Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([CH:10]2[CH2:12][CH:11]2[C:13]#[N:14])=[O:9])=[CH:6][CH:5]=1.O>C(O)C.C(OCC)(=O)C>[OH:9][CH:8]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:16][CH:15]=1)[CH:10]1[CH2:12][CH:11]1[C:13]#[N:14]
Reactant: Cc1ccc(C(=O)C2CC2C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(C(O)C2CC2C#N)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
607 mg (16.0 mmol) of sodium borohydride were added to 2.70 g (14.6 mmol) of the compound from Example 126A in 60 ml of ethanol and 16 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 2 h. The reaction mixture was added to water and extracted with dichloromethane, and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.56 g (94% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:6]2[N:13]([CH3:14])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1>CC(O)=O.C(Cl)Cl.[Fe]>[CH3:14][N:13]1[C:6]2[C:5]([O:4][C:3]3[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:2]=3[F:1])=[N:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12]1
Reactant: Cn1ccc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1ccc2ncnc(Oc3ccc(N)cc3F)c21
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methyl-5H-pyrrolo[3,2-d] pyrimidine (29) (253.6 mg, 0.879 mmol) in AcOH (3 mL) at 90° C. was added iron powder (245 mg, 4.4 mmol). The mixture was stirred vigorously for 10 min and filtered. The filtrate was concentrated under reduced pressure to produce a solid, which was dissolved in DCM. The resultant solution was washed with cold NaHCO3 solution and water, dried over Na2SO4 and concentrated to provide a residue which was purified by column chromatography (eluent MeOH—CH2Cl2 1:20) to afford the title compound 30 as a brown solid (120.6 mg, 53% yield). LRMS (M+1) 240.1 (100%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OCC6C=CC=CC=6)[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1.C1CC=CCC=1>C(O)C.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@@H:25]([NH2:29])[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](NC(=O)OCc6ccccc6)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](N)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Temperature: 100 °C
Yield: 71.8 %

Procedure:
In a 5-mL high-pressure vial was placed benzyl (4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate (110.0 mg, 0.18 mmol), 1,4-cyclohexadiene (102 μL, 1.09 mmol) in ethanol (8.3). 10% Pd on C (11.0 mg) was added, and the reaction mixture was vacuum purged with N2 3×. The vial was sealed and the reaction mixture was stirred at 100° C. After 2 h additional 10% Pd on C (11.0 mg) and 1,4-cyclohexadiene (102 μL) were added. The vial was resealed and the reaction mixture was stirred at 100° C. for 14 h. The cooled reaction was filtered reaction through a pad of Celite®, and the pad was rinsed with EtOAc (3×5 mL), MeOH (3×5 mL), DCM (3×5 mL), and a final rinse of EtOAc (3×5 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 0-80% MeOH in EtOAc+1% Et3N) to give (4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-amine as a solid (61.1 mg, 71.3%). LC/MS: m/z 473.3 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13]
Reactant: CC(=O)c1cc(Cl)c(Cl)cc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Temperature: 90 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
A solution of 1-(4,5-dichloro-2-hydroxyphenyl)ethanone (12 g, 59 mmol) in acetic acid (70 mL) was treated with N-iodosuccinimide (16 g, 71 mmol) and stirred at 90° C. for 18 h. The reaction mixture was treated with additional N-iodosuccinimide (8 g, 36 mmol) and stirred at 90° C. for 4 h. The reaction mixture was concentrated, diluted with ethyl acetate, and quenched with saturated sodium bicarbonate until the bubbling stopped. The organic layer was separated and the aqueous was re-extracted with ethyl acetate. The combined organic layers were dried and concentrated to give a brown solid. This material was recrystallized from methanol to give desired product (9.0 g, 46%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 13.36 (s, 1H), 7.85 (s, 1H), 2.65 (s, 3H). LCMS for C8H6Cl2IO2 (M+H)+: m/z=330.9, 332.9; Found: 330.8, 332.9.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=[CH:16][C:11]=2N=N1.[NH2:25][S:26]([C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([N:40](CCC)[CH2:41][CH2:42][CH3:43])=[O:39])[CH:37]=1)[C:32](O)=[O:33])(=[O:28])=[O:27].FC(F)(F)C(O)=O.[NH2:54][C@@H:55]([CH2:69][C:70]1[CH:75]=[C:74](F)[CH:73]=[C:72](F)[CH:71]=1)[C@H:56]([OH:68])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=1>CN(C=O)C>[NH2:25][S:26]([C:29]1[CH:37]=[C:36]([C:38]([NH:40][CH2:41][CH2:42][CH3:43])=[O:39])[CH:35]=[C:31]([CH:30]=1)[C:32]([N:54]([C@@H:55]([CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C@H:56]([OH:68])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=1)[CH2:12][CH2:11][CH3:16])=[O:33])(=[O:27])=[O:28]
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(S(N)(=O)=O)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)c1cc(C(=O)N(CCC)[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)cc(S(N)(=O)=O)c1
Reaction time: 18 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.0928 9, 0.244 mmol) is added to a mixture of, 3-(aminosulfonyl)-5-[(dipropylamino)-carbonyl]benzoic acid (XXXIX, PREPARATION 13, 0.0800 g, 0.244 mmol) and (2R,3S)-3-amino-1-[(3-methoxybenzyl)-amino]-4-phenyl-2-butanol (VIII, EXAMPLE 175, 0.0732 g, 0.244 mmol) in dry DMF (3 mL). The mixture is stirred for 18 hours at 20-25 degrees, and then partitioned between ethyl acetate and water. The organic phase is separated and washed with saline, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate is column chouromatographed (silica gel; methanol/dichloromethane, 5/95) to give the title compound, MS (ESI+) for C32H42N4O6S M/z (M+H)+=611.5; HRMS (FAB) calculated for C32H42N4O6S+H1=611.2903, found=611.2904.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][S:10]/[C:9]/2=[N:13]\[C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])=[CH:4][CH:3]=1.[I:21][CH3:22]>C(#N)C>[I-:21].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][S:10]/[C:9]/2=[N:13]\[C:14]([N:16]2[CH:20]=[CH:19][N+:18]([CH3:22])=[CH:17]2)=[O:15])=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(/N=C1\SCCN1c1ccc(Cl)cc1)n1ccnc1
Solvent: CC#N
Product: C[n+]1ccn(C(=O)/N=C2\SCCN2c2ccc(Cl)cc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-[(2Z)-3-(4-Chlorophenyl)-1,3-thiazolidin-2-ylidene]-1H-imidazole-1-carboxamide (320 mg, 1.043 mmol, Example 25A) was suspended in dry acetonitrile (5 mL), and then iodomethane (0.325 mL, 5.22 mmol) was added. The mixture stirred at room temperature. After four days, the solvent was evaporated to give the title product.
Reaction SMILES: [C:1]1(B(O)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:10]([NH:14][S:15]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22](Br)[CH:21]=1)(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([NH:14][S:15]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH:21]=1)(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)NS(=O)(=O)CCc1ccc(N)c(Br)c1
Reactant: OB(O)C1=CCCCC1
Product: CC(C)(C)NS(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1

Procedure:
The title compound was prepared according to the Suzuki coupling procedure of Example 44, step (b) using cyclohex-1-enyl boronic acid (117 mg, 0.931 mmol) and 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid tert-butylamide (as prepared in the previous step, 250 mg, 0.745 mmol) and purified on silica (20% EtOAc/hexanes) (228 mg, 91%). 1H-NMR (CDCl3; 400 MHz): δ 6.87 (dd, 1H, J=8.0, 2.1 Hz), 6.82 (d, 1H, J=2.1 Hz), 6.64 (d, 1H, J=8.0 Hz), 5.72 (br s, 1H), 4.12 (s, 1H), 3.82 (br s, 2H), 3.28 (m, 2H), 2.96 (m, 2H), 2.19-2.23 (m, 4H), 1.62-1.82 (m, 4H), 1.31 (s, 9H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.Cl[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[NH2:19])[O:14][CH3:15].[OH-].[Na+].[ClH:22]>CC(C)=O>[Cl:22][C:12]1[CH:11]=[C:18]([NH:19][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH:17]=[CH:16][C:13]=1[O:14][CH3:15]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1ccc(N)c(Cl)c1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Temperature: 0 °C
Yield: 96 %

Procedure:
To cyanuric chloride (36.911 g, 200.0 mmol) dissolved in acetone (250 mL) stirring at approximately 0-5° C. (ice-water bath), was added a solution of 3-chloro-p-anisidine (31.528 g, 200.0 mmol) in acetone (150 mL) followed by the addition of NaOH solution (80 mL, 2.5 N, 200.0 mmol). The reaction mixture was allowed to stir at approximately 0-5° C. (ice-water bath) for about 1 hour. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was washed with water and dried overnight under vacuum to afford 101 (58.3 g, 96%), mp 165° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 24.3 min, 97.8% purity); MS (ESI): m/z 305 (M+H, 100), 283 (26.3), 271 (26.9), 269 (75.2), 139 (16.2).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:28]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:33]([C:32]4[CH:36]=[CH:37][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=4)=[O:34])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 92 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7- pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxycarbonylbenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 92%. Melting point: 220-223° C. (Methanol)
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([CH:9]2[CH2:11][N@@:10]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[O:6][C:5]1=[O:24])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][CH2:34][C:33]1=[O:40]>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:33](=[O:40])[CH2:34][N:35]([CH2:11][C@H:9]([NH:10][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[C@@H:7]2[CH2:8][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:24])[O:6]2)[C:36]([CH3:39])([CH3:38])[CH2:37]1
Reactant: CC1(C)CN(c2ccccc2Cl)C(=O)CN1
Reactant: CC(C)[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC(C)[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 93.4 %

Procedure:
A solution of 192 mg of (3S,5S)-3-isopropyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (1g) (0.54 mmol) and 181 mg of 1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (1k) (0.76 mmol) in toluene (7 ml) was stirred at 110° C. for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride/ethyl acetate=5/1) to obtain 299 mg of the title compound (yield: 93%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([N+:29]([O-:31])=[O:30])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[N+:29]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)[C:3]([OH:32])=[O:2])([O-:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Yield: 61.9 %

Procedure:
A solution of 4.5 g of 3-nitro-5-(octadecyloxy)benzoic acid methyl ester and 4 ml of 6N NaOH in 200 ml of methanol and 50 ml of dioxane was stirredat reflux for 2.5 hours. The solvents were removed at reduced pressure and the residue was acidified with 1N HCl. The solid was filtered and recrystallized from methanol-water to give 2.7 g (62% yield, mp 101°-103°) of 3-nitro-5-(octadecyloxy)benzoic acid.
Reaction SMILES: [C@@H]1(NC2C3C=CN([C@H]4C[C@H:23]([OH:25])[C@H:22](CO)C4)C=3N=CN=2)C2C(=CC=CC=2)CC1.N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C.[Si:41]([O:48][CH2:49][C@@H:50]1[CH2:54][C@@H:53]([N:55]2[C:59]3[N:60]=[CH:61][N:62]=[C:63]([NH:64][C@@H:65]4[C:73]5[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=5)[CH2:67][CH2:66]4)[C:58]=3[CH:57]=[CH:56]2)[CH2:52][C@@H:51]1[OH:74])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C.N1C=CC=CC=1>[C:23]([O:74][C@H:51]1[CH2:52][C@H:53]([N:55]2[C:59]3[N:60]=[CH:61][N:62]=[C:63]([NH:64][C@@H:65]4[C:73]5[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=5)[CH2:67][CH2:66]4)[C:58]=3[CH:57]=[CH:56]2)[CH2:54][C@H:50]1[CH2:49][O:48][Si:41]([C:44]([CH3:47])([CH3:45])[CH3:46])([CH3:42])[CH3:43])(=[O:25])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Reactant: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol (3.00 g, 8.23 mmol), 1H-imidazole (1.68 g, 24.7 mmol) and 4-(dimethylamino)-pyridine (100 mg, 0.818 mmol) were dissolved in DMF (90.0 mL) under an atmosphere of argon and the solution was cooled to 0° C. tert-Butyldimethylsilyl chloride (1.24 g, 8.23 mmol) was added and the mixture was stirred at rt for 2 h. LC/MS indicated complete conversion. The reaction was quenched with saturated aqueous sodium chloride solution (30 mL), extracted with EtOAc (3×50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The remaining DMF was removed under high vacuum. Crude (1S,2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanol (3.94 g, 8.23 mmol) and 4-(dimethylamino)-pyridine (100. mg, 0.818 mol) were dissolved in pyridine (70.0 mL) and acetic anhydride (4.66 mL, 49.4 mmol) was added. The mixture was stirred at rt overnight. The solvent was evaporated and the remaining pyridine was removed under high vacuum. The residue was purified via silica gel chromatography eluting with a gradient of 10 to 66% EtOAc in hexanes to afford the title compound (3.66 g, 86%). LC/MS: Rt=2.51 min, ES+ 521 (AA standard).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:10]1[S:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)=[O:18]
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCCCl)Nc1nnc(-c2ccccc2)s1
Yield: 85.2 %

Procedure:
A mixture of 5-phenyl-1,3,4-thiadiazol-2-amine (7.1 g, 0.04 mol), 4-chloro-butyryl chloride (11.3 g, 9.0 ml, 0.08 mol) and potassium carbonate (5.5 g, 0.04 mole) in toluene (100 ml) was heated under reflux for 4 hr. The toluene was then evaporated under reduced pressure. The residue was then quenched with water, stirred, and filtered. The solid obtained was washed, dried and recrystallized from toluene to give the required product (9.6 g, 85% yield), mp 159-62° C., m/e 281, 87% (consistent with molecular formula C12H12ClN3OS, calcd. 281.04). 1H NMR (DMSO-d6): δ 2.07-2.10 (m, 2H, —CH2), 2.67-2.70 (m, 2H, —CH2), 3.70-3.72 (m, 2H, —CH2), 7.48-7.54 (m, 3H, ArH), 7.93-7.94 (m, 2H, ArH), 12.65 (br s, 1H, NH). 13C NMR: δ 27.9, 32.7, 45.1, 127.4, 129.8, 130.7, 131.0, 158.5, 162.4, 171.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Br:8])=[N:5][CH:4]=1.[CH3:9][NH:10][C:11](=[N:14][N+:15]([O-:17])=[O:16])SC.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:8][C:6]1[S:7][C:3]([CH2:2][NH:1][C:11]([NH:10][CH3:9])=[N:14][N+:15]([O-:17])=[O:16])=[CH:4][N:5]=1
Reactant: NCc1cnc(Br)s1
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Br)s1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A mixture of 0.39g of 5-(aminomethyl)-2-bromothiazole, 0.30g of 1,2-dimethyl-3-nitroisothiourea, 0.58g of cuprous bromide, 0.55g of anhydrous potassium carbonate and 4ml of dry acetonitrile was stirred in an oil bath of 60° C. for 45 minutes. The reaction mixture was purified by a column chromatography [developing solvent: dichloromethane-methanol (10:1)] to obtain 1-(2-bromo-5-thiazolylmethyl)-3-methyl-2-nitroguanidine (Compound No. 39), as white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([O:22][CH3:23])(=[O:21])[CH:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[OH:15].C(Br)C=CC>C1COCC1>[CH3:23][O:22][C:13](=[O:21])[C@@H:14]([OH:15])[C@@H:16]([CH2:9][CH:10]=[CH:11][CH3:12])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(O)C(=O)OC
Reactant: [Li]CCCC
Agent: CC=CCBr
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC=CC[C@@H](C(=O)OC)[C@H](O)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (14 mL, 100 mmol) in THF at 0° C. is added BuLi (2.5 M in hexane, 40 mL, 100 mmol) over 10 minutes. The mixture is stirred at rt for 30 minutes, and then added via cannula to a −78° C. solution of dimethyl malate B-1 (7.71 g, 47.6 mmol) in THF (130 mL). The mixture is warmed to −20° C. over 2 hours, and then cooled to −78° C. Crotyl bromide (8.1 g, 60 mmol) is added, then the mixture is allowed to warm to rt and then stirred overnight. The solution is then cooled to −10° C. and quenched with NH4Cl (10%, 100 mL). The THF is removed and the residue extracted with EtOAc (2×200 mL). The combined organic layers are washed with HCl (1 N, 3×50 mL), saturated aqueous NaHCO3 (3×50 mL), and brine, then dried over Na2SO4. The solution is filtered and concentrated to give a residue, which is purified on silica gel (EtOAc/hexane 1:4) to afford (2S,3R)-3-(2-butenyl)-2-hydroxysuccinic dimethyl ester B-2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9](O)[C:10]([NH2:12])=[O:11].[C:14](C1NC=CN=1)(C1NC=CN=1)=[O:15].[O:26]1CCCC1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14](=[O:15])[O:26][NH:12][C:10]1=[O:11]
Reactant: Cc1cccc(C)c1N(O)C(N)=O
Reactant: C1CCOC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: Cc1cccc(C)c1-n1c(=O)[nH]oc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 300 mL flask with side arm equipped with a nitrogen inlet and a thermometer was charged with 25 mL of tetrahydrofuran followed by 5.00 g (0.0277 mol) of 2,6-dimethylphenyl hydroxyurea. To this stirred suspension was added portion-wise 4.41 g (0.0277 mol) of carbonyl diimidazole over 5 min. While stirring at room temperature, the suspension turned into a solution before precipitate started to form slowly. After 18 h, the mixture was quenched with 50 mL of 1N HCl which caused the suspension to turn into a solution. It was partitioned between ethyl acetate (250 mL) and 1N HCl (50 mL). The organic layer was separated and washed with brine, then dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give the title compound as a red oil (5.20 g) which slowly crystallized upon standing at room temperature to give a solid melting at 90-100° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]2)=[CH:3][N:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][N:41]3[C:42](=[O:44])[CH2:43][O:39][C:40]3=[O:45])[CH2:15][CH2:16]2)=[CH:3][N:2]=1
Reactant: OCCC1CCN(c2cncc3ccccc23)CC1
Reactant: O=C1COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1COC(=O)N1CCC1CCN(c2cncc3ccccc23)CC1
Yield: 94.4 %

Procedure:
The procedure described in Example 5 (step 5.2) is used. Starting with 0.801 g (3.12 mmol) of 2-[1-(4-isoquinolyl)-4-piperidyl]ethanol, prepared in step 7.1, 0.902 g (3.44 mmol) of triphenylphosphine, 0.379 g (3.75 mmol) of 1,3-oxazolidine-2,4-dione and 0.632 g (3.12 mmol) of diisopropyl azodicarboxylate (DIAD), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 1 g of product is obtained in the form of a green paste.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:5]2.[CH3:27][NH2:28]>>[CH3:27][NH:28][C:18]([CH:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][C:6]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:5]3)[CH2:13][CH2:14]1)=[O:19]
Reactant: CN
Reactant: O=C(O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1
Product: CNC(=O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
4-(5-Chloro-2-phenyl-1H-indol-7-yl)amino-cyclohexane-1-carboxylic acid prepared in Example 102 and methylamine (HCl salt) were reacted according to the same procedure as Example 92 to give the title compound.