Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O[CH:3]([CH2:18]OC1C=CC(C(C)(C)C)=CC=1)[CH2:4]NC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>>[ClH:55].[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:3]([CH3:18])[CH3:4])[CH:50]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C(C)C)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15,0.1), 251 (18), 250 (100), 163 (6), 121 (21), 117 (5), 114 (10), 91 (9).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: COCCN
Solvent: COCCOC
Product: COCCNc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 2-methoxyethylamine in DME. ES-MS m/e (%): 280 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[C:30]([F:32])[C:29]([S:33](=[O:52])(=[O:51])[N:34]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[C:35]3[S:39][N:38]=[CH:37][N:36]=3)=[CH:28][C:27]=2[F:53])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=3[CH:24]=2)[CH:7]=1.C(N(CC)CC)C.[C:61](Cl)(=[O:63])[CH3:62]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:61]([N:16]([C:13]1[C:12]2[CH:24]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][C:26]3[CH:31]=[C:30]([F:32])[C:29]([S:33](=[O:52])(=[O:51])[N:34]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=4[O:49][CH3:50])[C:35]4[S:39][N:38]=[CH:37][N:36]=4)=[CH:28][C:27]=3[F:53])[CH:9]=[CH:10][C:11]=2[O:15][N:14]=1)[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])(=[O:63])[CH3:62]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(NC(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(C)=O)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of tert-butyl (5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate (0.20 g, 0.25 mmol), triethylamine (105 μL, 0.75 mmol) and 4-(dimethylamino)pyridine (0.030 g, 0.25 mmol) in dichloromethane (20 mL) at 0° C. was treated with acetyl chloride (36 μL, 0.5 mmol). The resulting solution was stirred for 1 h. The reaction mixture was diluted with ethyl acetate (70 mL), washed with saturated ammonium chloride (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to afford tert-butyl acetyl(5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate as a colourless solid in 35% yield (0.05 g): 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.68-7.63 (, m, 1H), 7.63-7.58 (m, 1H), 7.56-7.54 (m, 1H), 7.50-7.45 (m, 2H), 7.42-7.38 (m, 1H), 7.15-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.33-6.25 (m, 2H),6.19-6.17 (m, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 2.67 (s, 3H), 1.31 (s, 9H); MS (ES+) m/z 727.5 (M−100), 729.7 (M−100).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[O:9])[NH:6][CH:7]=1)#[N:2].ClC(OC)=O.CC[N:39](C(C)C)C(C)C.[OH-].[NH4+]>C1COCC1.CCOC(C)=O>[C:23]([C:17]1([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[N:4]=3)=[O:9])=[C:12]([C:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=3)[CH:13]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:24])[NH2:39]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(C(=O)O)CCOCC3)cc2C2=CCCCC2)n1
Agent: COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(C(N)=O)CCOCC3)cc2C2=CCCCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of 4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-tetrahydro-pyran-4-carboxylic acid (as prepared in Example 18, step (d), 14.5 mg, 0.0345 mmol) in 1 mL of THF was added ClCO2Me (3.6 mg, 0.038 mmol). The mixture was cooled to 0° C., DIEA (18 μL, 0.10 mmol) was added. After warming to RT and stirring for 1 h, the mixture was cooled back to 0° C. Concentrated ammonium hydroxide (25 μL, 0.37 mmol) was added and the resulting mixture was warmed to RT and stirred for 16 h. The reaction was treated with 30 mL of EtOAc and washed with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1-5 MeOH/DCM) to afford the title compound (4.7 mg, 32%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.00 (s, 1H), 9.53 (s, 1H), 8.33 (d, 1H, J=8.6 Hz), 7.74 (d, 1H, J=2.3 Hz), 7.33 (dd, 1H, J=8.6, 2.3 Hz), 7.20 (d, 1H, J=2.3 Hz), 5.85 (m, 1H), 5.81 (br s, 1H), 5.32 (br s, 1H), 3.82 (m, 4H), 2.38 (m, 2H), 2.19-2.34 (m, 4H), 2.11 (m, 2H), 1.82 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C23H25N5O3, 420.2 (M+H). found 420.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH2:13]1)([CH3:10])[CH3:9].[C:47](O)(=O)[CH3:48].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O.C(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([N:11]([CH2:47][CH3:48])[C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:39])=[O:40])[CH2:13]1)([CH3:10])[CH3:9]
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCN(C(C)C)[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.33 h
Yield: 32.2 %

Procedure:
To a solution of Example 48 (25 mg, 44 μmol) in 1,2-dichloroethane (3.0 mL) was added acetaldehyde (13 μL, 222 pmol) and acetic acid (30 μL, 0.14 mmol). The resulting mixture was stirred for 20 min, then sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added. After stirring for 2 h, the mixture was diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by preparative TLC (70:30 CH2Cl2/MeOH). After concentrating the material in vacuo, the resulting oil was dissolved in CH3CN/H2O/TFA and lyophilized to provide the title compound (10 mg, 34%) as a white solid and mixture of diastereomers: ESI MS m/z 591 [C30H37F3N4O3S+H]+.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[C:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1)(=[O:21])[CH3:20].C(N(CC)CC)C>CN1C(=O)CCC1>[N+:16]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:2]=1[NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([N:25]2[CH2:24][CH2:23][N:22]([C:19](=[O:21])[CH3:20])[CH2:27][CH2:26]2)[CH:29]=1)[C:6]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7])([O-:18])=[O:17]
Reactant: CN(C)CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)N1CCN(c2cccc(N)c2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2cccc(Nc3ccc(C(=O)OCCN(C)C)cc3[N+](=O)[O-])c2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 2-(dimethylamino)ethyl 4-chloro-3-nitrobenzoate (2.5 g, 9.1 mmol) and 2d (2.0 g, 9.1 mmol) in anhydrous NMP (5 ml) was added triethylamine (1.3 ml, 9.1 mmol), and the mixture was stirred at 80° C. for 4 hours. The cooled mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (4×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel using a mixture of dichloromethane and methanol (9:1 v/v) as the eluent to yield 2-(dimethylamino)ethyl 3-nitro-4-(3-(1-acetylpiperazin-4-yl)anilino)benzoate (1 g, 24%). This intermediate product was dissolved in ethanol (50 ml) and was hydrogenated quantitatively at ambient pressure, using Pd (5% on activated carbon) as the catalyst. The resulting diamine was dissolved in THF (50 ml) and triethyl orthoformate (0.7 ml, 4.2 mmol) was added, together with a catalytic amount of pTSA. The mixture was heated to reflux for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between aqueous sodium carbonate (1M) and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure, and the residue was chromatographied on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1) as the eluent. The product isolated from the eluate was treated with activated carbon in refluxing ethanol and the product thus obtained was triturated with petroleum ether to yield 4i (0.18 g, 20%). M.p. 101-103° C.
Reaction SMILES: OCC[O:4][C:5](=[O:8])[CH:6]=[CH2:7].CC(C1[CH:18]=[C:17]([OH:19])C=CC=1O)(C)C.CN(C)CCCCCCN(C)C.CCCCCCCCCCCC(O[Sn](OC(CCCCCCCCCCC)=O)(CCCC)CCCC)=O.C(N=C=O)CCCCC[N:76]=[C:77]=[O:78]>C1(C)C=CC=CC=1>[C:5]([OH:8])(=[O:4])[CH:6]=[CH2:7].[NH2:76][C:77]([O:19][CH2:17][CH3:18])=[O:78]
Reactant: O=C=NCCCCCCN=C=O
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: C=CC(=O)OCCO
Agent: CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC
Agent: CN(C)CCCCCCN(C)C
Solvent: Cc1ccccc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C

Procedure:
Under a flow of nitrogen, 200 g of hydroxy polyester (Uralac ZW 3896 P) were dissolved in 300 g of toluene at 100° C. Then, 39.5 g hydroxyethylacrylate, 0.3 g MTBHQ, 0.30 g N, N, N′, N′-tetramethyl-1,6-hexane diamine and 0.03 g DBTL were added. The solution was cooled to 70° C., and 58.7 g of hexamethylene diisocyanate was added in 2.5 hours. Thirty minutes after the addition was finished, the toluene was removed by vacuum distillation at 125° C. to yield solid urethane acrylate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:3]([NH:5][C@@H:6]([CH2:13][C:14]1[CH2:18][CH2:17][CH2:16][CH:15]=1)[C:7]([C@@:9]1([CH3:12])[CH2:11][O:10]1)=[O:8])=[O:4].[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH3:40])[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:14]1([CH2:13][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])[CH3:40])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:7]([C@@:9]2([CH3:12])[CH2:11][O:10]2)=[O:8])[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
To (S)-2-amino-N-((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(4-methoxyphenyl)propanamide (TFA salt, 2.00 g, 4.26 mmol) and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (805 mg, 4.26 mmol) in DMF (10 mL) at 0° C. was added HATU (1.94 g, 5.11 mmol) followed by DIEA (4.37 mL, 25.6 mmol) and the mixture was stirred for 15 min then quenched with NaHCO3 (sat., aq.), extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (1:1 hexanes/EtOAc) provided tert-butyl ((S)-1-(((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (1.94 g, 84%) as a colorless oil. MS(EI) for C29H41N3O7, found 544.3 (MH)+.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[N:23]1[C:30](Cl)=[N:29][C:27](Cl)=[N:26][C:24]=1[Cl:25].[OH-:32].[Na+].O>C1(C)C(C)=CC=CC=1>[Cl:25][C:24]1[N:23]=[C:30]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]2[CH2:7][C:8]([CH3:21])([CH3:22])[N:9]([O:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:10]([CH3:13])([CH3:12])[CH2:11]2)[N:29]=[C:27]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]2[CH2:7][C:8]([CH3:21])([CH3:22])[N:9]([O:32][CH:20]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:10]([CH3:13])([CH3:12])[CH2:11]2)[N:26]=1
Reactant: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 42.5 °C
Yield: 65.2 %

Procedure:
A solution of 36.0 g (116 mmol) of 4-n-butylamino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine in 100 ml of xylene is added over 20 minutes to a mixture of 10.9 g (59.2 mmol) of cyanuric chloride, 10.0 g of 50% aqueous sodium hydroxide, 10 ml of water, and 50 ml of xylene. The reaction temperature increases from 25 to 60° C. during the addition and is then maintained at 65°-70° C. for six hours. The phases are separated, and the organic phase is dried over magnesium sulfate and concentrated. The residue is purified by flash chromatography (39:1 heptane:ethyl acetate) on silica gel to afford 27.7 g (65% yield) of 2-chloro-4,6-bis-[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)-n-butylamino]-1,3,5-triazine, a white glass, m.p. 75°-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(-c2cccc(C)c2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2cccc(CBr)c2)ccc1Cl
Yield: 95.1 %

Procedure:
Methyl 4-chloro-3′-methylbiphenyl-3-carboxylate (1.77 g, 6.5 mmol) and NBS (1.27 g, 7.19 mmol) were dissolved in CCl4 (20 mL), a catalytic amount of AIBN was added and the mixture was heated at reflux overnight. The reaction mixture was filtered, the solvent was removed in vacuo and the residue was purified using automated medium pressure silica gel chromatography (ISCO) eluting with 20% ethyl acetate/hexane to obtain methyl 3′-(bromo-methyl)-4-chlorobiphenyl-3-carboxylate (2.10 g, 91%) as a pale brown solid. 1H NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.68-7.45 (m, 6H), 4.58 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[N:8]([C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:18])[C@@H:7]([CH3:19])[CH2:6][N:5]([CH2:20][C:21]([OH:23])=O)[CH2:4]1.[Cl:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27][C:21](=[O:23])[CH2:20][N:5]1[CH2:4][C@H:3]([CH3:2])[N:8]([C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:18])[C@H:7]([CH3:19])[CH2:6]1
Reactant: Nc1ccccc1Cl
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2c1ncn2C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1c1ncnc2c1ncn2C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Bromo-tris-oxy-tripyrrolidinophosphonium hexafluorophosphate (known as PyBroP) (0.18 g) was added to a stirred solution of the product from step (iv) (0.14 g), 2-chloroaniline (0.05 g) and N,N-diisopropylethylamine (0.3 g) in anhydrous dimethylformamide (6 ml). After stirring for 4 hours a further aliquot of 2-chloroaniline (0.1 ml) and PyBroP (0.18 g) were added and the mixture further stirred at room temperature for four days. Water was added and the precipitate filtered to give the crude product as a brown solid (0.07 g). This was purified by high pressure liquid chromatography (acetonitrile/0.1% aqueous ammonium acetate, gradient elution 25% to 75% organic phase) to give the title product as a white solid. Yield 0.04 g.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:3]1([CH3:19])[CH:2]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=[O:7])[CH2:18][C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1
Reactant: Cc1ccncc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1cccc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Cc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
Methyl 3-methylbenzoate (6.0 g, 40 mmol), tetrahydrofuran (50 mL), and 4-picoline (4.1 g, 44 mmol) were stirred at −78° C. under an atmosphere of nitrogen. Sodium bis(trimethylsilyl)amide 1.0 M in THF (88 mL, 88 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stir for 16 h when it was poured into saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (2×50 mL), dried over magnesium sulfate, and concentrated. The product was recrystallized from ethyl acetate/hexane to yield a light yellow solid (5.7 g, 67%): mp 118.0-119.0° C. 1H NMR (acetone-d6/300 MHz) 8.50 (m, 2H), 7.90 (m, 2H), 7.44 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H), 2.41 (s, 3H). ESHRMS m/z 212.1067 (M+H, C14H13NO requires 212.1075).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][OH:14])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4].C(N(CC)CC)C.[CH3:25][O:26][C@:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:31]([F:34])([F:33])[F:32])[C:28](Cl)=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][O:14][C:28](=[O:29])[C:27]([O:26][CH3:25])([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:31]([F:33])([F:34])[F:32])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4]
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc2c(c1C)OC(CO)CO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1C)OC(COC(=O)C(OC)(c1ccccc1)C(F)(F)F)CO2

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl 3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyloxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]=2[S:14][CH:13]=1.ClCCl.C(N(CC)CC)C.Br[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O>[CH2:39]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:20]2[C:15]3[S:14][CH:13]=[C:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:27][CH2:26]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCNCC4)ncnc23)c(F)c1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCN(Cc5ccccc5)CC4)ncnc23)c(F)c1
Reaction time: 1 h

Procedure:
50 mg of 7-(2-fluoro-4-methanesulfonyl-phenyl)-4-[piperidin-4-yloxy]thieno[3,2-d]pyrimidin was added to 1 ml of dichloromethane, and 32 μl of triethylamine was added thereto. 16 μl of (bromomethyl)benzene was added to the mixture, and after 1 hr, water was added thereto for terminating the reaction. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to obtain a bubble residue. The resulting residue was purified by column chromatography to obtain 30 mg of the title compound.
Reaction SMILES: [C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([O:40]CC)=[O:39])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:28][C:29](=[O:30])[NH:31][C:32]3[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:38]([OH:40])=[O:39])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)CC(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)CC(C)C
Yield: 56.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-isovaleryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (296 mg) was dissolved in methanol (14 ml), aqueous lithium hydroxide monohydrate (62 mg) solution (7 ml) and tetrahydrofuran (7 ml) were added, and the mixture was refluxed for 45 minutes. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 160 mg of the titled compound.