Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7](S(C)(=O)=O)=[N:8]2)=[CH:4][N:3]=1.[Si:23]([O:30][C@H:31]1[C@H:35]2[O:36][CH2:37][C@@H:38]([OH:39])[C@H:34]2[O:33][CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N12CCCC=C1CCCCN2>CN(C=O)C>[Si:23]([O:30][C@H:31]1[C@H:35]2[O:36][CH2:37][C@@H:38]([O:39][C:7]3[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]4[C:9](=[N:10][C:2]([Cl:1])=[N:3][CH:4]=4)[N:8]=3)[C@H:34]2[O:33][CH2:32]1)([C:26]([CH3:29])([CH3:27])[CH3:28])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(Cl)ncc21
Agent: C1=C2CCCCNN2CCC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(Cl)ncc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 2-chloro-8-(methylsulfonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine (182 mgs, 0.50 mmol) and (3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (131.0 mg, 0.50 mmol) in anhydrous DMF (4.1 mL) was added diazabicyclo[5.4.0]undec-7-ene (DBU, 0.11 mL, 0.75 mmol). The reaction was stirred under N2 at RT for 16 h and then evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 24 g silica RediSep Rf® Gold column and employing a 0-75% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C23H39ClN4O5Si2 542.21 observed m/e: 543.53 (M+H)+ (Rt 1.54/2.0 min)
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]2([OH:25])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:10]2=[O:24])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:26][C:27]1C=C2C(=C[CH:35]=1)N(CCC1C=CC=CC=1)C(=O)C2=O.CC1C=CC=CN=1>>[OH:25][C:9]1([CH2:8][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]([CH2:19][CH2:20][C:21]2[CH:23]=[CH:35][CH:27]=[CH:26][CH:22]=2)[C:10]1=[O:24]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCc1ccccc1
Reactant: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Solvent: Cc1ccccn1
Product: Cc1ccc2c(c1)C(O)(Cc1ccccn1)C(=O)N2CCc1ccccc1

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-methyl-1-phenethylindoline-2,3-dione and 2-methylpyridine (purchased from Fisher Scientific). 1H-NMR δ 8.6 (d, 1H), 7.65 (m, 1H), 7.27 (m, 6H), 7.05 (d, 1H), 6.98 (d, 1H), 6.71 (m, 2H), 4.6 (bs, OH), 3.5 (m, 1H), 3.8 (m, 1H), 3.1 (m, 2H), 2.95 (m, 2H), 2.21 (s, 3H). Calculated mass for C23H22N2O2, 358.17. Observed 359.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[Li+].[Cl-].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Prepared according to procedure H using dimethyl 2-(4-bromo-2-nitrophenyl)-malonate in DMSO (40 mL), LiCl (1.16 g, 27.4 mmol) and water (0.25 mL, 13.88 mmol) and heating at 100° C. for 15 h. After purification methyl 2-(4-bromo-2-nitrophenyl)acetate was obtained as an orange oil. Mass Spectrum (ESI) m/e=274 [(M+1) (79Br)] and 276 [(M+1) (81Br)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=O)[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:35][S:36]([OH:39])(=[O:38])=[O:37]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)([CH2:35][S:36]([OH:39])(=[O:38])=[O:37])[NH:13][CH2:12][CH2:11]2
Reactant: CS(=O)(=O)O
Reactant: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1OC)C(CCc1ccc(C(F)(F)F)cc1)(CS(=O)(=O)O)NCC2
Temperature: 90 °C

Procedure:
The compound 3 is suspended in toluene and heated to 80-100° C. After addition of 1.5 equivalents phosphorus oxychloride the mixture is heated for 6 hours to 80-100° C. and then cooled within 3 hours to 20° C. The suspension is added to water while maintaining the pH of the aqueous layer during addition and subsequent stirring between 7-8 by addition of a sodium hydroxide solution. The mixture is stirred until all precipitate is dissolved. After phase separation the water is removed by azeotropic distillation. Then 1.0 equivalent of methanesulfonic acid is added, the formed suspension stirred for some time and then slowly cooled to 0-10° C. and stirred at this temperature for another couple of hours. After filtration the product is washed with toluene and dried in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH3:25])[NH:6][C:7](=[O:24])[C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH3:2].[CH:26]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([CH3:28])[CH3:27].C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[C:5]([CH3:25])[N:6]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH:26]([CH3:28])[CH3:27])=[CH:31][CH:32]=2)[C:7](=[O:24])[C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
A mixture of 4′-[(4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.99 g), (4-isopropoxyphenyl)boronic acid (1.08 g), molecular sieves 4 A (0.49 g), triethylamine (2.1 mL), pyridine (1.0 mL), copper(II) acetate (1.09 g) and methylene chloride (20 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.68 g, 49%).
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ICc1ccccc1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: c1ccc(CN2CCN3c4c(cccc42)[C@@H]2CNCC[C@@H]23)cc1

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using benzyl iodide as the alkyl halide and following the procedure of Step B–D of Example 255, as a viscous liquid. 1H NMR(CDCl3, 300 MHz) δ 1.60–2.0 (m, 2H), 2.55–2.95(m, 4H), 2.95–3.15 (m, 2H), 3.20–3.45 (m, 3H), 4.40 (q, J=16.1 Hz, 2H), 6.41 (d, J=7.1 Hz, 1H), 6.51 (d, J=7.1 Hz, 1H), 6.62 (t, J=7.1 Hz, 1H), 7.20–7.40 (m, 5H) ppm. MS (CI): 306 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[O:10])=[CH:4][CH:3]=1.CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:9]([OH:19])=[O:10])=[CH:6][CH:7]=1
Reactant: O=CC(c1ccccc1)c1ccc(Br)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)C(c1ccccc1)c1ccc(Br)cc1
Yield: 36 %

Procedure:
To a stirring solution of compound 52 (5.27 g, 19.15 mmol) in acetone (60 mL) cooled to −10° C. was added Jones Reagent (2.93 mL, 2.5 M solution) drop wise. Isopropyl alcohol was then added until the reaction mixture turned green. The mixture was filtered through Celite, diluted with ethyl acetate and washed with NaOH. The organic layer was discarded and the aqueous layer was acidified with 1M HCl to pH 1 and further extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated to afford 2-(4-bromophenyl)-2-phenylacetic acid 53 (2 g, 36%) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:45][O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50]>ClCCl.O>[CH3:45][O:46][C:47](=[O:51])[CH2:48][CH2:49][NH:50][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:25][CH:24]=2)[CH2:8][CH2:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[CH:16][CH:17]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Racemic 4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid (7.46 g, 17.89 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (3.23 g, 18.43 mmol) and 4-methylmorpholine (2.07 mL, 18.78 mmol) are combined in anhydrous dichloromethane (100 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. Beta alanine methyl ester hydrochloride (2.76 g, 19.68 mmol) and 4-methylmorpholine (4.14 mL, 37.56 mmol) is added to the reaction mixture and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction is diluted with dichloromethane. The reaction is diluted with water and rinsed with 1N hydrochloric acid. Upon acidification, the two layers are separated. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and concentrated. Flash column chromatography gave the title compound (7.07 g, 14.1 mmol).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:30]=3[Cl:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(Cl)cc4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,4-Dichlorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 537.
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@:5]([C:12]([O:14]C)=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18](=[O:60])[CH2:19][NH:20][C:21](=[O:59])[CH2:22][N:23]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30][N:29]([CH2:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:28][CH2:27][N:26]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:25][CH2:24]1.O[Li].O>CO>[OH:1][C@H:2]1[C@H:9]2[C@:5]([C:12]([OH:14])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18](=[O:60])[CH2:19][NH:20][C:21](=[O:59])[CH2:22][N:23]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH2:31][CH2:30][N:29]([CH2:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])[CH2:28][CH2:27][N:26]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:25][CH2:24]1
Reactant: COC(=O)[C@@]12O[C@@H](CNC(=O)CNC(=O)CN3CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC3)[C@@H](O)[C@@H]1OC(C)(C)O2
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCC(=O)NC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 19a (1.0 g, 1.17 mmol) in MeOH (2 mL) was added a solution of LiOH.H2O (48.5 mg, 1.17 mmol, Aldrich). The resulting solution was stirred at room temperature for 4 h. Solvents were evaporated and the residue was purified by silica column chromatography. Product 20a was obtained as a white solid (0.8 g; yield 81%).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:13][CH2:14][CH:15]1[CH:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:23]2[C:18](=[C:19]([F:36])[CH:20]=[CH:21][C:22]=2[F:35])[O:17][CH2:16]1)[CH2:10][CH:11]=C)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[O:37]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[C:1]([Si:5]([CH3:6])([CH3:7])[O:8][CH:9]([CH2:13][CH2:14][CH:15]1[CH:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:23]2[C:18](=[C:19]([F:36])[CH:20]=[CH:21][C:22]=2[F:35])[O:17][CH2:16]1)[CH2:10][CH2:11][OH:37])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCC(CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1)O[Si](C)(C)C(C)(C)C
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC(CCO)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of tert-butyl-(1-{2-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-ethyl}-but-3-enyloxy)-dimethyl-silane (1.45 g, 2.60 mmol) in 1:1 MeOH/CH2Cl2 (25 mL) at −78° C. was purged with ozone until the blue color persisted. The reaction mixture was then purged with N2 for 5 min, treated with NaBH4 (300 mg, 7.8 mmol) portionwise and slowly warmed to ambient temperature. Over the next 4.5 h, 2 additional portions of NaBH4 (500 mg each) were added, and the reaction mixture was quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined organic extracts were washed saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. Flash chromatography (5→40% EtOAc/Hex) afforded the title compound (730 mg, 50%): 1H NMR (CDCl3 400 MHz) δ 7.72 (dd, J=8.8, 1.5 Hz, 2H), 7.52 (dd, J=8.8, 1.5 Hz, 2H), 7.02 (m, 1H), 6.38 (m, 1H), 4.90 (dd, J=11.7, 2.2 Hz, 1H), 4.33 (d, J=12.4 Hz, 1H), 4.28 (s, 1H), 3.85 (m, 1H), 3.73-3.64 (m, 2H), 2.76 (m, 1H), 1.91 (br s, 1H), 1.71-1.22 (m, 6H), 0.80 (s, 4.5H), 0.79 (s, 4.5H), 0.03 (s, 3H), −0.04 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.[Cl:12][CH:13](Cl)[C:14](=O)[CH3:15].C(=O)([O-])O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[S:10][CH:15]=[C:14]([CH2:13][Cl:12])[N:11]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=S)Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: ClCc1csc(Cc2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 72 h
Yield: 85.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)thioacetamide (3.51 g) in 1,4-dioxane (20 mL) were added dichloroacetone (2.64 g) and sodium hydrogen carbonate (1.75 g) at room temperature, and the mixture was stirred for 3 days. Insoluble material was removed by filtration, thionyl chloride (1.52 mL) was added to the filtrate, and the mixture was heated at 70° C. for 30 min. The reaction mixture was adjusted to pH=8-9 by the addition of saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate/hexane (1/1)(100 mL×2). The organic layer was washed with saturated brine, and concentrated under reduced pressure to give the title compound (4.19 g) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:9][C:3]1[CH:4]=[C:5]([N:10]2[C:18]3[C:13](=[C:14]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=5)[CH2:22][CH2:21]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Clc1ccc(I)cc1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-4-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.0 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:19][C:20]1[O:21][C:22]([CH3:36])([CH3:35])[CH:23]([C:28]2[CH:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=2)[S:24](=[O:27])(=[O:26])[N:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(C(C)(C)C)(C)C.[H][H]>CO.[Pd]>[CH3:35][C:22]1([CH3:36])[O:21][C:20]([NH:19][C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:10][CH2:9][OH:8])=[N:25][S:24](=[O:26])(=[O:27])[CH:23]1[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1c1ccc(Cl)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2F)=NS(=O)(=O)C1c1cccnc1
Reaction time: 2 h
Yield: 47.6 %

Procedure:
To a solution of [(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]-[5-(6-chloropyridin-3-yl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-2-yl]amine (310 mg) in methanol was added palladium on charcoal (5%, 119 mg), and the mixture was stirred in a hydrogen atmosphere for 19 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in methanol (10 ml) and treated with conc. HCl (1 ml). After 2 h, the solution was purified in a purification laboratory by means of preparative HPLC. This gave the product (108 mg) with a molecular weight of 407.5 g/mol (C19H22FN3O4S); MS (ESI): m/e=408 (M+H+).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl.N1CCCNCC1.Cl.CS(O[CH2:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)=O.[Na+].[I-]>CCO>[C:26]1([CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:24][CH2:23][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1CNCCNC1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A suspension of homopiperazine (2.9 g, 28.9 mmol) and homopiperazine dihydrochloride (5.0 g. 28.9 mmol) in EtOH was heated to 70° C. for 2 h, at which point a homogeneous solution of monohydrochloride salt (2.5 equiv) was obtained. The reaction mixture was treated with 3,3-diphenylpropyl methanesulfonate (6.7 g, 23.1 mmol, 1 equiv) and NaI (8.65 g, 57.7 mmol, 2.5 equiv) and heated to reflux for 16 h. The reaction mixture was cooled to 25° C. and the solvent was removed in vacuo. The crude product was partitioned between 2N aqueous NaOH (100 mL) and EtOAc (100 mL), and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was washed with saturated aqueous NaCl (1×100 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 4×20 cm. 10% CH3OH— 5% Et3N-CH2Cl2) afforded the monoalkylated product (6.44 g, 6.79 g theoretical, 95%) as an amber oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:5][C:4]([C:16]2[C:21]([CH:22]=[O:23])=[C:20]([N:24]3[CH2:35][CH2:34][N:33]4[C:26](=[CH:27][C:28]5[CH2:29][C:30]([CH3:37])([CH3:36])[CH2:31][C:32]=54)[C:25]3=[O:38])[N:19]=[CH:18][CH:17]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:23][CH2:22][C:21]1[C:20]([N:24]2[CH2:35][CH2:34][N:33]3[C:32]4[CH2:31][C:30]([CH3:36])([CH3:37])[CH2:29][C:28]=4[CH:27]=[C:26]3[C:25]2=[O:38])=[N:19][CH:18]=[CH:17][C:16]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccncn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
A mixture of 144a (98 mg, 0.19 mmol), NaBH4 (30 mg, 0.8 mmol) and MeOH (5 mL) was stirred at 25° C. for 30 mins. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to give 144 (25 mg, 42%). LCMS: [M+H]+ 512. 1H NMR (500 MHz, DMSO) δ 9.18 (s, 1H), 8.76-8.74 (m, 1H), 8.64 (s, 1H), 8.50-8.47 (m, 1H), 8.31-8.30 (m, 1H), 7.68-7.69 (m, 1H), 7.37-7.36 (m, 1H), 7.33-7.31 (m, 1H), 6.56 (s, 1H), 5.07-5.04 (m, 1H), 4.44-4.41 (m, 2H), 4.23-4.18 (m, 3H), 3.86-3.84 (m, 1H), 3.61 (s, 3H), 2.61-2.56 (m, 2H), 2.42 (s, 2H), 1.21-1.20 (m, 6H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([O:17][C:18]([N:20]([CH2:25][CH:26](OCC)OCC)[CH2:21][C:22](O)=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[CH2:10]([O:17][C:18]([N:20]1[CH:25]=[CH:26][N:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:22](=[O:23])[CH2:21]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(CN(CC(=O)O)C(=O)OCc1ccccc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NN1C=CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.7 %

Procedure:
A solution of tert-butoxycarbonylhydrazine (3.96 g) and N-benzyloxycarbonyl-N-(2,2-diethoxyethyl) glycine (9.76 g) in acetonitrile (100 ml) was treated with WSC (5.75 g) and stirred at room temperature for 15 hours. The reaction mixture was concentrated to obtain a residue, which was partitioned between ethyl acetate and water, and then the organic phase was washed with water, aqueous sodium bicarbonate, aqueous solution of citric acid and brine, dried and then concentrated. The residue obtained was dissolved in toluene (200 ml), combined with p-toluenesulfonic acid hydrate (285 mg) and then stirred at 100° C. for 90 minutes. The reaction mixture was washed with saturated aqueous sodium bicarbonate and brine, dried and then concentrated. The residue thus obtained was purified by a column chromatography on a silica gel (hexane:ethyl acetate=3:2) to obtain 4-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydropyrazine (1.84 g) as a colorless oil.