Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].FC(F)(F)C(O)=O>O1CCCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C@@H:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[C:3]([N:5]2[CH2:10][CH2:9][C:8]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)([CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[CH2:7][CH2:6]2)=[O:4])=[CH:29][CH:28]=1
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 2-(R)-amino-3-(4-chlorophenyl)-1-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-propan-1-one, 20, (400 mg, 0.93 mmol) in tetrahydrofuran (10 mL) at 0° C. is added triethylamine (0.78 mL, 5.58 mmol) and methanesulfonyl chloride (0.09 mL, 1.11 mmol). The resulting suspension is allowed to stir at room temperature overnight and the solvent removed under reduced pressure. The crude product is purified by preparative HPLC to afford 314.5 mg (54% yield) of the desired compound as the trifluoroacetic acid salt. 1H NMR (300 MHz, CD3OD) δ 0.80–1.92 (m, 15H), 2.78–3.08 (m, 5H), 3.30–3.90 (m, 4H), 4.25–4.40 (m, 2H), 4.65–4.75 (m, 1H), 7.25–7.40 (m, 4H), 8.00–8.08 (m, 1H), 8.52 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.C([N-]C(C)C)(C)C.[Li+].C(=O)=O.[C:17]([O:21][C:22]([NH:24][C@H:25](C(OC)=O)[CH3:26])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C>O1CCCC1.C(OCC)C.O>[Cl:1][CH2:2][C:3](=[O:5])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:26]
Reactant: O=C(O)CCl
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of chloroacetic acid (23.2 g, 246 mmol) in tetrahydrofuran (100 mL) was added over 35 minutes to a −78° C. solution of lithium diisopropylamide in tetrahydrofuran (2.05 M, 240 mL, 492 mmol), at a rate that kept the internal temperature below −65° C. After 30 minutes, the reaction mixture was quickly transferred into a (dry ice)-jacketed addition funnel and added over 5 minutes to a solution of methyl N-(tert-butoxycarbonyl)-L-alaninate (10.0 g, 49.2 mmol) in tetrahydrofuran (120 mL). Mechanical stirring was used for this reaction. The mixture was stirred for 30 minutes, during which time the reaction mixture warmed to 0° C. It was cooled to −78° C. and treated over 10 minutes with a solution of acetic acid (41 mL, 720 mmol) in tetrahydrofuran (41 mL). At this point, the flask was immersed in an ice bath, and stirring was continued for 1.5 hours, while the reaction warmed to 5° C. Water (250 mL) was added, followed by diethyl ether (400 mL); the organic layer was washed with saturated aqueous sodium bicarbonate solution (150 mL) and with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a waxy, light yellow solid. Yield: 9.47 g, 42.7 mmol, 87%. 1H NMR (400 MHz, CDCl3) δ 5.11 (br d, J=6 Hz, 1H), 4.48-4.58 (m, 1H), 4.28 (AB quartet, JAB=15.9 Hz, ΔνAB=8.3 Hz, 2H), 1.44 (s, 9H), 1.38 (d, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:13][CH2:14][CH3:15])=[N:8]2.[C:16]([O:20][C:21]([C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35]Br)=[CH:31][CH:30]=2)=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[N:8]2[CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2ncnc(Cl)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (0.20 g) in dry DMF (3 ml), 6-chloro-8-propyl-purine (0.06 g, 0.3 mmol) was added, and the mixture was stirred at 40° C. for 20 minutes. t-Butyl-4-bromomethylbiphenyl-2'-carboxylate (0.11 g, 0.31 mmol) was then added at room temperature and stirring continued for 3 hours at 40° C. The content of the flask was poured into ice-water (100 ml and extracted with ethylacetate. The organic phase was separated and dried over MgSO4. Removal of the solvent under reduced pressure gave the crude product which was then purified by flash-chromatography on silica-gel using ethylacetate-hexane (1:1). The pure titled compound was obtained as a glass-like solid (0.073 g, 53%). NMR (CDCl3): δ1.04 (t, J=9 Hz, 3H), 1.213 (s, 9H), 1.91 (m, 2H), 2.89 (t, 2H), 5.52 (s, 2H), 7.15-7.52 (m, 7H), 7.79 (dd, J1 =8 Hz and J2 =2 Hz, 1H), 8.72 (s, 1H); FAB-MS: m/e 463 and 465 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH:33]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)([CH3:35])[CH3:34].C([Li])CCC>O1CCCC1>[CH:1]1([CH2:6][C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([N:37]2[C@@H:36]([CH:33]([CH3:35])[CH3:34])[CH2:40][O:39][C:38]2=[O:41])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared in Example 38, 5.00 g, 17.4 mmol) in tetrahydrofuran (150 mL) cooled to −78° C. was treated with triethylamine (2.77 mL, 19.9 mmol) followed by trimethylacetyl chloride (2.24 mL, 18.2 mmol). The resulting white slurry was stirred at −78° C. for 15 min and then at 0° C. for 45 min. In a separate flask, a solution of (S)-4-isopropyl-2-oxazolidinone (2.14 g, 16.57 mmol) in tetrahydrofuran (80 mL) cooled to −78° C. was treated with a 2.0M solution of n-butyllithium in hexanes (8.7 mL, 17.4 mmol). The solution was stirred at −78° C. for 10 min and then allowed to warm to 25° C. where it was stirred for an additional 10 min. At this time, the first reaction mixture was recooled to −78° C. The second reaction mixture was added to the first reaction mixture over a period of 5 min via cannula. The combined reaction was then stirred at −78° C. for 15 min and then allowed to warm to 25° C. where it was stirred for an additional 1.5 h. At this time, the reaction was quenched by the addition of a saturated aqueous sodium bisulfite solution (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (1×20 mL) and a saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded (1) 3-[3-cyclopentyl-2(S)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (2.15 g, 33%) as a clear oil: [α]23589=+87.5° (c=0.160, chloroform); EI-HRMS m/e calcd for C20H25Cl2NO3 (M+) 397.1211, found 397.1215 and (2) 3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (1.88 g, 28%) as a white solid: mp 71.9-74.6° C.; [α]23589=−27.6° (c=0.188, chloroform); EI-HRMS m/e calcd for C20H25Cl2NO3 (M+) 397.1211, found 397.1212.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:22][C:23]1([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:24]1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:28]([CH:24]1[C:25]([CH3:27])([CH3:26])[C:23]1([CH3:31])[CH3:22])=[O:29])=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cccc(OCc4ccccc4)c23)C1(C)C
Yield: 33.3 %

Procedure:
A mixture of 4-benzyloxyindole (1.1 g, 4.8 mmol), ethylmagnesium bromide (1.0 M solution in THF, 5.2 mL, 5.2 mmol), zinc chloride (1.0 M solution in Et2O, 5.2 mL, 5.2 mmol) and the product of Example 1A (4.8 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.56 g, 1.6 mmol, 34% yield). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: CO[C@H]1CC[C@H](C[N:10]2C(=O)CNC3N=CC(C4C(C)=CC(C(N)=O)=NC=4)=[N:20][C:11]2=3)CC1.[CH3:31][O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][N:40]2[C:45](=[O:46])[CH2:44][NH:43][C:42]3[N:47]=[CH:48][C:49]([C:51]4[C:52]([CH3:59])=[CH:53][C:54]([C:57]#[N:58])=[N:55][CH:56]=4)=[N:50][C:41]2=3)[CH2:35][CH2:34]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:31][O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][N:40]2[C:41]3=[N:50][C:49]([C:51]4[CH:56]=[N:55][C:54]([C:57]5[N:20]=[CH:11][NH:10][N:58]=5)=[CH:53][C:52]=4[CH3:59])=[CH:48][N:47]=[C:42]3[NH:43][CH2:44][C:45]2=[O:46])[CH2:35][CH2:34]1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(N)=O)cc4C)nc32)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(-c5nc[nH]n5)cc4C)nc32)CC1
Temperature: 65 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide. 5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinonitrile (0.607 g, 1.55 mmol), trifluoroacetic acid (2.0 mL, 26.0 mmol) and sulfuric acid (0.5 mL, 9.38 mmol) were combined and heated at 65° C. for 1 h. Reaction pH was adjusted to 10 with sodium carbonate and the resulting solution was extracted with ethyl acetate (3×15 mL). Organic layers were collected, dried over magnesium sulfate, concentrated and purified using reverse-phase preparatory HPLC (10-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined and condensed under reduced pressure and dried under high vacuum to afford the title compound as a yellow solid (0.425 g, 1.04 mmol, 67% yield). MS (ESI) m/z 411.5 [M+1]+.
Reaction SMILES: C([O:8][C:9](=[O:36])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH3:33])[S:18]2(=[O:35])=[O:34])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][N:19]1[S:18](=[O:35])(=[O:34])[N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([OH:36])=[O:8])=[CH:11][CH:12]=2)[CH2:21][C:20]1=[O:22]
Reactant: [H][H]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)OCc4ccccc4)cc3)S2(=O)=O)c(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)cc3)S2(=O)=O)c(OC)c1

Procedure:
The title A compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid benzyl ester (2.04 g, 4.0 mmol) is suspended in EtOAc/EtOH (1:1, 100 mL) along with 10% palladium on carbon (300 mg) and treated with hydrogen (48 psi) for 4 h on a Parr Shaker. The reaction mixture is filtered through celite and concentrated to give a white solid which is recrystallized from MeOH to yield 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid: [M-1]-=419.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:16](=[O:29])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:30][CH3:31].[CH3:32][Si](Cl)(C)C>CO>[CH3:32][O:14][C:13](=[O:15])[CH2:12][NH:11][C:8]1[O:9][C:10]2[C:2]([OH:1])=[C:3]([O:30][CH3:31])[CH:4]=[CH:5][C:6]=2[C:7]=1[C:16](=[O:29])[C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: COc1cc(C(=O)c2c(NCC(=O)O)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)CNc1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
[7-hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-ylamino]acetic acid (30 mg, 0.07 mmol) was dissolved in dry methanol (5 mL) and trimethylsilyl chloride (100 μL) was added to it. The reaction was stirred at room temperature for 6 hours (monitored by tlc). Solvent was distilled under vacuum and the crude was purified over silica gel plate to afford the title compound as yellow solid (23 mg, 79%); 1H NMR (300 MHz, CDCl3) δ 9.11 (b, 1H, NH), 6.97 (s, 2H, benzoyl Hs), 6.62 (d, 1H, J=8.56 Hz), 6.51 (d, 1H, J=8.49 Hz), 4.42 (d, 1H, J=6.09 Hz), 3.91 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe), 3.81 (s, 3H, OMe).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9](O)=[O:10].B.C1COCC1.O>O1CCCC1>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[CH2:9][OH:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1C1SCCCS1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C2SCCCS2)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled, stirred solution of the Compound 3b (5.00 g, 17.5 mmol) in tetrahydrofuran (100 mL) was added dropwise over 30 minutes 1.0 MBH3.THF (20 mL). The solution was allowed to warm to room temperature and was stirred overnight. Additional 1.0 M BH3.THF (5 mL) was added, and the solution was stirred another 4 hours. Water was added to hydrolyze the reaction, and the solution then was evaporated to dryness. The residue was dissolved in diethyl ether, and this solution was washed with a saturated solution of sodium carbonate, brine, and was dried over anhydrous magnesium sulfate. Evaporation of the solvent and recrystallization of the product from acetonitrile afforded the Compound 3c; m.p. 130°-131° C.; IR 3600 cm-1 (OH); 1H NMR (CDCl3 +D2O)δ1.8-2.2 (m, 2H, --CH2CH2CH2 --), 2.8-3.2 (m, 4H, --CH2CH2CH2 --), 4.61 (s, 2H, CH2O), 5.48 (s, 1H, SCHS), 7.7-8.3 (m, 3H, ArH).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:29]=[C:30]([NH:34]N)[CH:31]=[CH:32][CH:33]=1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:26]([F:25])([F:36])[F:37])[CH:29]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: NNc1cccc(OC(F)(F)F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1cccc(OC(F)(F)F)c1

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and 3-trifluoromethoxy-phenylhydrazine according to the method described for example 91. MS: M=465.2 (M+H)+
Reaction SMILES: ClC1C=CC(C(C2C=C[C:24]([O:27]C)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([C:51]2[CH:56]=[CH:55][C:54](Cl)=[CH:53][CH:52]=2)[C:37]2[C:45]3[C:40](=[C:41]([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([C:51]2[CH:56]=[CH:55][C:54]([O:27][CH3:24])=[CH:53][CH:52]=2)[C:37]2[C:45]3[C:40](=[C:41]([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: COc1ccc(C(c2ccc(Cl)cc2)c2c[nH]c3c(CSC)cccc23)cc1
Product: COc1ccc(C(c2ccc(Cl)cc2)c2c[nH]c3c(CS(C)(=O)=O)cccc23)cc1

Procedure:
The title compound was prepared starting from 150 mg (0.37 mmol) of the compound from Example 282 in analogy to the synthesis of the compound from Example 312. 130 mg (80% of theory) of the target compound were obtained.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[N:17]2[C:18]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=3[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:23])[CH2:22][C:16]2=[N:15][N:14]=1)=O)C1C=CC=CC=1.Br>C(O)(=O)C>[NH2:11][CH2:12][C:13]1[N:17]2[C:18]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=3[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:23])[CH2:22][C:16]2=[N:15][N:14]=1
Reactant: O=C(NCc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NCc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2

Procedure:
4.5 g of 1-[[(benzyloxycarbonyl)amino]-methyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 60 ml acetic acid saturated with hydrogen bromide is stirred at 20° for 1 hour. The reaction mixture is concentrated to one-half its original volume in vacuo and diluted with ether. The precipitate is filtered off, suspended in methylene chloride and shaken with excess 2 N aqueous sodium bicarbonate. The organic phase is separated, washed with water, dried and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[N:11])=[CH:4][C:3]=1[N+:12]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[N:11])=[CH:4][C:3]=1[NH2:12]
Reactant: N#CCSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: N#CCSc1ccc(N)c(N)c1
Reaction time: 2 h

Procedure:
4.1 G. of 1-amino-2-nitro-4-cyanomethylthiobenzene in 60 ml. of methanol and 12 ml. of water is treated with 1.25 g. of ferrous sulfate and 3.3 g. of iron powder at reflux. After 2 hours, 1.25 g. of ferrous sulfate and 3.3 g. of iron powder are added and heating is continued for 4 hours. The mixture is poured into 600 ml. of hot tetrahydrofuran and filtered. 1,2-Diamino-4-cyanomethylthiobenzene is obtained from the filtrate by evaporation.
Reaction SMILES: O=[O+][O-].[CH2:4]([O:11][C:12]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH3:27])=[CH:15][N:16]2[C:23]([O:25][CH3:26])=[O:24])C1C=CC=CC=1>>[CH2:22]([O:21][C:20]1[C:12]([O:11][CH3:4])=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:23]([O:25][CH3:26])=[O:24])[CH:15]=[C:14]2[CH3:27])[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:13]=1
Reactant: COC(=O)n1cc(C)c2c(OCc3ccccc3)c(OC)ccc21
Agent: O=[O+][O-]
Product: COC(=O)n1cc(C)c2c(OC)c(OCc3ccccc3)ccc21

Procedure:
The N-methoxycarbonyl-2-[3-(but-1-enyl)]-4-benzyloxy-3-methoxyaniline (7.6 g) was subjected to ozone degradation and dehydration in the same manner as in the preparation of 4-benzyloxy-5-methoxy-1-methoxycarbonyl-3-methylindole in Experimental Example 4 to give 5-benzyloxy-4-methoxy-1-methoxycarbonyl-3-methylindole (4.7 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([Cl:23])[C:5]([Cl:22])=[C:6]([CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])[CH:7]=1.[I:24]I.N(OC(C)(C)C)=O>CS(C)=O>[Cl:22][C:5]1[C:4]([Cl:23])=[CH:3][C:2]([I:24])=[CH:7][C:6]=1[CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc(N)cc(Cl)c2Cl)c1=O
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc(I)cc(Cl)c2Cl)c1=O
Yield: 110.3 %

Procedure:
By the method of Example 2, Step B, 2.67 grams (0.00725 mole) of 3-(5-amino-2,3-dichlorophenylmethyl)-1-methyl-6-trifluoromethyluracil, 1.84 grams (0.00725 mole) of iodine, and 1.12 grams (0.0109 mole) of tertiarybutyl nitrite were reacted in 10 mL of dimethyl sulfoxide, yielding 3.83 grams of 3-(2,3-dichloro-5-iodophenylmethyl)-1-methyl-6-trifluoromethyluracil as a light brown solid, m.p. 142°-144° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@:9]1([CH2:22][OH:23])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(C)=C(N=C=O)C=CC=1C#N>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@:9]1([CH2:22][OH:23])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@]1(C)CO
Agent: Cc1c(N=C=O)ccc(C#N)c1Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(C)CO
Yield: 68.9 %

Procedure:
Compound 4D (84.0 mg) was prepared from compound 4C (122 mg) and compound 1G (82.0 mg) following procedures analogous to those used in Example 1 for the preparation of compound 1H. LCMS: m/z 438 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN1CCN(C(=O)CCl)CC1
Product: CCN1CCN(CCOc2ccc(CN(CC)c3cc(OC)ccc3C3CCc4cc(O)ccc4C3)cc2)CC1
Yield: 18.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 2-chloro-1-(4-ethylpiperazin-1-yl)ethanone (20 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.2 mg) was obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[C:8](I)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[C:24]([O:28][C:29](=[O:38])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([SH:37])[CH:32]=1)([CH3:27])([CH3:26])[CH3:25]>[Cu]I.CN(C=O)C>[C:24]([O:28][C:29](=[O:38])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37][C:8]2[C:9]3[C:14]([NH2:15])=[N:13][CH:12]=[N:11][C:10]=3[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH:32]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1cccc(S)c1
Reactant: Nc1ncnc2c1c(I)cn2C1CCCC1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1cccc(Sc2cn(C3CCCC3)c3ncnc(N)c23)c1
Temperature: 110 °C
Yield: 85 %

Procedure:
To a round bottom flask with DMF (5 mL), was added 7-Cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, CuI, N-methylmorphline and (3-Mercapto-phenyl)-carbamic acid tert-butyl ester. The reaction was heated at 110° C. overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (80 mL) and saturated sodium bicarbonate solution (60 ml). The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. Purification through flash column afforded the product as a light yellow solid (108 mg, 85%). MS: 426.1 (MH+); HPLC Rf: 6.332 min.; HPLC purity: 96%.