Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][N:22]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([C:40](=[O:41])[CH2:39][N:22]2[CH2:23][CH2:24][CH2:25][C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-benzhydrylpiperidine (0.13 g, 0.5 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.16 g, 0.50 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.19 g, 1.00 mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.15-7.34 (m, 20H), 4.52-4.60 (m, 1H), 4.27 (d, J=15.7 Hz, 1H), 4.11 (d, J=15.7 Hz, 1H), 3.64-3.76 (m, 1H), 3.45-3.50 (m, 3H), 2.93-3.02 (m, 1H), 2.54-2.65 (m, 3H), 2.20-2.44 (m, 1H), 1.78-1.87 (m, 2H), 1.55-1.65 (m, 2H), 1.00-1.20 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[CH:5]([CH2:22][C:23]#[CH:24])[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(N[C:31]1[CH:36]=CC=[CH:33][CH:32]=1)C>>[CH2:26]([N:3]([C:1]1[CH:33]=[CH:32][CH:31]=[CH:36][CH:2]=1)[C:4](=[O:25])[CH:5]([CH2:22][C:23]#[CH:24])[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])=[O:7])[CH3:27]
Reactant: CCNc1ccccc1
Reactant: C#CCC(C(=O)NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N(CC)CC
Product: C#CCC(C(=O)NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N(CC)c1ccccc1

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (4.00 g) obtained in Example 152 (4) and N-ethylaniline (1.53 mL). This was purified by silica gel column chromatography to give the title compound (98 mg) as a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCCCl
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nn(CCCC(=O)O)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 21 h
Yield: 67.6 %

Procedure:
To a solution of 9.7 g of the compound of Example 1 in 70 ml of dimethylformamide are added 5.5 g of potassium carbonate and 6 g of ethyl 4-chlorobutyrate, and the mixture is stirred at 60° C. for 21 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated. To a solution of the residue in 100 ml of 80 % methanol is added 3 g of potassium hydroxide, and the mixture is stirred at room temperature for two hours. After completion of the reaction, the methanol is distilled off under reduced pressure and the residue is dissolved into water and the aqueous solution is acidified with dilute hydrochloric acid. The precipitated crystals are collected by filtration and then recrystallizing from ethanol to give 8.3 g of 4-[3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]butyric acid as pale yellow crystals, melting at 192°-194° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:9]=[CH:8]2.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C(#N)C>[F:20][C:19]([F:22])([F:21])[C:15]1[CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]3[C:12](=[C:3]([CH2:2][NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1cccc(-c2ccc3cccc(CCl)c3n2)c1
Reactant: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1cccc(-c2ccc3cccc(CNC4CCCC4)c3n2)c1
Yield: 91.8 %

Procedure:
A solution of 8-(chloromethyl)-2-(3-(trifluoromethyl)phenyl)quinoline (70 mg, 0.22 mmol), cyclopentylamine (0.1 ml, 1.09 mmol) and DIPEA (0.18 ml, 1.09 mmol) in acetonitrile (2 ml) was stirred at 100° C. under microwave for 10 min. The mixture was concentrated. Purified by Prep-TLC to give a white solid (74.8 mg, 91% yield). MS (ESI) calcd for C22H21F3N2 (m/z): 370.17. found: 371 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=[C:23]4[C:34]([F:37])([F:36])[F:35])=[O:19])=[C:13]([Cl:38])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:41]I>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:41])[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=[C:23]4[C:34]([F:35])([F:37])[F:36])=[O:19])=[C:13]([Cl:38])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)Cc3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)ccc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)C(C)c3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)ccc2n1

Procedure:
In analogy to Example 1, step 2, 2-chloro-4-{3-chloro-4-[2-(2-isopropoxy-4-trifluoromethyl-quinolin-6-yl)-2-oxo-ethyl]-phenoxy}-benzonitrile was reacted with sodium hydride and methyl iodide to give the title compound as a yellow oil. MS (m/e, ISP neg. ion)=571.1 [M−H+].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>C(Cl)Cl.O>[CH:12]([C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Oxalyl chloride (12.0 ml, 0.14 mol) was added dropwise with stirring to methylene chloride (200 mL) at -78° C., under nitrogen. Ten min. after addition was complete, DMSO (20 mL) was slowly added and stirring was continued for an additional 10 min. (R)-t-Butyl 2-(hydroxymethyl)-1-pyrrolidinecarboxylate (15.0 g, 0.075 mol) in methylene chloride was added to the stirred solution and after 30 min triethylamine (56 mL) was added. The solution was held at -78° C. for 30 min. and was then allowed to warm to room temperature. Water (100 mL) was added, the phases separated, and the aqueous phase reextracted with methylene chloride (200 mL). The combined organic phases were washed with water (30 mL), evaporated, and the residual oil was chromatographed on silica gel using ethyl acetate:Skellysolve B (1:2) as eluant to give 14.2 g (95%) of product.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH3:9])(=[O:5])[C:2]([CH3:4])=[O:3].C(ON1C[C@@H](P(C2CCCCC2)C2CCCCC2)C(=C=O)[C@H]1CP(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C1C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH3:9])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCOC(=O)C(C)=O
Agent: CC(C)(C)ON1C[C@@H](P(C2CCCCC2)C2CCCCC2)C(=C=O)[C@H]1CP(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCCOC(=O)C(C)O
Yield: 96.2 %

Procedure:
To 50 ml of benzene were added 13.0 g (100 m-mol) of propyl pyruvate, 1 mg of rhodium 1,5-cyclooctadiene chloride complex compound and 3.1 mg (0.0055 m-mol) of (2S,4S)-N-tert-butoxy-carbonyl-4-dicyclohexylphosphino-2-diphenylphosphinomethylpyrrolidine (BCPM) obtained in Example 4. An autoclave equipped with a stirrer, a pressure gauge and a thermometer was charged with the above mixture and a treatment was carried out in the same manner as described in Example 13 whereby 12.7 g (yield: 96.2%) of propyl lactate was obtained. [α]D =+10.5° (optical yield: 87%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48](I)=[CH:49][S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Ag]=O.[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([CH2:48][CH3:49])=[CH:44][CH:43]=4)=[CH:49][S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1csc2cc3c(cc12)[C@]1(OC3)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=[Ag]
Agent: [Fe+2]
Solvent: C1COCCO1
Product: CCc1ccc(Cc2csc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 160.9 %

Procedure:
(3′R,4′S,5S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-3-iodo-3′,4′,5′,6′-tetrahydro-spiro[thieno[2,3,f]isobenzofuran-5(7H),2′-[2H]pyran] (0.05 g, 0.061 mmol), potassium carbonate (25.5 mg, 0.184 mmol), silver oxide (35.6 mg, 0.154 mmol) and diphenylphosphino ferrocene palladium dichloride (5.1 mg, 0.006 mmol) were dissolved in 1,4-dioxane (0.308 mL). To the resultant solution was added 2-(4-ethyl-benzyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborane (18.2 mg, 0.073 mmol), and then the solution was stirred for 3 hours at 100° C. under a nitrogen stream. The reaction solution was filtered, and the resultant product was then concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (14:100)), to thereby obtain the titled compound (39.4 mg, 79%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Cl[CH2:23][C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]([CH3:26])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:25])[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: CC(C)(CCl)c1ccccc1
Product: Cc1nc(-c2ccn(CC(C)(C)c3ccccc3)n2)sc1C(=O)NCc1cccnc1
Yield: 20 %

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and (2-chloro-1,1-dimethyl-ethyl)benzene as described in Example 49 and isolated as a white solid, (0.025 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 8.65 (bs, 1H), 8.57 (d, J=4 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.23-7.49 (m, 6H) 6.69 (d, J=2 Hz, 1H), 6.63 (d, J=2 Hz, 1H), 6.12-6.18 (bm, 1H), 4.64 (d, J=4 Hz, 2H), 4.28 (s, 2H), 2.75 (s; 3H), 1.40 (s, 6H); MS (M+H)+=432.2; Rt=1.39 min; HRMS (M+H)+=432.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:5][CH:4]=1.C=O.[C:33]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH2:10][CH2:11][N:12]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[CH2:17][CH2:16]3)=[O:14])[CH2:33][C:7]=2[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(SCCNC(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: C=O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CN(C(=O)N1CCN(C(=O)OCc3ccccc3)CC1)CCS2
Temperature: 72.5 °C
Reaction time: 48 h

Procedure:
A mixture of compound 18 (30 mg), paraformaldehyde (100 mg), p-toluenesulfonic acid (30 mg) in benzene (5 mL) was stirred at 70-75° C. for 2 days. The reaction mixture was filtered, washed with sat. NaHCO3 and concentrated to give crude product 19, which was purified by chromatography on SiO2 (CH2Cl2/EtOAc 10:1). Yield: 21 mg, 69%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:41])=[C:38]([OH:40])[CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:17]=2[O:40][C:38]2[CH:39]=[C:34]([F:33])[CH:35]=[CH:36][C:37]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccc(F)cc3)c3ccncc23)CC1
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cnccc2n1-c1ccc(F)cc1

Procedure:
The crude title compound was prepared from the compound of step 5 (50.0 mg, 109 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
21.6 g (79.5 mmol) 3-iodo-1H-indazole-5-carbaldehyde (Example 3A), dissolved in DMF (100 ml), and 31.1 g (95.4 mmol) cesium carbonate were slowly treated with 15.9 g (95.4 mmol) 2-(trimethylsilyl)ethoxymethyl chloride at 0° C. The mixture was warmed to room temperature, and stirring was continued for 12 h. The solids were then filtered off, and the filtrate was evaporated to dryness yielding the title compound (26.4 g, 82% of th.).
Reaction SMILES: [CH3:1][C@:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:12][CH2:11][CH2:10][C@:4]2([O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:3]1.[H-].[Na+].[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH2:34]Br)[CH:29]=1>CN(C)C=O.[NH4+].[Cl-]>[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH2:34][N:6]2[CH2:5][C@@:4]3([CH2:10][CH2:11][CH2:12][C@@:2]([CH2:13][N:14]4[C:18]5[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)([CH3:1])[CH2:3]3)[O:8][C:7]2=[O:9])[CH:29]=1
Reactant: BrCc1cc(Br)ccn1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CNC(=O)O2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CN(Cc3cc(Br)ccn3)C(=O)O2)C1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of 1-{[(5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (1.0 g, 3.08 mmol) in N,N-Dimethylformamide (DMF) (7 mL) was added 60% sodium hydride in mineral oil (0.160 g, 4.01 mmol) and stirred for 30 minutes. To the mixture was added 4-bromo-2-(bromomethyl)pyridine (0.928 g, 3.70 mmol) and stirred overnight. The reaction was diluted with saturated NH4Cl and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated NaCl (2×), dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography (ISCO, 120 g silica, 60 mL/min, 0-10% MeOH/CH2Cl2 over 45 min) to afford 1-(((5S,7S)-3-((4-bromopyridin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.41 g, 93%). MS (m/z) 494.1 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][S:20](=[O:23])[CH2:19][CH2:18]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[OH:24][CH2:25][CH2:26][NH2:27]>>[OH:24][CH2:25][CH2:26][NH:27][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][S:20](=[O:23])[CH2:19][CH2:18]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1
Reactant: NCCO
Reactant: O=S1CCN(c2nc(Cl)nc3c(N4CCCC4)ncnc23)CC1
Product: O=S1CCN(c2nc(NCCO)nc3c(N4CCCC4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 3 from 2-chloro-4-(1-oxido-thiomorpholino)-8-pyrrolidinopyrimido[5,4-d]pyrimidine (melting point: 243°-244° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=2)[N:7]=1.[N:19]1[N:20]=[C:21]([SH:28])[N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12.BrC1C=CC2N(C(SC3C=CC4N(C=C(NC(C5CC5)=O)N=4)N=3)=NN=2)C=1>>[N:19]1[N:20]=[C:21]([S:28][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=3)[N:7]=2)[N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Reactant: Sc1nnc2ccccn12
Agent: O=C(Nc1cn2nc(Sc3nnc4ccc(Br)cn34)ccc2n1)C1CC1
Product: CC(C)(C)OC(=O)Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1

Procedure:
The title compound was prepared from tert-butyl 6-iodoimidazo[1,2-b]pyridazin-2-ylcarbamate and [1,2,4]triazolo[4,3-a]pyridine-3-thiol following the procedure for the synthesis of compound 4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]1.[I:22]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:22])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]1
Reactant: II
Reactant: CCOC(=O)CN1CCC(c2ccc(OC)cc2F)CC1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CCOC(=O)CN1CCC(c2cc(I)c(OC)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl [4-(2-fluoro-4-methoxyphenyl)piperidin-1-yl]acetate (Step A; 21.6 mg; 0.073 mmol), iodine (45.6 mg; 0.146 mmol) and silver sulfate (37 mg; 0.146 mmol) in MeOH (1.5 mL) was stirred at room temperature for 2 h. The reaction was filtered through Celite and the filtrate was concentrated in vacuo. The residue was redissolved in ether (25 mL) and washed with H2O (25 mL). The aqueous layer was extracted with ether (3×25 mL) and the combined extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc/hexanes gradient) to afford ethyl [4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidin-1-yl]acetate as a yellow oil. LCMS=421.8 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.61 (d, J=8.3 Hz, 1H), 6.45 (d, J=11.9 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 3.26 (s, 2H), 3.05 (d, J=11.2 Hz, 2H), 2.80 (tt, J=12.0, 3.9 Hz, 1H), 2.33 (t, J=10.6 Hz, 2H), 1.87 (qd, J=12.3, 3.2 Hz, 2H), 1.78 (d, J=12.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([NH2:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[P-](F)(F)(F)(F)F.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCO>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13](=[NH:15])[NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:10]([CH3:12])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: NCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 201.6 %

Procedure:
To a stirred solution of Boc-D-Valine amide (10 g, 46 mMol) in CH2Cl2 (200 mL) was added Triethyloxoniuim hexafluorophosphate (13.0 g, 48 mMol). (The reaction started out as a suspension which gradually cleared.) The reaction was stirred for 48 h at RT, poured into a separatory funnel, washed with 1 N Na2CO3, dried (Na2SO4), filtered and concentrated under vacuum. To the remaining oil was added Benzylamine (5.0 mL, 23 mMol) and EtOH (20 mL). The reaction was stirred at 60° C. for 24 h. After cooling to RT the reaction was evaporated under vacuum. The title compound (14.16 g, >95% pure by LCMS) was obtained without purification as a pale yellow oil which eventually solidified to a waxy solid: MS (ES) m/e 306.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17].O>ClCCl.CC(O)C>[OH:17][CH2:16][C:15]([NH:14][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1])([CH3:19])[CH3:18]
Reactant: CC(C)(N)CO
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: Cc1c(C(=O)NC(C)(C)CO)cccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution of 2-methyl-3-nitrobenzoyl chloride, 0.2 mol, (U.S. Pat. No. 4,065,477) in dichloromethane is added to 0.4 mol of 2-amino-2-methyl-1-propanol (Aldrich Chemical Company) with ice cooling. The mixture is allowed to stand overnight, water added and the solid filtered to give 20.8 g. The organic layer is washed with water, separated and evaporated to give 28.1 g. The two crops of material are combined and dissolved in 2-propanol. The 2-propanol solution is concentrated to give 40.2 g of N-(2-hydroxy-1,1-dimethylethyl)-2-methyl-3-nitrobenzamide; mp 144°-145° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[OH:10][CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(C(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Sodium borohydride (1.04 g, 27.4 mmol) was added to the solution of tert-butyl 4-benzoylbenzoate (1.54 g, 5.46 mmol) in ethanol (50 mL). Then the mixture was stirred at room temperature for 2 hours. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give tert-butyl 4-(hydroxy(phenyl)methyl)benzoate (1.55 g, 100%). 1H NMR (300 MHz, d6-DMSO): δ 7.82 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.36-7.26 (m, 4H), 7.22-7.17 (m, 1H), 6.04 (d, J=3.9 Hz, 1H), 5.76 (d, J=3.9 Hz, 1H), 1.52 (s, 9H).