Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[N:16]=[C:17]([C:20]2[S:21][C:22]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[C:27]([C@H:36]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:26]([CH3:47])=[CH:25][C:23]=3[N:24]=2)[S:18][CH:19]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:43]([O:42][C@@H:36]([C:27]1[C:26]([CH3:47])=[CH:25][C:23]2[N:24]=[C:20]([C:17]3[S:18][CH:19]=[C:15]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[N:3]=[CH:4]5)[N:16]=3)[S:21][C:22]=2[C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH3:44])([CH3:45])[CH3:46]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(Br)cs3)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(-c4ccc5c(cnn5C)c4)cs3)sc2c1-c1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
In a 10 mL reaction vial, 1-methyl-1H-indazol-5-ylboronic acid (31 mg, 0.173 mmol) and (S)-ethyl 2-(2-(4-bromothiazol-2-yl)-7-(4chlorophenyl)-5methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.173 mmol) were mixed with dioxane (5 mL) and water (1 mL). The resulting reaction mixture was bubbled with argon for 5 min. Then potassium carbonate (60 mg, 0.432 mmol) and Pd(PPh3)4 were added sequentially. The reaction mixture was sealed and heated in oil bath at 95° C. for 2 h. The brown mixture was then diluted with EtOAc (20 mL), filtered and the filtrate was concentrated and purified on silica gel column with 0-30% EtOAc/Hex to afford the title compound. LCMS-ESI+: calc'd for: C33H31ClN4O3S2: 631.2, 633.2, 632.2 (M+H+); found: 631.0, 633.1, 632.1 (M+H+).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)=[O:26]>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:10][CH2:11]3)=[O:2])=[CH:29][CH:28]=1)(=[O:26])[CH3:24]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(=O)c1ccc(N)cc1
Product: CC(=O)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 35.8 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminoacetophenone (46.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-acetylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (24.4 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2=[CH:6][C:7]3[S:8][CH:9]=[CH:10][C:11]=3[CH:12]=[C:2]12.C([Li])(C)(C)C.[CH3:18][Sn:19](Cl)([CH3:21])[CH3:20]>O1CCCC1>[CH3:18][Sn:19]([CH3:21])([CH3:20])[C:5]1[S:1][C:2]2=[CH:12][C:11]3[CH:10]=[C:9]([Sn:19]([CH3:21])([CH3:20])[CH3:18])[S:8][C:7]=3[CH:6]=[C:3]2[CH:4]=1
Reactant: c1cc2cc3sccc3cc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2cc3sc([Sn](C)(C)C)cc3cc2s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A dry 1 L three-neck round bottom flask was flushed with N2 and was charged with benzo[1,2-b:4,5-b′]dithiophene (5.20 g, 26.3 mmol) and anhydrous tetrahydrofuran (THF) (300 mL, 0.01 M) via deoxygenated syringe. The reaction flask was cooled to −78° C. and a 1.3 M solution of tert-butyllithium in hexanes (53.0 mL, 68.8 mmol) was added dropwise via deoxygenated syringe. After 30 minutes of stirring at −78° C., the solution was chilled to 0° C. and stirring was continued for 5 minutes, at which point the reaction mixture was cooled back to −78° C. A 1 M solution of trimethyltin chloride (105 mL, 100 mmol) in hexanes was added to the reaction flask dropwise and stirring continued for 30 minutes at −76° C. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. As the reaction was completed, cool DI water (50 mL) was slowly added to the reaction flask. Then, the reaction mixture was poured into 300 mL of cool water and extracted with MTBE (300 mL) three times. The combined organic layer was washed with water two times and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified by precipitation into methanol from a THF solution to yield white solid (12.0 g, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C1(NC2CCCCC2)CCCCC1>[Cu]I.C(#N)C>[N:4]1[CH:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:7]=[N:6][CH:5]=1
Reactant: C#CCCCCO
Reactant: Brc1cncnc1
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Product: OCCCCC#Cc1cncnc1
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
A mixture of 5-bromopyrimidine (3.96 g), 5-hexynol (2.44 g), dicyclohexylamine (4 g) and acetonitrile (50 ml) was de-oxygenated by bubbline nitrogen through the solution for 10 min. BTPC (150 mg) and copper (I) iodide (25 mg) were added and the mixture was heated to 60°-70° under nitrogen for 1 h, cooled and evaporated in vacuo. Ether (175 ml) was added, the mixture filtered and evaporated in vacuo and the residue purified by FCC. Elution with ether followed by System C (19:1-92:8) gave the title compound as a pale yellow oil (3.79 g), t.l.c. (System C 17:3) Rf 0.55.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11].[S:14]1C=CC=C1CSCCC(OC)=O>>[S:14]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11]
Reactant: NNC(=O)CCSCc1ccco1
Reactant: COC(=O)CCSCc1cccs1
Product: NNC(=O)CCSCc1cccs1

Procedure:
3-[(2-thienylmethyl)thio]propanoic acid, hydrazide (56) was prepared in the manner that 3-[(2-furanylmethyl)thio]propanoic acid, hydrazide (12) was prepared (Example 12) on a 23 mmol scale from methyl 3-[(2-thienylmethyl)thio]propanoate (55). After the solvent was removed under vacuum, 2.77 g (69%) of the product, which was a water white viscous liquid, was recovered and was used immediately in the manner described in Example 57, below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1.BrN1C(=O)CCC1=O.N1C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1
Reactant: Cc1nc2c(c(=O)[nH]1)-c1cc(Br)ccc1CC2
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1

Procedure:
A mixture of 9-Bromo-5,6-dihydro-3-methylbenzo[f]quinazolin-1(2H)-one (1.0 g, 3.4 mmoles), N-bromosuccinimide (0.63 g, 3.5 mmoles) and pyridine (0.3 ml, 3.7 mmoles) in dry benzene (350 ml) was reacted in the same manner as for the corresponding 3-pivalamide (Example 2). After cooling, benzene and excess pyridine were removed under reduced pressure. The residue was triturated with methanol:water (1:1) and filtered to leave a crude product which was recrystallized from methanol to give 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one as an off-white solid. (0.47 g, 37%) 1H NMR(DMSO-d61 200MHz) δ: 2.57(s, 3H, CH3); 7.73(d, J=9.0 Hz, 1H, Ar); 7.86(dd, J=8.6, 2.0 Hz, 1H, Ar); 8.09(d, J=8.7 Hz, 1H, Ar); 8.41(d, J=8.8 Hz, 1H, Ar); 9.92(d, J=2.0 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[O:3]1.[Li]C(C)(C)C.CN([CH:28]=[O:29])C>C1COCC1.CCCCC.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:28]=[O:29])[CH:8]=2)[O:3]1
Reactant: Cc1ccc(C2=CC(C)(C)Oc3ccc(Br)cc32)s1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(C=O)cc32)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (-78° C.) solution of 2,2-dimethyl-4(5-methyl-thien-2-yl)-6-bromo-chrom-3-ene (Compound R, 1.2 g, 3.6 mmol) in THF (10 mL), was added t-BuLi in pentane (1.7M solution, 2.3 mL). After 30 minutes, DMF (465 mg, 5 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was diluted with ethyl acetate (150 mL), washed with brine (10 mL), dried and the solvent was removed by evaporation. Purification by chromatography on silica gel column gave the title compound as a colorless oil.
Reaction SMILES: [Cl-].[In+3:2].[Cl-].[Cl-].[CH2:5]([Mg]I)[CH3:6].[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23].C(O[CH2:27][CH3:28])C>>[CH2:27]([In:2]([CH2:5][CH3:6])[CH2:20][CH3:21])[CH3:28].[CH3:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH3:9]
Reactant: CCOCC
Reactant: CC[Mg]I
Reactant: [In+3]
Agent: COCCOCCOCCOCCOC
Agent: [Cl-]
Product: CC[In](CC)CC

Procedure:
By a procedure substantially similar to that of Example 3, an adduct of triethyl indium (TEI) and diethyl ether was prepared from indium (III) chloride and ethyl magnesium iodide. To this adduct sufficient tetraglyme was added to give a molar ratio of TEI to tetraglyme was 3:1. Diethyl ether was removed in vacuo at a bottom temperature of 74° C. Subsequently, pure TEI was obtained via dissociation of the adduct at 74°-115° C. and a pressure of <1 mbar. The TEI thereby obtained was subsequently subjected to fractional distillation at a pressure of <1 mbar. No metal impurities could be detected by ICP-OES in the distilled TEI.
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)C.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC1=CC(=O)CC1
Reactant: Cl[Mg]Cc1ccccc1
Product: O=C1C=C(Cc2ccccc2)CC1

Procedure:
The general procedure for the preparation of substrates using 3-ethoxycyclopentenone (0.88 g, 7.0 mmol) and benzylmagnesium chloride (10 mmol, 1 M in diethyl ether) gave, after flash chromatography (2:1 hexanes:ethyl acetate) and Kugelrohr distillation (0.4 torr, 200° C.), the title compound as a white solid (0.58 g, 50%). m.p. 32-33° C. Spectroscopic data were consistent with previously reported data for this compound.3
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[Si:27]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of 2.42 g (10 mmol) thymidine in 15 ml DMF was added 1.7 g (25 mmol) imidazole and 1.6 g (10.6 mmol) tert-butyldimethyl silyl chloride. The solution was stirred at room temperature for 3 hours. DMF was then removed in vacuo and the residue was dissolved in 150 ml of ethyl acetate. The solution was washed with water and the organic layer was dried over MgSO4. After removing the solvent, the solid was recrystallized with ethyl acetate/pentane to obtain 2.5 g pure 5′-O-(tert-butyldimethylsilyl) thymidine 1 (70% yield).: m.p. 193-194° C.; 1H NMR (500 MHz, CDCl3) δ 9.0 (s, 1H, NH), 7.50 (s, 1H, H-6), 6.36 (dd, J=5.8, 8.1 Hz, 1H, H-1′), 4.44 (m, 1H, H-3′), 4.03 (m, 1H, H-4′), 3.85 (m, 2H, H-5′), 2.66 (d, J=3.8 Hz, 1H, OH), 2.35 (m, 1H, H-2′), 2.07 (m, 1H, H-2′), 1.89 (s, 3H, C═CMe), 0.89 (s, 9H, CMe3), 0.09 (s, 6H, SiMe2); 13C NMR (125 MHz, CDCl3) δ 163.8 (C-4), 150.4 (C-2), 135.4 (C-6), 110.9 (C-5), 87.2 (C-4′), 85.0 (C-1′), 72.6 (C-3′), 63.6 (C-5′), 41.1 (C-2′), 25.9 (SiCMe3), 18.3 (SiCMe3), 12.5 (C═CMe), −5.4 (SiMe2), −5.5 (SiMe2).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2([CH3:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([OH:27])=[C:24]([CH3:26])[CH:25]=3)[C:29]([N:46]3[CH2:45][CH2:44][C:43]([CH3:49])([N:40]4[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]4)[CH2:48][CH2:47]3)=[O:30])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: CN1CCN(C2(C)CCNCC2)CC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C)(N3CCN(C)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 1i from 80 mg (0.17 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1h) and 36 mg (0.18 mmol) 1-methyl-4-(4-methyl-piperidin-4-yl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:14]3[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:14]3[CH2:19][CH2:18][N:17]([CH2:22][C:21]([O:25][CH3:26])=[O:24])[C@H:16]([CH3:20])[CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(C2(c3ccc(Cl)cc3)CCCCC2)CCN1
Reactant: COC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CN1CCN(C2(c3ccc(Cl)cc3)CCCCC2)C[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
To a solution of (R)-1-(1-(4-chlorophenyl)cyclohexyl)-3-methylpiperazine (0.6 g, 2.05 mmol) in dichloromethane at room temperature were added methyl glyoxalate (0.23 g, 2.61 mmol), acetic acid (0.18 g, 3 mmol) and Na(OAc)3BH (1.08 g, 5.1 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. It was purified by silica gel (100-200 mesh) column chromatography eluting with ethyl acetate in n-hexanes to afford 0.49 g of (R)-methyl 2-(4-(1-(4-chlorophenyl)cyclohexyl)-2-methyl-piperazin-1-yl)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([OH:13])[CH2:6][N:7]2[CH3:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25]>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH:5]([OH:13])[CH2:6][N:7]3[CH3:12])=[O:23])=[CH:17][C:16]=1[C:24]([F:25])([F:26])[F:27]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN1CC(O)Cc2c(N)cccc21
Solvent: C1CCOC1
Product: CN1CC(O)Cc2c(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cccc21
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 5-amino-1-methyl-1,2,3,4-tetrahydroquinolin-3-ol and 4-chloro-3-trifluoromethyl-phenyl isocyanate in tetrahydrofuran is stirred at 50° C. for 5 hours. After removing the solvent, the resulting residue is purified by silica gel column chromatography to provide N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(3-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)urea.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CO.C=O.[C:29]([BH3-])#N.[Na+]>O1CCCC1>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH:15][CH3:29])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [BH3-]C#N
Reactant: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (0.10 M in acetonitrile, 1.0 mL, 0.09 mmol), prepared using procedures similar to those described in Example 2, in 1:1 ratio of methanol and tetrahydrofuran (2.0 mL) was added formaldehyde (37% wt, 6.7 μL, 0.09 mmol) followed by sodium cyanoborohydride (11.0 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 16 h, at which time it was quenched with saturated aqueous ammonium chloride. The solution was then purified directly by reverse phase HPLC to afford the title compound (14.9 mg). 1H NMR (400 MHz, CDCl3): 8.13 (br s, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 7.09-7.04 (m, 1H), 6.84-6.78 (m, 1H), 6.60-6.54 (m, 1H), 4.46-4.33 (br m, 4H), 3.93 (br m, 1H), 2.64 (s, 3H). MS (EI) for C17H15F3IN3O: 462 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:31])[CH:5]=[C:6]([Cl:30])[C:7]=1[CH2:8][C@@H:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1)[O:10][C:11](=[O:14])[CH2:12][OH:13].[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:30][C:6]1[CH:5]=[N+:4]([O-:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:10][C:11](=[O:14])[CH2:12][O:13][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][C:33]([Cl:32])=[N:34][CH:35]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(COC(=O)c1ccc(Cl)nc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 78 %

Procedure:
To a mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (See Scheme 21, step 6-9) (200 mg, 0.418 mmol), 6-chloronicotinic acid (72.5 mg, 0.460 mmol) and EDC (240 mg, 1.255 mmol) in dry DCM (10 ml), DMAP (51.1 mg, 0.418 mmol) was added, and stirring was continued for a week-end at room temperature. The solvent was evaporated; the residue was portioned between sat. sol. NaHCO3 and ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate and evaporated, the residue was purified by flash chromatography on silica gel (eluent: DCM/MeOH/32% NH4OH 98/2/0.2) and (S)-3,5-dichloro-4-(2-(2-(6-chloronicotinoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide was obtained as a white solid (202 mg, 0.327 mmol, 78% yield, MS/ESI+ 617.2 [MH]+).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH3:11][C@H:12]1[C:20]2[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:18][CH:17]=[N:16][C:15]=2[C:14](=[O:34])[CH2:13]1.O[C@H]1C2N=CN=C(N3CCN(C(OC(C)(C)C)=O)CC3)C=2[C@H](C)C1>C(Cl)Cl>[OH:34][C@@H:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:20]=2[C@H:12]([CH3:11])[CH2:13]1
Reactant: C[C@@H]1CC(=O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
Triethylamine (4.33 mL, 31.1 mmol) (degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 mL, 36.1 mmol) (degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The reaction mixture was stirred for 5 minutes, and then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on a high vacuum. 1H NMR of the crude looked like 85% diastereoselectivity. The crude was flashed on Biotage 65M (loaded 1:1 DCM:ethyl acetate 500 mL flushed, then 1:4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (major) and tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (minor) (9.35 g, 95.3% yield) as a beige foam. LC/MS (APCI+) m/z 335 [M+H]+. 1H NMR (CDCl3) shows 88% diastereoselectivity by integration of carbinol methine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]#[N:12].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11](=[N:14][OH:15])[NH2:12]
Reactant: NO
Reactant: N#Cc1sccc1C1OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1sccc1C1OCCO1
Temperature: 40 °C

Procedure:
To a solution of the foregoing nitrile (5.0 g, 27.59 mmol) in ethanol (20 ml) was added a solution of hydroxylamine hydrochloride (3.7 equivalents) and sodium carbonate (1.7 equivalents) in water (50 ml). The resulting mixture was heated to 40° C. for 5 h, then cooled to room temperature. The colourless precipitate was isolated by filtration, dried under a stream of air and azeotroped with toluene (2×) to give 3-(1,3-dioxolan-2-yl)thiophene-2-amidoxime as an off-white solid (4.36 g). 1H NMR (DMSO-d6): δ 9.83 (1H, s), 7.48 (1H, d, J 5.18), 7.15 (1H, d, J 5.18), 6.05 (1H, s), 5.77 (2H, bs), 4.05 (2H, m), 3.91 (2H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15](=O)[C:16]2[CH:21]=[C:20]([Cl:22])[C:19](OCC3C=CC=CC=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:40].[NH2:41][NH2:42]>CCO.C1COCC1.C(OC(=O)C)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[NH:41][N:42]=[C:15]([C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([O:40][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][C:17]=3[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1C(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O
Reactant: NN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1cc(-c2n[nH]c3c2CN(Cc2ccccc2)CC3)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 174.9 %

Procedure:
To a stirred solution of 1-benzyl-3-(2,4-bis-benzyloxy-5-chloro-benzoyl)-piperidin-4-one (26.1 g, 48 mmol) in EtOH (150 mL) and THF (100 mL) was slowly added drop wise a solution of hydrazine hydrate (10 mL, 200 mmol, 4 eq) in EtOH (25 mL). After stirring overnight, the solution was diluted with ethylacetate and thoroughly washed with water, then with brine, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel eluting with ethylacetate to give 5-benzyl-3-(2,4-bis-benzyloxy-5-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (a) (22.5 g, 86% yield).