Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:20])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([S:20][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[NH:9][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Sc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Reactant: Ic1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(Sc3cccs3)[nH]c2-c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
6.43 g of 4,5-bis(4-chlorophenyl)-2-mercaptoimidazole is dissolved in 150 ml of absolute dimethylformamide and combined with 0.6 g of sodium hydride (80% strength in white oil). The mixture is agitated for another 30 minutes, and then 4.25 g of 2-iodothiophene in 30 ml of dimethylformamide is added dropwise thereto; the mixture is heated under reflux for 16 hours under argon. The solution is then poured into 600 ml of ice water, the product is extracted with ethyl acetate; the organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from ether, yielding 7.02 g of 4,5-bis(4-chlorophenyl)-2-(2-thienylthio)imidazole, mp 219°.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[NH2:20][NH2:21]>C(O)C>[N:1]1([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]([NH:20][NH2:21])=[O:17])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(=O)NN2CCOCC2)s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(C(=O)NN2CCOCC2)s1
Temperature: 25 °C
Yield: 68 %

Procedure:
Methyl 5-(morpholin-4-ylcarbamoyl)thiophene-2-carboxylate (237 mg, 0.87 mmol) in ethanol (6.0 mL) was refluexed with heating with hydrazine monohydrate (0.40 mL) for 6 hours and allowed to cool to room temperature and the solvent was evaporated at 40° C. 5 mL of diethyl ether was added to the resulting oil, and the precipitated solid was collected by filtration, washed with water and dried to give 160 mg of the desired product (yield 68%).
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7].[H-].[Na+].[CH2:13]([O:15][C:16](=[O:19])[CH2:17]Br)[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][CH:5]([C:6](=[O:8])[CH3:7])[C:4](=[O:9])[CH2:3][CH:2]([CH3:10])[CH3:1])[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)CC(=O)CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(C)=O)C(=O)CC(C)C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Add a solution of 6-methylheptane-2,4-dione (5.0 g, 35.16 mmol) in tetrahydrofuran (50 mL) dropwise to a cooled suspension (0° C.) of sodium hydride (1.69 g, 42.2 mmol, 60% dispersion in oil) in tetrahydrofuran (50 mL). After 1 hr., add bromoacetic acid ethyl ester (4.28 mL, 38.68 mmol) dropwise and stir at 0° C. to room temperature over 88 hr. Partition the reaction mixture between ethyl acetate (200 mL) and saturated aqueous ammonium chloride solution (100 mL). Separate the organic layer, dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography (95:5 hexanes:ethyl acetate) to give 3-acetyl-6-methyl-4-oxoheptanoic acid ethyl ester (5.81 g, 73%). 1H-NMR (400 MHz, CDCl3) δ 4.10 (m, 4H), 2.81 (d, 2H), 2.41 (t, 1H), 2.22 (s, 3H), 1.23 (m, 4H), 0.92 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C@@H:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[C:17]([OH:19])=O)[CH:10]=2)[NH:5][CH:4]=1)#[N:2].Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]=[C:3]2[C:1]#[N:2])=[O:19]
Reactant: CNOC
Reactant: N#Cc1c[nH]c2ccc([C@@H]3CCC[C@H]3C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1CCC[C@H]1c1ccc2[nH]cc(C#N)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of trans-2-(3-Cyano-1H-indol-5-yl)-cyclopentanecarboxylic acid (0.66 g, 2.60 mMol), N,O-dimethylhydroxylamine hydrochloride (0.51 g, 5.20 mMol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g, 2.86 mMol), and dichloromethane (20 mL) was treated with triethylamine (1.05 g, 10.4 mMol) and stirred at ambient temperature for 18 h. The resulting solution was diluted with 30 mL dichloromethane, washed with 1M hydrochloric acid, 1M sodium hydroxide, and brine, dried over sodium sulfate and concentrated in vacuo to give the crude product as a clear oil which was used without further purification (0.51 g, 66%). LC-MS: 1.38 min (2 min gradient); 298.11 (MH)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([NH:33]C(=O)C)([CH2:28][O:29]C(=O)C)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:12]=1)(=O)C.O.[OH-].[Li+]>CO.O>[NH2:33][C:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:12]=1)([CH2:6][CH2:5][OH:4])[CH2:28][OH:29]
Reactant: CCCCCCCCCCCc1ccc(CCCC(CCOC(C)=O)(COC(C)=O)NC(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCc1ccc(CCCC(N)(CO)CCO)cc1
Yield: 25.9 %

Procedure:
3-Acetamido-3-acetoxymethyl-6-(4-undecylphenyl)hexyl acetate (1.70 g) and lithium hydroxide monohydrate (1.42 g) were dissolved in methanol (17 ml) and water (17 ml), and the mixture was refluxed under heating for 3 hours while stirring. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled away. The crude crystals obtained were recrystallized from ether-hexane-ethyl acetate (2:2:1) to give the subject compound (330 mg) as white crystals, melting at 73-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17](I)=[CH:18][C:19]=1[N:20]([C:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[O:14].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:18][C:19]=1[N:20]([C:28]([C@H:30]1[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]1)=[O:29])[CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1)=[O:14]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Temperature: 70 °C

Procedure:
To the mixture of 4-chlorophenylboronic acid (46.9 mg, 0.3 mmol) and 5-iodo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (50 mg, 0.099 mmol), from step 5, in 5:1 mixture of toluene/MeOH (2.0 mL) was added a solution of Pd(PPh3)4 (12.0 mg, 0.01 mmol, 10 mol %) in toluene (1.0 mL) followed by aqueous 2M Na2CO3 solution (0.1 mL, 0.2 mmol). The resultant reaction mixture was heated at 70° C. for 16 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC (1 mm, 60 A°) using DCM/CHCl3/MeOH/Et3N (100:90:16:1) as an eluent furnished 5-(4-chloro-phenyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (35.0 mg, 71.5% yield). NMR 1H (CDCl3, 400 MHz): 7.53 (d, J=8.3, 2H), 7.4 (d, J=8.5, 2H), 7.0 (s, 1H), 4.67-4.58 (m, 1H), 3.84 (s, 3H), 2.82-2.64 (m, 1H), 2.2 (s, 3H), 2.14-1.35 (m), 0.763 (d, J=6.6, 3H), 0.76-0.56 (m, 2H).
Reaction SMILES: C([O:4][C:5]1([CH2:22][N:23]([CH:27]([CH3:29])[CH3:28])C(=O)C)[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:8]=2[O:7][CH2:6]1)(=O)C.Cl.C(O)C.[OH-].[Na+]>O>[OH:4][C:5]1([CH2:22][NH:23][CH:27]([CH3:28])[CH3:29])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:8]=2[O:7][CH2:6]1
Reactant: CCOC(=O)Nc1ccc2c(c1)OCC(CN(C(C)=O)C(C)C)(OC(C)=O)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Nc1ccc2c(c1)OCC(O)(CNC(C)C)CO2

Procedure:
3-Acetoxy-3-(N-acetylisopropylaminomethyl)-7-carbethoxyamino-3,4-dihydro-2H-1,5-benzodioxepin (4.1 g., 10 millimoles) is warmed five hours at 40°C. with 6 ml. of concentrated hydrochloric acid and 34 ml. of ethanol. The solution is cooled, taken to the basic side with sodium hydroxide, diluted with water, and extracted with diethyl ether to give 3-hydroxy-3-isopropylaminomethyl-7-carbethoxyamino-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[N:43]1[CH:48]=[CH:47][C:46]([C:49](O)=[O:50])=[CH:45][CH:44]=1>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([C:46]3[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=3)=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: O=C(O)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)c2ccncc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and pyridine-4-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.02 minutes; C31H33ClN6O3 (573.10); mass spectrum: (M−H)−=572.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@H:4]([OH:39])[C@@H:5]([NH:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])=[O:22])[CH:18]=[C:17]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:40])[C@H:4]([O:39][CH:42]1[CH2:43][CH2:44][CH2:45][CH2:46][O:41]1)[C@@H:5]([NH:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])=[O:22])[CH:18]=[C:17]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1=COCCC1
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(C(=O)N[C@H](C)c2ccccc2)cc(N(C)S(C)(=O)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](OC1CCCCO1)[C@H](Cc1ccccc1)NC(=O)c1cc(C(=O)N[C@H](C)c2ccccc2)cc(N(C)S(C)(=O)=O)c1
Yield: 69 %

Procedure:
The (2R,3S)-2-hydroxy-3-{[3-[methyl(methylsulfonyl)amino]-5-({[(1R)-1-phenylethyl]amino}carbonyl)benzoyl]amino}-4-phenylbutanoic acid methylester obtained in Reference Example 25 2.30 g (4.06 mmol) was dissolved in tetrahydrofuran 8 mL and thereto were added 3,4-dihydro-2H-pyrane 4.80 mL and p-toluenesulfonic acid pyridinium 204 mg (0.81 mmol) and the mixture was stirred under reflux for 8 hours. After distillating tetrahydrofuran off, the residue was extracted by adding ethyl acetate and 5% aqueous sodium carbonate solution. The organic layer was washed with an aqueous saturated sodium chloride solution and dried on magnesium sulfate, filtered and concentrated. The concentrated residue was purified by a column chromatography on silica gel (eluted with chloroform-methanol system) and recrystallized from a mixed solvent of ethyl acetate and hexane. A precipitated material was collected by filtering and dried to give 1.81 g (2.78 mmol) of the title compound (yield: 69%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:33][NH:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[CH3:33][N:34]([CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([C:11]2[O:12][C:8]([CH3:7])=[C:9]([CH2:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[N:10]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: CNCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)N(C)Cc4cccnc4)cc3)oc2C)cc1
Yield: 67.7 %

Procedure:
Reaction of oxalyl chloride (132 λL, 1.5 mmol) and benzoic acid 4 (376 mg, 1.0 mmol) with subsequent coupling to N-methyl-N-(3-pyridinylmethyl)amine (51 mg, 1.1 mmol) gave benzamide 11 (322 mg, 67%) as a white powder: mp (EtOAc) 77-80° C.; 1H NMR δ 8.59 (br s, 1H, H-2′), 8.52 (br d, J=4.5 Hz, 1H, H-6′), 7.87 (br d, J=7.6 Hz, 2H, H-2, H-6), 7.77 (br s, 1H, H-4′), 7.66 (br d, J=8.2 Hz, 2H, H-2″, H-6″), 7.58 (br s, 2H, H-3, H-5), 7.38-7.44 (m, 3H, H-5′, H-3″, H-5″), 4.71 (br s, 2H, CH2N), 4.62 (s, 2H, CH2SO2), 2.90 (s, 3H, NCH3), 2.39 (s, 3H, CH3), 2.11 (s, 3H, CH3); 13C NMR δ 169.7, 158.0, 149.7, 149.1, 148.6, 144.5, 137.6, 135.6, 135.5, 132.9, 129.6 (2), 128.2 (2), 127.8 (2), 127.4, 125.9, 125.5 (2), 123.7, 52.9, 47.8, 37.0, 21.0, 9.6; MS m/z 476.7 (MH+, 100%). Anal. calcd for C26H25N3O4S: C, 65.67; H, 5.30; N, 8.84. Found: C, 65.46; H, 5.37; N, 8.67%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21]([OH:23])=O)=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:16]=2[Cl:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:38](CC)CC)C.N>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([C:21](=[O:23])[NH2:38])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:16]=2[Cl:27])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc([N+](=O)[O-])cc2C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc([N+](=O)[O-])cc2C(N)=O)CC1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-carboxy-3-chloronitrobenzene (2.6 g) in dichloromethane (80 ml) were added isobutyl chloroformate (1.0 ml) and triethylamine (1.1 ml) in an ice bath and the mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 28% aqueous ammonia (0.5 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol 19/1 as an eluant to give the desired compound (2.2 g, yield 84%) as a pale yellow amorphous solid.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH2:19][Zn+])[CH:12]=[N:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH:6]=[CH:7][CH:8]=1.BrCCBr.C[Si](Cl)(C)C.BrC[C:32]1[CH:33]=[C:34](C2C=CC=C(Cl)C=2)[C:35](OC(F)F)=[N:36][CH:37]=1>C1COCC1.[Zn]>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([O:15][CH:16]([F:18])[F:17])=[N:13][CH:12]=[C:11]([CH2:19][C:35]3[CH:34]=[CH:33][CH:32]=[CH:37][N:36]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)Oc1ncc(CBr)cc1-c1cccc(Cl)c1
Reactant: FC(F)Oc1ncc(C[Zn+])cc1-c1cccc(Cl)c1
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: FC(F)Oc1ncc(Cc2ccccn2)cc1-c1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)zinc(II) bromide. To a suspension of zinc (42.77 mg, 0.65 mmol) in THF (1 mL) was added 1,2-dibromoethane (2.48 μL, 0.03 mmol). The resulting mixture was heated at 70° C. for 10 minutes before being cooled to room temperature. Once cooled, trimethylsilylchloride (2.92 μL, 0.02 mmol) was added and the solution was stirred at room temperature for an additional 30 min. To the activated zinc solution was added 5-(bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine (Intermediate 12, 200 mg, 0.57 mmol) and the resulting mixture was heated at 70° C. for 8 h. The reaction mixture was cooled to room temperature and decanted from the solids to afford a ˜0.5 M solution of the title compound.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:16](Cl)(=[O:18])=[O:17]>S1(CCCC1)(=O)=O.O>[CH3:1][NH:2][S:16]([C:4]1[CH:5]=[CH:6][C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]=2[CH:3]=1)(=[O:18])=[O:17]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc2sc3ccccc3c2c1
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CNS(=O)(=O)c1ccc2sc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A large excess of aqueous methylamine was added to a suspension of dibenzo[b,d]thiophene-2-sulfonyl chloride (2.83 g) in sulfolane (15 ml) and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with water, and the precipitate was recovered, washed with water, dried and purified by silica gel chromatography eluting with a gradient of ethyl acetate:DCM of 0:100 to 10:90 to give the title compound (1.79 g, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH:22]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2.O[CH2:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:50]([O:49][C:47]([N:44]1[CH2:45][CH2:46][CH:41]([CH2:40][N:35]2[C:34]([CH:22]([NH:21][C:19]([N:16]3[CH2:15][CH2:14][CH:13]([N:8]4[CH2:7][C:6]5[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=5)[NH:10][C:9]4=[O:12])[CH2:18][CH2:17]3)=[O:20])[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[N:38][N:37]=[N:36]2)[CH2:42][CH2:43]1)=[O:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2nnn[nH]2)cc2cn[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2nnnn2CC2CCN(C(=O)OC(C)(C)C)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3[4H]-yl)-N-(2{7-methyl-1H-indazol-5-yl}-1-{1H-tetrazol-5-yl}ethyl)piperidin-1-carboxamide (50 mg, 0.1 mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (22 mg, 0.11 mmol) in dry tetrahydrofuran (3.0 mL) at 0° C. was added in one portion triphenylphosphine (27.5 mg, 0.11 mmol) followed by a dropwise addition of diethylazodicarboxylate (10 μL, 0.105 mmol). The resulting mixture was stirred briefly at 0° C. and then allowed to warm to room temperature. After 16 h, the solvent was removed and the residue purified by column chromatography to afford tert-butyl-4-({5-(1-[4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3 [4H]-yl)piperidine-1-carboxamido]-2-(7-methyl-1H-indazol-5-yl)ethyl)-1H-tetrazol-1-yl}methyl)piperidine-1-carboxylate. MS: tR=1.44 min, 716.17 (MH)+ and tert-butyl-4-({5-(1-[4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3[4H]-yl)piperidine-1-carboxamido]-2-(7-methyl-1H-indazol-5-yl)ethyl)-2H-tetrazol-1-yl}methyl)piperidine-1-carboxylate. MS: tR=1.45 min, 716.16 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].[C:17]([C:19](=[C:25]([O:29]CC)[O:26][CH2:27][CH3:28])[C:20]([O:22][CH2:23][CH3:24])=O)#[N:18]>C(O)C>[CH2:27]([O:26][C:25]([C:19]1[C:20]([O:22][CH2:23][CH3:24])=[N:16][N:15]([C:3]2[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])[C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[C:17]=1[NH2:18])=[O:29])[CH3:28]
Reactant: CCOC(=O)C(C#N)=C(OCC)OCC
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1c(OCC)nn(-c2cc(SCC(F)(F)F)c(C)cc2F)c1N
Yield: 17.9 %

Procedure:
5.0 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was dissolved in 50 mL of ethanol, and 5.0 g of ethyl 2-cyano-3,3-diethoxyacrylate was added, followed by stirring under reflux with heating for 6 hours. Then, the solvent was distilled off under reduced pressure, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 1.48g of ethyl-5-amino-3-ethoxy-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole-4-carboxylate.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1>CN1C(=O)CCC1>[CH3:1][NH:2][C:3]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:24][C@H:25]4[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)sc3c2)ccn1
Temperature: 105 °C
Reaction time: 120 h
Yield: 40 %

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (104 mg, 0.3 mmol) in 2 ml of NMP was added (S)-tert-butyl 3-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol). The reaction solution was stirred at 105° C. for 5 days. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)-tert-butyl 3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (56 mg, 0.12 mmol) as white powder. ES/MS m/z 484.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8]O)[CH:7]=1.[ClH:11]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][Cl:11])[CH:7]=1
Reactant: OCc1cc(Br)ccc1Cl
Reactant: Cl
Product: ClCc1cc(Br)ccc1Cl
Temperature: 75 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
(5-Bromo-2-chlorophenyl)methanol (11.37 g, 51.22 mmol) was taken in aqueous HCl (35%) (1.54 L) and stirred at 70-80° C. for 18 h. After completion of the reaction as confirmed by TLC, the reaction mixture was cooled in an ice bath. The precipitate obtained was collected over Buchner filter, washed with water (2×500 mL) and dried in vacuo to afford the title compound (12.2 g, 99%).