an oil bath. After cooling, the reaction mixture was poured into 100 ml of water and was extracted with chloroform (20 ml×3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]([CH3:40])([CH3:39])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][C:20](=[O:22])[N:19](CC[Si](C)(C)C)[S:18]2(=[O:30])=[O:29])=[C:13]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]([CH3:40])([CH3:39])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][C:20](=[O:22])[NH:19][S:18]2(=[O:30])=[O:29])=[C:13]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)(/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of ((E)-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-1,1-dimethylallyl)-carbamic acid tert-butyl ester (150 mg, 0.2 mmol) in DMF (3 mL) is added CsF (83 mg, 0.53 mmol) and the mixture is stirred at 60° C. for 3 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using 10-20% MeOH/EtOAc as eluent to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([CH:18]([F:20])[F:19])=[CH:4][C:3]=1[NH:21][C:22]1[N:27]=[C:26]([N:28]([CH:38]2[CH2:40][CH2:39]2)CC2C=CC(OC)=CC=2)[C:25]2=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]2[N:23]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([CH:18]([F:19])[F:20])=[CH:4][C:3]=1[NH:21][C:22]1[N:27]=[C:26]([NH:28][CH:38]2[CH2:40][CH2:39]2)[C:25]2=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]2[N:23]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C(F)F)cc(N4CCN(C5COC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc2c(NC3CC3)nc(Nc3cc(C(F)F)cc(N4CCN(C5COC5)CC4)c3Cl)nn12
Temperature: 40 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
2-((2-Chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (69 mg, 0.108 mmol) was dissolved in DCE (1 mL) at room temperature. Anisole (59.2 μl, 0.542 mmol) followed by 200 μl of TFA were added and the reaction was stirred at 40° C. overnight and concentrated. The residue was dissolved in MeOH and loaded onto a 1 g/6 mL Strata SCX ion exchange column, washing with CH3OH. The desired product was eluted with 7 N NH3—CH3OH, concentrated under a stream of N2. Column chromatography (12 g SiO2, 0 to 20% CH3OH—CH2Cl2 gradient elution) followed by trituration with ACN afforded 2-((2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (14.6 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:19]1[C:26]2([C:27](Cl)=[O:28])[N:22]([CH2:23][CH2:24][CH2:25]2)[CH2:21][CH2:20]1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:27]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)=[O:28])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1C(=O)Nc1cccnc1Cl
Reactant: O=C(Cl)C12CCCN1CCC2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1NC(=O)C12CCCN1CCC2
Temperature: 10 °C
Reaction time: 17 h
Yield: 77.1 %

Procedure:
To a solution of 2-chloro-3-(2-aminobenzoyl)aminopyridine (15.0 g, 61.0 mmol), in 200 ml of anhydrous pyridine, pyrrolizidine-7a-carbonyl chloride hydrochloride (14.0 g, 80.5 mmol), prepared as described in Reference Example 3) was added at -20° C. The mixture was stirred for 17 hours at 10° C. and evaporated in vacuo to dryness. The remaining residue was partitioned between saturated sodium biscarbonate solution and chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. To the remaining residue, methanol was added. After stirring, the resulting crystals was obtained through filtration and washed with small amount of methanol to give 18.1 g (77.2%) of the desired compound.
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCC1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH2:29][C:30]1[C:31]([C:48](=O)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:32]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36]>>[NH2:29][C:30]1[C:31]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:32]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36]
Reactant: Nc1cc(C(=O)O)cc(OCc2ccc(Cl)cc2)c1C(=O)c1ccccc1
Agent: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Product: Nc1cc(C(=O)O)cc(OCc2ccc(Cl)cc2)c1Cc1ccccc1

Procedure:
By replacing in Example 24, step A, 4-benzoyl3-benzyloxy-5-nitrobenzoic acid with 5-amino-4-benzoyl-3-(p-chlorobenzyloxy)benzoic acid and following the procedure described, 5-amino-4-benzyl-3-(p-chlorobenzyloxy)benzoic acid is obtained with a melting point of 199°-200° C.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].[C:20]1([C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:31]([C:29]1[NH:28][N:27]=[C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:30]=1)=[O:32]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
EDCI (288 mg, 1.5 mmol) was added to a solution of 1,2-diaminobenzene (0.141 g, 1.31 mmol), 3-phenyl-1H-pyrazole-5-carboxylic acid (188 mg, 1.0 mmol) and HOBT (203 mg, 1.5 mmol) in anhydrous DMF (5 mL). The reaction was stirred under nitrogen at room temperature. After twelve hours the reaction was concentrated in vacuo and precipitated from methanol with a small amount of water. The solid was collected by vacuum filtration and further purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the corresponding amide (60 mg, 38% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([CH3:38])[CH:37]=1)[C:5]([N:7]([CH3:34])[C@@H:8]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6].Cl.COC(=O)[C@H](C[C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)NC=1)N>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([CH3:38])[CH:37]=1)[C:5]([N:7]([CH3:34])[C@@H:8]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:46][C:54]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[CH:12][CH:11]=1)=[O:6]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(O)cc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Agent: Cl
Product: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-O-benzyl-(D)-tyrosine (prepared by O-benzylation of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine (example 64)) with (L)-tryptophan methyl ester hydrochloride according to example 1 followed by hydrolysis of the methyl ester moiety according to example 12 gives N-(3,5-dimethylbenzoyl)-N-methyl-O-benzyl-(D)-tyrosyl-(L)-tryptophan; FAB-MS m/e 602 (M-H)-.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.N1CCCCC1>CO>[C:1]([O:5][C:6](=[O:20])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1/[CH:18]=[C:26]1\[C:27](=[O:31])[NH:28][C:29]2[C:25]\1=[CH:24][CH:23]=[C:22]([Cl:21])[CH:30]=2)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 83.8 %

Procedure:
To a mixture of 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (5.17 g, 17.3 mmol) and 6-chlorooxindole (2.89 g, 17.3 mmol) were anhydrous methanol (100 mL) at room temperature was slowly added piperidine (1.7 mL, 17.3 mmol). The reaction mixture was heated at 70° C. for 0.5 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester as a yellow solid (Yield 6.5 g, 84%).
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Cl.C([O-])(O)=O.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]([NH2:25])=[N:22][C:21]=1[CH3:26])=[O:19]>O.O1CCOCC1>[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]2=[N:25][CH:1]=[CH:2][N:22]2[C:21]=1[CH3:26])=[O:19]
Reactant: CCOC(CBr)OCC
Reactant: COC(=O)c1sc(N)nc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2nccn2c1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of bromoacetaldehyde diethyl acetal (29.3 mmol, 1.26 eq) in water (200 mL) is treated dropwise with conc. HCl (3.0 mL), stirred for 14 h at RT and heated for additional 30 min at 80° C. After cooling to RT NaHCO3 (37.9 mmol) is added carefully and the mixture is stirred for 2 h and treated with 2-Amino-4-methyl-thiazole-5-carboxylic acid methyl ester (23.2 mmol, 1.00 eq). After 1 h dioxane (130 mL) is added and the mixture is stirred at RT for 30 min and at 100° C. for 48 h. The organic solvents are removed in vacuo and the mixture is extracted several times with DCM and chloroform. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give the desired ester which is used without further purification. LC-MS: tR=0.55 min; [M+H]+=197.0.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:11]2[CH2:10][CH2:9][C:8](=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12]2)=[CH:31][CH:30]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
A mixture of 99.9 g (0.4 mole) of 4-(diphenylmethylene)piperidine, 88 g (0.44 mole) of 4-chloro-4'-fluorobutyrophenone, 64.0 g (0.64 mole) of potassium bicarbonate, and a small amount of potassium iodide in 1500 ml of toluene was refluxed for 5 days. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure leaving a residue which was dissolved in about 800 ml of ethyl acetate. This solution was concentrated to about 500 ml and allowed to stand for one day. The resulting precipitate was recrystallized from methanol-ethyl acetate, made basic with sodium hydroxide solution, water washed, and the product recrystallized from petroleum-ether to give the title compound, M.P. 111°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12](Cl)(=[O:16])[C:13]([Cl:15])=[O:14]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12](=[O:16])[C:13]([Cl:15])=[O:14]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: COc1ccc2[nH]cc(C(=O)C(=O)Cl)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-methoxyindole (10.00 g, 67.95 mmol) in diethylether (200 mL), oxalyl chloride (7.79 mL, 88.33 mmol) was added at 0° C. After stirring at rt for 3 h, the solid was filtered off and washed with cold diethylether to yield 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride as a orange solid which was used as such in the next step. LC-MS conditions B: tR=0.46 min, no ionization.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][S:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH3:17][C:18]1[S:22][C:21]([C:23](O)=[O:24])=[CH:20][CH:19]=1.ON1C2C=CC=CC=2N=N1>>[CH3:15][CH:14]([CH3:16])[CH2:13][C@H:2]([NH:1][C:23]([C:21]1[S:22][C:18]([CH3:17])=[CH:19][CH:20]=1)=[O:24])[CH2:3][S:4][CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)C[C@H](N)CSCC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)O)s1
Agent: On1nnc2ccccc21
Product: Cc1ccc(C(=O)N[C@H](CSCC(=O)OC(C)(C)C)CC(C)C)s1
Yield: 14.4 %

Procedure:
3.00 g (0.012 mol) of (S)-1,1-dimethylethyl [(2-amino-4-methylpentyl)thio]acetate, 172 g (0.012 mol) 5-methyl-2-thiophene carboxylic acid, 1.64 g (0.012 mol) 1-hydroxybenzotriazole, and 2.50 g (0.012 mol) N,N-dicyclohexylcarbodiimide are reacted according to the procedure for Example 3 to give 0.64 g of (S)-1,1-dimethylethyl [[4-methyl-2-[[[5-methyl-2-thienyl]carbonyl]amino]pentyl]thio]acetate as a crystalline solid, mp 81°-83°; [α]D25 +56.5° (C 0.63, methanol).
Reaction SMILES: [H-].[Na+].FC(F)(F)C(O)=O.[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:18][S:19][C:20]1[N:25]=[C:24]([NH:26][S:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[C:22]([O:36][CH3:37])[N:21]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1COCC1.O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:33]1[CH2:32][CH2:31][N:30]([S:27](=[O:29])(=[O:28])[NH:26][C:24]2[CH:23]=[C:22]([O:36][CH3:37])[N:21]=[C:20]([S:19][CH2:18][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=3[F:10])[N:25]=2)[CH2:35][CH2:34]1)[CH3:44]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)CC1

Procedure:
The subtitle compound was prepared by adding 60% sodium hydride (0.18 g) portionwise to a solution of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, trifluoroacetate salt (the product from example 36) (0.53 g) and ethyl 2-bromoacetate (0.36 mL) in THF (10 mL). The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine and evaporated to give the subtitle compound as an oil.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>N1C=CC=CC=1.CC(C)=O.C(Cl)Cl>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:8]2[S:7][C:6]3[C:17]4[C:22]([CH:23]=[CH:24][C:5]=3[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3](=[O:30])[C@@H:2]2[O:1][C:36](=[O:37])[C:35]2[CH:34]=[C:33]([O:32][CH3:31])[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[CH:39]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:14][CH:13]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 17 h
Yield: 55.6 %

Procedure:
To a solution of 1.50 g (0.0035 mol) of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one, in 20 ml of dry pyridine was added dropwise 1.4 g (0.0059 mol) of 3,4,5-trimethoxybenzoyl chloride at ice-bath temperature. The mixture was stirred at this temperature for 17 hours and concentrated to dryness. The residue was partitioned between methylene chloride and dilute ammonium hydroxide. The methylene chloride extracts were washed with brine and dried (MgSO4). Removal of the solvent gave a residue, which was dissolved in a mixture of acetone-methylene chloride (70:30) and chromatographed on 40 g silica gel. The column was eluted with 50 ml portions of acetone-methylene chloride (70:30). Fractions 4-15 were combined and the solvent was removed under reduced pressure to give 1.3 g of crude product, which after crystallization from ethanol afforded 1.2 g (55%) of (±)-cis-2,3-dihydro-2-(4-methoxyphenyl)-3 -[(3,4,5-trimethoxybenzoyl)oxy]-5-[2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one, mp 189°-190°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(-c2cnc(N)c([N+](=O)[O-])c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2cnc(N)c(N)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
A solution of 3.25 g of 2-amino-5-(p-tolyl)-3-nitro-pyridine (compound G3) and 325 mg of Pd/C (10%) in 260 ml of methanol is treated with hydrogen under vigorous stirring at room temperature for 18 h. The suspension is filtered with suction through a celite pad. The colorless filtrate is evaporated to dryness to afford 2.63 g of the pure title compound of m.p. 141° C. MS: 200.3 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([Cl:22])[N:6]=1)=O.[BH4-].[Li+].C1COCC1>C(COC)OC>[Cl:22][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:8]=1
Reactant: COC(=O)c1cc(NCCc2ccc(OC)cc2)nc(Cl)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1ccc(CCNc2cc(CO)nc(Cl)n2)cc1
Temperature: 3 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid methyl ester [7.43 g, 23.09 mmol, Intermediate (55)] in dimethoxyethane (100 mL) is chilled in an ice/water bath to 3° C. and treated dropwise via syringe with a solution of 2M lithium borohydride in THF (17.3 mL, 34.6 mmol) not allowing the reaction temperature to exceed 7° C. After complete addition stirring is continued at 5° C. for 1 hour. The reaction mixture is poured into ice/water (250 mL) and extracted four times EtOAc (100 mL). The combined organic extracts are washed with water (100 μL), them with brine (100 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator to afford {2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-methanol [6.51 g, 96%, Intermediate (57)].
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]([CH:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12](OC)=[O:13])(=O)[CH3:9]>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:6]=[C:5]2[N:7]=[C:8]([CH3:9])[C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:12]([OH:13])[N:4]2[N:3]=1
Reactant: Nc1cc(Br)n[nH]1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)nc2cc(Br)nn2c1O
Yield: 54.2 %

Procedure:
To a solution of 3-bromo-1H-pyrazol-5-amine (0.2 g, 1.235 mmol) and dimethyl 2-acetylsuccinate (0.697 g, 3.70 mmol) in xylene (10 mL) was added p-toluenesulfonic acid monohydrate (2 mg, 10.51 μmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 8 h. The solid was filtered and washed with hexanes to afford the title compound (0.201 g, 54.2%). 1H NMR (400 MHz, MeOD) δ 2.37 (3H, s), 3.65 (2H, s), 3.71 (3H, s), 6.20 (1H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH2:12][Br:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1
Temperature: 52 °C
Yield: 76.2 %

Procedure:
To a suspension of 4′-acetamido-acetophenone 2 (21.84 g, 123 mmol) in acetic acid (184 mL), bromine (6.5 mL, 127 mmol) was added. The mixture was heated (inner temp: 52° C., oil bath temp: 60˜65° C.) with vigorous stirring until the suspension make a clear solution. The heating bath was rapidly removed, and the mixture was stirred at room temperature for 15 min and then stirred in an ice-water bath for 2 h(inner temp. 50° C.˜20° C.). The precipitation was filtrated, washed with 30% EtOH in water, and dried under reduced pressure to give 3 as a pale brown solid (24.0 g, 75% yield): MS(ES) m/e 257 [M+H].