Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([O:8][CH3:9])[O:4][CH2:5][CH:6]=[O:7].[BH4-].[Na+]>O.CO>[OH:1][CH2:2][C@@H:3]([O:8][CH3:9])[O:4][CH2:5][CH2:6][OH:7]
Reactant: CO[C@H](C=O)OCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CO[C@H](CO)OCCO
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
1,5-dioxo-2(S)-methoxy-3-oxa-pentane (D4) (1.5 g, 11 mmole), prepared as described in "Methods on Carbohydrate Chemistry" Acad. Press., Vol. 1, 445, (1962), was dissolved in a mixture of water (10 ml) and methanol (10 ml) and treated with sodiumborohydride (0.1 g) dissolved in water (2 ml). After 20 minutes the solution was brought to pH 7 with an acidic resin Dowex 50WX2, filtered off and the solvent was removed under reduced pressure to give 1.4 g (Yield 93%) of the title compound. TLC on Kieselgel Plate F254 (Merck), eluting system methylene chloride:methanol (10:1 by volume) brown spot at Rf =0.24 after heating the TLC plate previously sprayed with sulforic acid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH:15]1[CH2:18][CH:17]([C:19]#[N:20])[CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH3:10])[C:11]([N:15]1[CH2:18][CH:17]([C:19]#[N:20])[CH2:16]1)=[O:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: N#CC1CNC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
In a round-bottomed flask were combined Boc-D-alanine (500 mg, 2.64 mmol), azetidine-3-carbonitrile hydrochloride (376 mg, 3.17 mmol), HOBT (445 mg, 2.91 mmol) and HATU (1.11 g, 2.91 mmol). Then added DMF (5 mL) followed by N,N-diisopropylethylamine (1.38 mL, 7.93 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (50% to 100% EtOAc/hexanes) to afford 493 mg (74%) of [(R)-2-(3-cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[C:31]4[C:26](=[C:27]([CH2:32][NH:33][C:34]5[N:39]=[CH:38][CH:37]=[CH:36][N:35]=5)[CH:28]=[CH:29][CH:30]=4)[C:13]4([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.[ClH:40]>>[ClH:40].[ClH:40].[CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[C:31]4[C:26](=[C:27]([CH2:32][NH:33][C:34]5[N:35]=[CH:36][CH:37]=[CH:38][N:39]=5)[CH:28]=[CH:29][CH:30]=4)[C:13]4([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]4)[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CNc5ncccn5)cccc43)c21
Agent: Cl
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CNc5ncccn5)cccc43)c21
Yield: 99 %

Procedure:
A solution of (R)-tert-butyl 1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-((pyrimidin-2-ylamino)methyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (4 mg, 7.58 μmol) and HCl (50.0 μL; 4N in dioxane) was stirred at ambient temperature overnight. The solvent was removed to yield (R)-N-((1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)pyrimidin-2-amine bishydrochloride as a solid (4.0 mg, 7.6 mmol, >99%). 1H NMR (400 MHz, CD3OD) δ 8.77 (s, 1H), 8.59 (br s, 2H), 7.99 (br d, J=6.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 6.98 (t, J=5.1 Hz, 1H), 4.95 (d, J=3.12 Hz, 2H), 4.69 (d, J=10.2 Hz, 1H), 4.26 (d, J=10.5 Hz, 1H), 3.96-3.91 (m, 1H), 3.74-3.71 (m, 1H), 3.64-3.58 (m, 4H), 3.60-3.52 (m, 2H), 3.46 (m, 2H), 3.14-3.10 (m, 2H), 2.95-2.85 (m, 1H), 2.65-2.55 (m, 2H), 1.92 (d, J=12.9 Hz, 114), 1.95-1.88 (m, 2H), 1.27 (m, 6H), 1.13 (d, J=5.9 Hz, 1H). LCMS (APCI+) M+H+428 (100%); Rt=2.49 min. HPLC purity at 254 nm>99%, Rt=1.84 min.
Reaction SMILES: Br[CH2:2][C@H:3]1[C@@:5]2([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]23)[CH2:4]1.Cl.[CH2:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]3[C@@:5]3([CH2:4][C@H:3]3[CH2:2][NH:31][CH2:29][CH3:30])[N:11]=2)=[CH:13][CH:14]=1
Reactant: CCN
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CBr)c1nnc(C)n1-2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Reaction time: 96 h
Yield: 69.6 %

Procedure:
To a solution of (1S,2R)-2-(bromomethyl)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro-[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine](50 mg, 0.108 mmol) in anhydrous N,N-dimethylformamide (3 mL) were added ethanamine hydrochloride (221 mg, 2.71 mmol) and Hunig's base (473 μl, 2.71 mmol) at rt. After 4 days at rt, silica gel was added to the reaction, and the solvent was removed under vacuum. The dry silica gel was packed and the product was purified by chromatography (Hexane/EtOAc 5:5 to 0:10 then DCM/MeOH 10:0 to 9:1). A second chromatography was performed (2-propanol 100% then DCM/MeOH 9:1) to give a tan solid (32 mg). LRMS (M+H)+: 426 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1)=[O:8].[CH3:21][NH2:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:22][CH3:21])[N:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Reactant: CN
Product: CNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-3-(4-(chloromethyl)thiazol-2-yl)urea and excess methylamine (2.0 M solution in tetrahydrofuran) was heated for 15 minutes at 60° C. under microwave irradiation. The volatiles were removed in vacuo and the product was purified by column chromatography (DCM/0-15% NH3 saturated MeOH) to afford the title compound.
Reaction SMILES: O[C:2]12[NH:13][CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=31)[C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=1[C:3]2=[O:18].O1CCOCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O.C(O)(C)C.O1CCCC1>[OH:18][CH:3]1[CH:2]2[NH:13][CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=32)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: O=C1c2ccccc2C2NC1(O)c1ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: O
Product: OC1c2ccccc2C2NC1c1ccccc12

Procedure:
8 g of 10-hydroxy-10,11-dihydro-5,10-imino-[5H]-dibenzo (a,d) cycloheptene-11-one dl were added at 10° C to 400 ml of dioxane containing 16 g of lithium aluminum hydride and the mixture was refluxed for 3 days. 8 g of lithium aluminum hydride were added thereto and the mixture was refluxed for another 48 hours and after cooling, 700 ml of tetrahydrofuran, 150 ml of isopropanol, 50 ml of water and then 250 ml of concentrated hydrochloric acid were added thereto. The tetrahydrofuran and the dioxane were distilled off and 1000 ml of methylene chloride containing 20% methanol were added thereto. The mixture was made alkaline with sodium hydroxide addition and was extracted with methylene chloride containing 20% methanol. The extracts were washed with water, dried over magnesium sulfate and concentrated to dryness. The oil residue was dissolved in methylene chloride and the solution was washed with 2N hydrochloric acid. The combined acid wash waters were made alkaline with sodium hydroxide and extracted twice with ether. The ether solution was washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 92.5-7.5 chloroform-methanol mixture. Crystallization from methylene chloride gave 11-hydroxy-10,11-dihydro-5,10-imino-[5H]-dibenzo (a,d) cycloheptene dl cis melting at 200° and then 210° C.
Reaction SMILES: [P:1](Cl)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:29]=[O:30])=[C:21]2[N:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[CH2:33][CH2:32]2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.O>O1CCCC1>[CH2:4]([O:3][P:1](=[O:2])([O:6][CH2:7][CH3:8])[O:39][CH2:38][CH2:37][N:34]1[CH2:35][CH2:36][N:31]([C:21]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:15][CH:16]=3)[C:28]3[C:23]([C:22]=2[CH:29]=[O:30])=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:32][CH2:33]1)[CH3:5]
Reactant: CC(C)(C)c1ccc(-n2c(N3CCN(CCO)CC3)c(C=O)c3ccccc32)cc1
Reactant: CCOP(=O)(Cl)OCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)OCCN1CCN(c2c(C=O)c3ccccc3n2-c2ccc(C(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Diethyl chlorophosphate (0.22 mL, 1.52 mmol) is added to a solution of 1-(4-tert-butylphenyl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-indole-3-carboxaldehyde (510 mg, 1.26 mmol) and triethylamine (0.35 mL, 2.49 mmol) in tetrahydrofuran (5 mL). The resulting orange solution is stirred overnight at room temperature. Water is added and the mixture is extracted with ethyl acetate. The combined ethyl acetate layers are washed with water, with brine, dried and concentrated to give an oil that is purified by chromatography eluting with ethyl acetate and ethyl acetate-5% methanol to afford the phosphoric acid 2-{4-[1-(4-tert-butylphenyl)-3-formyl-1H-indol-2-yl]-piperazin-1-yl}-ethyl ester diethyl ester (280 mg, 68% yield) as a white powder. ESI/MS 542 (M+H)Rt 3.52 min; 1H NMR 10.13 (1H, s); 8.11 (1H, d, J=6 Hz); 7.66 (2H, d, J=6 Hz); 7.46 (2H, d, J=9 Hz); 7.19 (2H, m); 6.92 (1H, d, 9 Hz); 4.04 (6H, m); 3.33 (2H, br s); 3.26 (4H, br s); 2.49 (4H, br s); 1.36 (9H, s); 1.30 (6H, t).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:31](O)(=[O:33])[CH3:32].C(O)C=O>CO>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][CH:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[C:16]4[CH2:22][N:21]([CH2:32][CH2:31][OH:33])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)O
Reactant: c1ncc(-c2ccc(Nc3nc4c(c(NCC5CCOCC5)n3)CNCC4)cc2)o1
Agent: O=CCO
Solvent: CO
Product: OCCN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NCC3CCOCC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.6 %

Procedure:
N2-(4-(Oxazol-5-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (134 mg, 0.33 mmol, example 85a) was dissolved in methanol (3 mL). Acetic acid (0.019 mL, 0.33 mmol) was added followed by glycoaldehyde (19.80 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 15 minutes and MP—CNBH3 was added. The reaction mixture was stirred overnight, the MP—CNBH3 was filtered off, the solvent was evaporated under reduced pressure, the crude was purified twice by HPLC yielding 2-(2-(4-(oxazol-5-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (38.0 mg, 22.58%) as acetate salt. MS (ES+) m/z 451.3 (M+H)+
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[F:9][C:10]([F:24])([C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:12][OH:13]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:7][CH2:12][CH2:11][C:10]([F:9])([F:24])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])(=[O:8])[C:2]([CH2:4][C:5]([O:13][CH2:12][CH2:11][C:10]([F:24])([F:9])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])=[O:6])=[CH2:3]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=C1CC(=O)OC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(CC(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 68.7 %

Procedure:
13.5 g (0.12 moles) of itaconic anhydride, 69.8 g (0.26 moles) of 3,3,4,4,5,5,6,6,6-nonafluorohexanol, and 1.14 g (6 millimoles) of p-toluene sulfonic acid first hydrate were heated and refluxed in 500 mL of toluene for 12 hours, while distilling off water which was generated therein. Then, the mixture was cooled to room temperature, to this ethyl acetate was added, and an organic phase was washed with 1 mol/L of sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution to obtain 51.3 g (69% yield) of compound as oil-state compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C@H:7]([N:9]1[N:13]=[N:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2[C:20]2[CH:48]=[CH:47][C:23]([C:24]([N:26]([C:40]3[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]3)=[O:25])=[CH:22][CH:21]=2)=[N:10]1)[CH3:8])=[O:5])[CH3:2].Cl.O1CCOCC1>C(#N)C>[C:4](=[O:5])([O:6][C@H:7]([N:9]1[N:13]=[N:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2[C:20]2[CH:48]=[CH:47][C:23]([C:24](=[O:25])[N:26]([C:40]3[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[C@@H:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)=[CH:22][CH:21]=2)=[N:10]1)[CH3:8])[O:3][CH2:1][CH3:2]
Reactant: CCOC(=O)O[C@@H](C)n1nnc(-c2c(-c3ccc(C(=O)N(c4ncccc4C)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cc3)cnn2C)n1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CCOC(=O)O[C@@H](C)n1nnc(-c2c(-c3ccc(C(=O)N(c4ncccc4C)[C@@H]4CCCNC4)cc3)cnn2C)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Preparation 27, tert-butyl (3R)-3-[{4-[5-(2-{(1S)-1-[(ethoxycarbonyl)oxy]ethyl}-2H-tetrazol-5-yl)-1-methyl-1H-pyrazol-4-yl]benzoyl}(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (438 mg, 0.664 mmol) was dissolved in acetonitrile (3.3 mL). To this was added HCl in dioxane (2.49 mL, 4M solution, 15 eq.) dropwise at room temperature. After 1 h, the reaction was concentrated in vacuo, and concentrated with toluene (3×15 mL). The crude material was suspended in EtOAc and heated to 80° C. for 16 h. Filtration of the material provided the hydrochloride salt of ethyl (1S)-1-{5-[1-methyl-4-(4-{(3-methylpyridin-2-yl)[(3R)-piperidin-3-yl]carbamoyl}phenyl)-1H-pyrazol-5-yl]-2H-tetrazol-2-yl}ethyl carbonate (242 mg, 65%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[CH2:10](Br)[CH:11]=[CH2:12].[NH4+].[Cl-]>CCOC(C)=O>[CH2:8]([O:7][C:3](=[O:6])[CH2:4][O:5][CH2:12][CH:11]=[CH2:10])[CH3:9]
Reactant: CCOC(=O)CO
Reactant: C=CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: C=CCOCC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A round-bottom flask was charged with NaH (1.76 g, 44 mmol, 60% dispersion in mineral oil) and flushed with argon. Hexane (10 ml×2) was added and decanted. DMF (10 ml) was added into the flask and the resulting solution was cooled to 0° C. Ethyl glycolate (4.16 g, 40.0 mmol) was added over 10 min. The solution was allowed to gradually warm to 25° C. and was maintained at that temperature for 2H. The solution was cooled to 0° C. and allyl bromide (5.32 g, 44.0 mmol) was added over 10 min. The solution was allowed to gradually warm to 25° C. and stirred at that temperature for 2 h. Aqueous solution NH4Cl (10 ml) was added to the reaction and the mixture was diluted with EtOAc (60 ml). The organic layer was separated and washed with H2O (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by distillation under reduced pressure
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CO.O.CCOC(C)=O>[NH2:1][C:2]1[C:11]([F:23])=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cnc(N)c(Cl)c1Nc1ccc(I)cc1F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-amino-5-chloro-4-(2-fluoro-4-iodophenylamino)nicotinate (2.0 g, 4.74 mmol) (Example 11, step E) in a mixture of MeOH/water (1/1) (20 ml) is added selectfluor (1.6 g, 4.74 mmol). The mixture is stirred at room temperature overnight, diluted with EtOAc and washed with 0.5 N HCl and brine. The organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by HPLC (reverse phase) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[C:22]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])[CH2:23][CH2:24][C:25](OC1C=CC=CC=1)=[O:26].Cl>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(Cc2c[nH]c3ccccc23)c1
Reactant: O=C(CCC(=O)Oc1ccccc1)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCC(=O)n1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.1 %

Procedure:
A solution of 3-(3-nitrobenzyl)indole (280 mg) in N,N-dimethylformamide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 66.6 mg) in N,N-dimethylformamide (10 ml) at 0° C. The mixture was stirred at 25° C. for 40 minutes, and a solution of benzyl phenyl succinate (316 mg) in N,N-dimethylformamide was added at -40° C. After stirred at -40° C. for 20 minutes, the reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over, magnesium sulfate. After evaporation of the solvent, the crude crystals were washed with hot isopropyl ether to give benzyl 4-[3-(3-nitrobenzyl)indol-1-yl]-4-oxobutyrate (364 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[H-].[Na+].I[CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:22])[CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
A solution of 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4a (1.86 g, 6.6 mmole) in THF (150 ml) was cooled to −10° prior to addition of NaH (920 mg, 23 mmole as a 60% by wt. mineral oil dispersion). The resultant mixture was stirred at 0° for 40 minutes. Iodomethane (4 ml, 9.12 g, 64 mmole) was then added to the reaction which was stirred for another 3 hours, gradually warming to room temperature. The crude reaction mixture was quenched with saturated NaHCO3 (150 ml), then extracted with EtOAc (2×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 2.4 g of an amber paste, which was purified by silica gel chromatography. Elution with CH2Cl2: CH3OH (98:2) and evaporation of the appropriate fractions gave 1.64 g (84%) of a yellow solid. 1H NMR (DMSO-d6): δ 8.73 (1H, d, J=5.1 Hz), 8.15 (1H, s), 7.69 (1H, d, J=5.1 Hz), 4.11–3.83 (3H, m), 3.69–3.47 (2H, m), 3.27, 3.24 (3H, s), 2.18–1.93 (2H, m). Anal. Calcd. for C13H23N2O2SCl: C, 52.61; H, 4.42; N, 9.44; S, 10.80; Cl, 11.95. Found: C, 52.76; H, 4.47; N, 9.38; S, 10.84; Cl, 12.01.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:18]1([C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[CH:25][CH:26]=2)[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(N2CCNCC2)ccc1N1CCNCC1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution in methylene chloride (1 ml) of 1,4-bis(4-tert-butoxycarbonyl-1-piperazinyl)benzene (59 mg; 0.13 mmol) synthesized by the above process under ice cooling, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the resultant concentrated residue (81 mg) was dissolved in methanol-chloroform (1:2). The solution was applied to a column packed with alumina (3 g), and the column was eluted with methanol-chloroform (1:2). The eluate was concentrated under reduced pressure, thereby obtaining 31 mg (yield: 88%) of the title compound as a colorless oil.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[O:38])=[CH:33][CH:32]=1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([N:39]4[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]4)=[O:38])=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)nn12
Yield: 38.2 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and (4-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone (0.191 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 73.56 mg of {4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone as a lyophilized powder. (M+H)=443.8. 1H NMR (400 MHz, DMSO, d6) δ 9.74 (s, 1H), 9.00 (s, 1H), 7.76 (m, 3H), 7.48 (m, 1H), 7.33 (d, 2H, J=8.64 Hz), 7.23 (d, 1H, J=8.28 Hz), 7.13 (t, 1H, J=7.48 Hz), 6.97 (m, 2H), 3.81 (s, 3H), 3.06 (m, 4H), 3.26 (m, 2H), 3.07 (m, 2H), 2.83 (s, 3H).