Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:17][C:18]1[N:23]=[C:22]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([NH2:35])=[O:34])[C:21]([C:36]([F:39])([F:38])[F:37])=[CH:20][N:19]=1.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.C(Cl)Cl>CO.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:40])[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:17][C:18]1[N:23]=[C:22]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([NH2:35])=[O:34])[C:21]([C:36]([F:37])([F:38])[F:39])=[CH:20][N:19]=1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
Formaldehyde solution (37% aq.; 32 μL, 0.39 mmol) was added to a stirred solution of 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2) (40 mg, 78 μmol) in dry MeOH (2 mL). Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added under nitrogen and the resulting mixture was stirred at room temperature for 2 hours. The crude mixture was diluted with ethyl acetate and adsorbed onto silica gel. Chromatography (SiO2, 0-20% MeOH/DCM) gave the title compound (3) (25 mg, 61%) as a solid; 1H NMR (400 MHz, CD2Cl2) δ 8.53 (s, 1H), 8.34 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 7.29-7.15 (m, 4H), 6.92 (dd, J=8.3, 1.4 Hz, 1H), 6.82 (d, J=1.7 Hz, 1H), 6.12 (bs, 1H), 5.84 (bs, 1H), 3.91 (s, 3H), 3.68 (s, 2H), 3.60 (d, J=10.6 Hz, 2H), 3.24-3.03 (m, 4H), 2.80 (s, 3H), 2.79 (m, 2H), 2.71 (m, 1H), 2.42-2.20 (m, 2H), 2.01 (m, 2H). LCMS Method C: rt 4.92 min; m/z 528.1 [M+1]+, 526.1 [M−1]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7](=[O:9])[CH3:8].[C:10]([Mg]Br)#[CH:11]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]([OH:9])([C:10]#[CH:11])[CH3:8]
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1ncccn1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1ncccn1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A solution of 1-(pyrimidin-2-yl)ethan-1-one (2.5 g, 20.47 mmol) in tetrahydrofuran (60 mL) was added dropwise into a ethynylmagnesium bromide (0.5 M in tetrahydrofuran, 60 mL, 30 mmol) solution with stirring at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hr and then quenched by the addition of saturated aqueous ammonium chloride (200 mL). The resulting solution was extracted with ethyl acetate (2×300 mL) and the combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified on a silica gel column, elution with ethyl acetate/petroleum ether (0:1-1:1) afforded 2-(pyrimidin-2-yl)but-3-yn-2-ol (1.5 g, 50%) as yellow oil. 1H NMR (400 MHz, CDCl3) delta 8.82 (d, J=4.4 Hz, 2H), 7.33-7.29 (m, 1H), 5.1 (s, 1H), 2.56 (s, 1H), 1.93 (s, 3H); LC-MS: m/z=149 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([N:24]([CH2:27][C:28]1[N:33]=[C:32]2[CH2:34][O:35][C:36](=O)[C:31]2=[CH:30][CH:29]=1)[CH2:25][CH3:26])[CH3:23].Cl>C1COCC1>[CH2:22]([N:24]([CH2:27][C:28]1[N:33]=[C:32]2[CH2:34][O:35][C:36](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:31]2=[CH:30][CH:29]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCN(CC)Cc1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reaction time: 0.33 h
Yield: 39.2 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (88 mg, 0.58 mmol.) in THF (4 mL) is placed under an argon atmosphere cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (1.55 mL of a 1M solution in THF, 1.55 mmol) is added slowly at 0° C. and the resulting solution is stirred for 20 min. The ice-bath is then removed and a solution of 2-diethylaminomethyl-7H-furo[3,4-b]pyridin-5-one (85 mg, 0.39 mmol) in THF (1 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 3 h and then poured into 10% aqueous HCl solution (20 mL) and stirred for 48 h at room temperature. The solid which precipitated from solution is collected by filtration. The solid is purified by chromatography (silica gel, gradient elution, 100:1 Chloroform/MeOH to 10:1 Chloroform/MeOH). The product containing fractions are concentrated to give the title compound (54 mg, 39%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[CH:31][C:23]=2[CH3:22])[NH:27][C:26]1=[O:32]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 73.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-methyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (50 mg, 73.3%) as a yellow solid.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([CH:24]1[CH2:26][CH2:25]1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O>CS(C)=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:11]([CH:24]2[CH2:25][CH2:26]2)([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:32][CH:31]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CSCc1cccc2c(C(CCC#N)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
16 mg (0.25 mmol) of potassium cyanide were added to 57 mg (0.12 mmol) of the compound from Example 116A in 1 ml of DMSO. The mixture was stirred at 80° C. for 16 h, water was added to the reaction solution, and the crude product was purified directly by preparative HPLC (mobile phase: acetonitrile/water gradient). 29 mg (60% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[C:12]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:13]=1
Reactant: N#Cc1cnccn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cnccn2)sc2ccccc12
Temperature: 120 °C
Yield: 22.4 %

Procedure:
A mixture of methyl thiosalicylate (1.68 g, 10.0 mmol), cyanopyrazine (1.06 g, 10.1 mmol), triethylamine (2.10 ml, 15.1 mmol) and toluene (10.0 ml) was refluxed at 120° C. for 8 hrs. The solvent was evaporated and the residue was recrystallized from dioxane-hexane to give the titled compound (0.54 g, 22%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C:6]1[N:7]=[C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[S:9][C:10]=1[C:11](O)=[O:12].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53]>CN(C)C=O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C:6]1[N:7]=[C:8]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[S:9][C:10]=1[C:11]([NH:53][O:52][CH:47]1[CH2:48][CH2:49][CH2:50][CH2:51][O:46]1)=[O:12]
Reactant: O=C(O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 4-(3,4-dichlorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylic acid.Na (125 mg, 0.316 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (72.8 mg, 0.380 mmol), and 1-hydroxybenzotriazole (51.3 mg, 0.380 mmol) in N,N-dimethylformamide (1.50 mL) was added O-(tetrahydropyran-2-yl)hydroxylamine (55.6 mg, 0.474 mmol). The reaction was stirred at rt for 15 hrs. The mixture was distributed between water and EtOAc, and the aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with NaHCO3(aq) saturated solution and 10% LiCl(aq) soln (×2), dried over Na2SO4, and concentrated to provide 4-(3,4-dichlorobenzyl)-2-(morpholin-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,3-thiazole-5-carboxamide as a white solid (153 mg, quantitative). LCMS: (AA) ES+ 472, 474, 476; 1H NMR (400 MHz, CDCl3) δ 7.49-7.43 (d, J=1.9 Hz, 1H), 7.30-7.26 (m, 1H), 7.26-7.17 (m, 1H), 5.01-4.89 (d, J=2.8 Hz, 1H), 4.31-4.21 (m, 2H), 3:96-3.86 (td, J=10.4, 9.1, 2.8 Hz, 1H), 3.80-3.70 (t, J=4.9 Hz, 4H), 3.66-3.56 (m, 1H), 3.51-3.42 (t, J=4.9 Hz, 4H), 1.90-1.73 (m, 3H), 1.69-1.49 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[O:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=3)=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:12][CH2:13][CH:14]([CH2:17][C:18]([C:20]3[O:21][C:22]([CH:25]=[O:26])=[CH:23][CH:24]=3)=[O:19])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)c1ccc(CO)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of the product from Example 138 (179 mg, 0.35 mmol) in dichloromethane (17 mL) was added Dess-Martin periodinane (374 mg, 0.88 mmol). The reaction was stirred at room temperature for one hour, filtered through Celite®, evaporated, and the residue purified by column chromatography on silica to afford the desired product (94 mg) as a white solid. MS (ES+) 507 ([MH]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[C:14]1[CH:15]=[C:16]([C:28]([O:30][CH3:31])=[O:29])[C:17]2[NH:18][C:19]3[CH:20]=[C:21]([Cl:27])[CH:22]=[CH:23][C:24]=3[C:25]=2[N:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:27][C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[N:26]=[C:14]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=4)[CH:15]=[C:16]([C:28]([O:30][CH3:31])=[O:29])[C:17]=3[NH:18][C:19]=2[CH:20]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(Cl)ccc12
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nc2c1[nH]c1cc(Cl)ccc12
Temperature: 70 °C
Yield: 76.1 %

Procedure:
A flask containing a mixture of 3-fluoro-4-methoxyphenylboronic acid (0.901 g, 5.30 mmol), methyl 2-bromo-7-chloro-5H-pyrido[3,2-b]indole-4-carboxylate (1.5 g, 4.4 mmol), powdered potassium phosphate tribasic (2.25 g, 10 6 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.363 g, 0.883 mmol), and Pd(OAc)2 (0.099 g, 0.44 mmol) was flushed with nitrogen, THF (22 mL) was added, and the reaction was heated at 70° C. for 20 hr. This was partitioned between EtOAc and water and the organic phase was washed with water and brine and then dried with sodium sulfate. Removal of the solvent followed by silica gel chromatography (step gradient elution with DCM containing 75 to 0% hexane) afforded methyl 7-chloro-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (1.29 g, 3.35 mmol, 76% yield) as a light green solid. MS (ESI) m/z 385.13 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.89 (1H, s), 8.19 (1H, d, J=8.24 Hz), 7.92 (1H, s), 7.76 (1H, d, J=1.53 Hz), 7.35 (1H, dd, J=8.55, 1.83 Hz), 4.04 (3H, s).
Reaction SMILES: O.C(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=[O:16])=[O:14])CCC.[CH3:17][C:18]([NH2:30])([CH3:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1>CS(C)=O>[CH3:29][C:18]([N:30]=[C:15]([O:16][CH2:12][CH2:7][CH2:8][CH3:9])[C:13]([C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1
Reactant: CCCCOc1ccccc1C(=O)C=O
Reactant: CC(C)(N)Cc1ccc2c(c1)OCO2
Solvent: CS(C)=O
Solvent: O
Product: CCCCOC(=NC(C)(C)Cc1ccc2c(c1)OCO2)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 700 mg of 2-n-butoxyphenylglyoxal hydrate, 500 mg of α,α-dimethyl-3,4-methylenedioxyphenethylamine and 1.5 ml of dimethylsulfoxide is stirred at room temperature for 45 minutes, whereby a solution of α-(α,α-dimethyl-3,4-methylenedioxyphenethylimino)-2-n-butoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:21])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[N+:18]([O-])=O)=[O:8])[CH2:2][CH2:3][CH3:4]>[Pd].CO>[NH2:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:21]
Reactant: CCCCNC(=O)C(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)C(=O)Nc1ccc(OC)cc1N
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A mixture of 27.0 g (91 mmol) of N-butyl-N′-(4-methoxy-2-nitrophenyl)-oxalamide, 1200 ml of methanol and 7.3 g of 10% Pd/C catalyst is hydogenated for 3 h. The catalyst is filtered off, washed with aceton, the filtrate is concentrated and the residue is treated with 100 ml of diethyl ether. The obtained product is filtered, washed with diethyl ether a nd dried to yield 21.8 g (90%) of the title compound. Mp.: 180-181° C. (diethyl ether).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]([CH2:25][C@H:26]([OH:28])[CH3:27])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=O)=O)=CC=1.[H-].[Na+].O>C1COCC1>[CH3:27][C@H:26]1[O:28][CH2:12][CH2:13][N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C[C@@H](C)O)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCO[C@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-{[(2R)-2-hydroxypropyl][(4-methylphenyl)sulfonyl]amino}ethyl 4-methylbenzenesulfonate (340 g, 0.80 mol) in dry THF (3 L) at 0° C. was added NaH (60%, 120 g, 3.00 mol) portion wise. The reaction mixture was warmed to room temperature and stirred for 14 h. The reaction was then cooled to 0° C., and water (100 mL) was added to quench the reaction. The mixture was completely quenched by pouring into water (1 L) and the phases were separated. The aqueous phase was extracted with EtOAc (3×500 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (8:1 petroleum ether:EtOAc) to yield the title compound as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:11]=2)[CH:9]=1)=[O:4].[CH3:46][NH2:47]>>[N:47]1[CH:21]=[CH:20][CH:19]=[CH:23][C:46]=1[CH2:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:11]=2)[CH:9]=1)=[O:4]
Reactant: CN
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NCc5ccccn5)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid methylamide (Example 173), by substituting C-pyridin-2-yl-methylamine for methylamine.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Br)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CBr)nc1
Reactant: C1COCCN1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CN2CCOCC2)nc1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)nicotinamide (0.11 mmol) was used in general procedure 5 with morpholine (0.12 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(morpholinomethyl)nicotinamide. MS (Q1) 450.0 (M)+
Reaction SMILES: OC[C@@H](N)CC(C)C.COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][CH:24]([CH3:34])[CH2:25][C@H:26]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:27]O.[Cl-].C([NH3+])C(C)C.[C:41]([C:43]1[CH:48]=[CH:47][C:46]([N:49]=[C:50]=[S:51])=[CH:45][CH:44]=1)#[N:42]>>[C:41]([C:43]1[CH:44]=[CH:45][C:46]([N:49]=[C:50]2[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:26]([CH2:25][CH:24]([CH3:34])[CH3:23])[CH2:27][S:51]2)=[CH:47][CH:48]=1)#[N:42]
Reactant: CC(C)CN[C@H](CO)CC(C)C
Reactant: N#Cc1ccc(N=C=S)cc1
Agent: CC(C)C[C@H](N)CO
Agent: CC(C)C[NH3+]
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: CC(C)C[C@H]1CSC(=Nc2ccc(C#N)cc2)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (2S)-4-methyl-2-(isobutylamino)pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(1S)-1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)ammonium chloride according to Method B7c. 4-Cyanophenyl isothiocyanate was reacted with N-(1S)-1-(chloromethyl)-3methylbutyl)N-(isobutyl)ammonium chloride to Method C1f to afford (4S)-2-(4-cyanophenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].Cl[Sn]Cl>CCO>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([NH2:10])[C:3]=1[NH2:4]
Reactant: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(F)cc(Br)c1N
Yield: 83.5 %

Procedure:
A suspension of 2-bromo-4-fluoro-6-nitroaniline (14 g, 59 mmol) and SnCl2 (66 g, 295 mmol) in EtOH (50 mL) was heated at reflux for 5 h. The reaction mixture was concentrated in vacuo. To the residue was added EtOAc (100 mL) and satd. aq. NaHCO3 (200 mL). The mixture was filtered over Celite® and washed with EtOAc (100 mL×3). The combined organic layers were washed with satd. aq. NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 3-bromo-5-fluorobenzene-1,2-diamine as a gray solid (10.1 g, 100%). MS (ESI): m/z=205 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:25]>C(O)C.[Pd]>[ClH:25].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 1.5 h

Procedure:
To a solution of 1-tert-butyloxycarbonyl-4-(4-nitro-3-methylphenyloxy)piperidine (3.6 g) in ethanol (30 ml) was added conc. hydrochloric acid (0.9 ml). By using 10% palladium/carbon (containing 48% water, 0.3 g) as a catalyst, catalytic reduction was conducted under reduced pressure for 1.5 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 1-tert-butyloxycarbonyl-4-(4-amino-3methylphenyloxy)piperidine hydrochloride (1.7 g) as light brown crystals, m.p. 160°-180° C.
Reaction SMILES: [I:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>C(Cl)(Cl)Cl.O.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Ic1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(I)ccc3Sc3ccccc32)CC1

Procedure:
5.9 g of 1-(10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 3.3 g of powdered potassium carbonate, 0.07 g of potassium iodide and 40 ml of toluene, with 4.35 g of N-(β-chloroethyl)-oxazolidinone and the mixture is heated under reflux for 27 hours. The mixture is then poured on to water and diluted with chloroform. The organic phase is extracted with 2-N hydrochloric acid. The aqueous phase is made alkaline with sodium hydroxide and extracted with chloroform. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed over aluminium oxide. There is obtained 3-[ 2-[4-(10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl ]-2-oxazolidinone which is converted into the maleate by treatment with maleic acid. The maleate melts at 176°-177° C.