Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].O.[ClH:6].Cl.Cl.[NH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH2:18][CH:19]([OH:33])[CH2:20][NH:21][CH2:22][CH2:23][NH:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:32]>C(O)(=O)C>[ClH:6].[ClH:6].[NH:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:17][CH2:18][CH:19]([OH:33])[CH2:20][NH:21][CH2:22][CH2:23][NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:32])[C:10]=2[N:9]=[N:1]1
Reactant: Cc1cccc(C)c1NCCNCC(O)COc1cccc(N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2[nH]nnc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.38 g. Sodium nitrite dissolved in 2.2 ml. water are added to a solution, cooled to 0° C., of 9.1 g. 2,3-diamino-1-{2-hydroxy-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propoxy}-benzene trihydrochloride in 12 ml. water and 4.6 ml. glacial acetic acid. After stirring for 2 hours at ambient temperature, the reaction mixture is evaporated to dryness, the residue is taken up in chloroform and the solution is washed with 1M hydrochloric acid and water, dried and evaporated. The residue is recrystallized from ethanol-ethyl acetate, with the addition of active charcoal, to give 2.2 g. (26% of theory) of the desired compound; m.p. 230°-232° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.O=S(Cl)[Cl:19]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([Cl:19])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Solvent: ClCCl
Product: O=C(Cl)c1ccc(CN2CCOCC2)cc1
Yield: 105 %

Procedure:
2.33 g of α-morpholinoparatoluic acid are placed in 30 mL of CH2Cl2 and 3.76 g of SOCl2 are added. The not very homogenous solution is taken to reflux for 48 hours The white precipitate obtained is filtered, washed with CH2Cl2 and dried. 2.65 g of product is obtained (Yield=70%).
Reaction SMILES: [Cl:1][C:2]1[C:28]([CH2:29][CH2:30][OH:31])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:24][CH2:23][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH2:21][CH3:22])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:7][CH2:6]1.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[CH:33]=[CH2:34]>O.C(#N)C>[Cl:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:6][CH2:7][C:8]3([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]4[N:17]=[C:18]([CH2:21][CH3:22])[S:19][CH:20]=4)=[O:15])[CH2:9]3)[CH2:23][CH2:24]2)=[CH:25][CH:26]=[CH:27][C:28]=1[CH2:29][CH2:30][O:31][CH2:34][CH2:33][C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: O
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4Cl)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Triton-B (0.3 molar equivalents of a 40% solution in water) was added to a solution of (9-(2-chloro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-ethylthiazol-4-yl)methanone (limiting reagent) (step c) and tert-butyl acrylate (5 molar equivalents) in acetonitrile (3.4 volumes). The reaction was stirred at ambient temperature for 1 hr. The solvent was evaporated and the residue was partitioned between water (2 volumes) and 2-MeTHF (2 volumes). The layers were separated and the organics were dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. Yield: 94% of theoretical.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N:6][CH:7]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(CCC(=O)O)nc1
Solvent: c1ccncc1
Product: O=C(O)CCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cn1
Yield: 63.4 %

Procedure:
A solution of 3-(5-aminopyrid-2-yl)propionic acid (1.00 g) and 4-chlorobenzenesulphonyl chloride (1.27 g) in pyridine (15 ml) was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in dilute sodium hydroxide (30 ml) and extracted with chloroform (4×50 ml). The aqueous layer was acidified with dilute hydrochloric acid (pH 3) and extracted with ethyl acetate (4×100 ml). The ethyl acetate extracts were combined, dried over magnesium sulphate, the solvent was removed and the residue was recrystallised from acetonitrile to give the title compound (1.30 g). m.p. 144°-146° C.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)(=O)CC.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[C:7]([C:6](=[O:5])[CH2:7][CH3:8])[CH:8]=1
Reactant: CCC(=O)Oc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1cc(Br)ccc1O
Yield: 191.3 %

Procedure:
4-Bromophenyl propionate (115 g) (see Preparation 1) and aluminium chloride (150 g) were heated together at approximately 90° C. for 15 minutes. The solution became dark and hydrogen chloride gas was evolved. After cooling the black mass was carefully added to ice and a brown solid formed. The mixture was extracted with dichloromethane. The organic extract was separated, washed with brine, dried (anhydrous magnesium sulphate) and the solvent removed under reduced pressure to yield 1-(5-bromo-2-hydroxyphenyl)propane-1-one (110 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10](O)([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([Br:29])[CH:20]=3)[C:11]=1[C:12]([NH:14][C:15](=[O:18])[CH2:16][Cl:17])=[NH:13])=[CH:8][CH:7]=[C:6]1[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=21>C1(C)C(C)=CC=CC=1.O>[Br:29][C:21]1[CH:20]=[C:19]([CH:10]2[C:9]3[C:4](=[C:5]4[CH:34]=[CH:33][CH:32]=[CH:31][C:6]4=[CH:7][CH:8]=3)[O:3][C:2]([NH2:1])=[C:11]2[C:12]2[N:14]=[C:15]([CH2:16][Cl:17])[O:18][N:13]=2)[CH:24]=[C:23]([O:25][CH3:26])[C:22]=1[O:27][CH3:28]
Reactant: COc1cc(C2(O)C(C(=N)NC(=O)CCl)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1cc(C2C(c3noc(CCl)n3)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Temperature: 25 °C

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-chloroacetylhydroxy-4H-benzo[h]chromene-3-carboxamidine (23) (137 mg, 0.25 mmol) is taken in 10 ml xylene and refluxed under LC-MS control and is stirred further at room temperature till the reaction is complete. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:16])=[C:4]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(=O)([O-])[O-:18].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([I:16])=[C:4]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:5]([C:8]([NH2:9])=[O:18])=[N:6][CH:7]=1
Reactant: CCC(CC)Nc1c(C#N)ncc(Cl)c1I
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(CC)Nc1c(C(N)=O)ncc(Cl)c1I
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 5-chloro-4-iodo-3-(pentan-3-ylamino)picolinonitrile (55 mg, 0.16 mmol) in DMSO (1 mL) was added solid potassium carbonate (210 mg, 0.64 mmol). The mixture was cooled in an ice water bath (0° C.) and aqueous hydrogen peroxide (30%, 0.5 mL) was added. The reaction was allowed to warm to room temperature and monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with EtOAc, and the organic layer was washed repeatedly with water. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was filtered through a silica gel plug to provide the title compound as a white solid (50 mg, 83%). m/z=368.1 [M+H]+ and 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([F:30])[CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([F:30])[CH:20]=3)[CH3:18])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(F)c1
Reactant: O=C(O)Cn1cnc2cccc(Cl)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2cccc(Cl)c21)c1ccc(C(C)(C)C#N)c(F)c1

Procedure:
The amide is synthesized according to example 1 by mixing (7-chloro-1H-benzimidazol-1-yl)acetic acid (521 mg, 2.48 mmol) prepared according to scheme 1, 2-[4-(1-Aminoethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride 721 mg, 2.97 mmol) prepared according to scheme 7, Et3N (824 μL, 5.95 mmol) and HATU (1.13 g, 2.97 mmol) in DMF (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5 u) 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA), (421 mg as TFA salt, 0.82 mmol, 33%); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38 (d, J=7.03 Hz, 3H), 1.64-1.76 (m, 6H), 4.88-4.98 (m, 1H), 5.27 (s, 2H), 7.18-7.28 (m, 3H), 7.28-7.33 (m, 1H), 7.41 (t, J=8.30 Hz, 1H), 7.65 (d, J=7.81 Hz, 1H), 8.47 (s, 1H), 8.85 (d, J=7.62 Hz, 1H). MS [M+H], calcd: 399.9, found: 399.3.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:27][N:28](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[C:27]([C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cccc(C#N)c2CC1

Procedure:
1,1-dimethylethyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 13) (5 g), zinc (II) cyanide (1.5 g) and tetrakis(triphenylphoshine)palladium(0) (1.5 g) were heated in dry DMF at 150° C. for 18 hours. The cooled reaction mixture was diluted with EtOAc (200 ml) and filtered. The filtrate was washed with saturated sodium bicarbonate, (200 ml), water (200 ml) and brine (200 ml). The crude reaction mixture was dried in the usual manner and evaporated. Purification by chromatography (eluting with DCM) yielded the title compound (3.4 g). δH (400 MHz, CDCl3) 7.50 (1H, d), 7.35 (1H, d), 7.27-7.21 (1H), m), 3.62-3.56 (4H, m), 3.22-3.20 (2H, m), 2.97-2.94 (2H, m), 1.47 (9H, s); MS (ES) C16H20N2O2 requires 272; found 217 [M+H−56]+, 273 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=3)O)[C:5]=2[O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:13]3[NH:14][CH:15]=[N:16][CH:17]=3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2c1OCCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(Cc2cnc[nH]2)c2c(c1)OCCO2
Yield: 72.3 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanol (Intermediate A3) (1 g, 2.11 mmol) in dichloromethane (30 mL) was reacted with TFA:trifluoroacetic acid (5.3 mL, 68 mmol)) and triethylsilane (TES) (2.8 mL, 17 mmol) at rt for 24 h. The mixture was evaporated under reduced pressure and quenched with solid NaHCO3. This material was subjected to an aqueous work-up and the residue was purified by chromatography on silica gel with 5% NH3-MeOH:CH2Cl2 to yield 5-(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-1H-imidazole (Intermediate A4) 330 mg (72%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)(=O)=O.[I-:23].[Na+]>>[I:23][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Product: ICCCc1cccc(OCc2ccccc2)c1
Yield: 85 %

Procedure:
Using 3-[3-(benzyloxy)phenyl]propyl methanesulfonate (19.7 g) and sodium iodide (29.25 g), the same reaction as Reference Example 9-(v) was carried out to yield the titled compound (18.4 g) as an oily substance.
Reaction SMILES: [C:1](=[O:8])([S:5][CH2:6][CH3:7])[O:2][CH2:3]I.[C:9]([O-:14])(=[O:13])[CH2:10][CH2:11][CH3:12].[Na+]>CN(C=O)C>[C:1](=[O:8])([S:5][CH2:6][CH3:7])[O:2][CH2:3][O:14][C:9](=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)[O-]
Reactant: CCSC(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)OCOC(=O)SCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Crude 5b (23.6 g, 96 mmol) is added during 30 min to a stirred suspension of sodium butanoate (10.5 g, 96 mmol) in dry DMF (125 mL) at -20° C. followed by stirring overnight at ambient temperature. After filtration and washing with DMF (5 mL) and Et2O (10 mL),Et2O (250 mL) and ice-cold H2O (100 mL) are added to the combined filtrates. The aqueous phase is separated and extracted with Et2O (100 mL). The combined organic phases are washed (all solutions ice-cold) with 5% aqueous NaHCO3 (50 mL), H2O (50 mL), 0.01N HCl (100 mL), and H2O (2×50 mL). After drying (MgSO4) and evaporation of solvents the residue is distilled to yield 15.0 g (76%) of 6db, bp 75°-80° C./0.5 mbar.
Reaction SMILES: N[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].N([O-])=O.[Na+]>>[S:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:2]=[C:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1sc2cccnc2c1N
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc2ncccc2s1

Procedure:
The synthesis is carried out according to the general procedure; for work-up, the resulting precipitate is filtered off with suction and washed repeatedly with water, ethyl acetate and THF. The organic phases of the resulting filtrates are separated off, the aqueous phase is washed with ethyl acetate and the combined organic phases are dried and concentrated. The resulting product is purified by preparative HPLC. Using 2.40 g (11.53 mmol) of methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate and 2.54 g (36.88 mmol) of sodium nitrite, 0.12 g (5% of theory) of the desired product are obtained.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=O)[CH3:2].[CH2:8]([NH:10][C:11]([NH2:13])=[O:12])[CH3:9].C(O)C.S(=O)(=O)(O)O>CCOCC>[CH2:8]([N:10]1[C:1]([CH3:2])=[CH:4][C:5]([CH3:6])=[N:13][C:11]1=[O:12])[CH3:9]
Reactant: CCNC(N)=O
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: CCn1c(C)cc(C)nc1=O
Reaction time: 240 h

Procedure:
Acetylacetone (9.0 g., 0.09 moles) and ethylurea (7.13 g., 0.081 moles) are dissolved in 30 ml. ethanol. The solution is cooled in an ice-water bath while 30 g. of cold concentrated sulfuric acid is added. The resulting yellow solution is stored at room temperature for 10 days and diluted with a large volume of ether. The ether-ethanol mixture is decanted from the thick syrupy residue which is washed with additional fresh ether. The residue is made basic with 2.5 N sodium hydroxide and extracted throughly with methylene chloride. The organic extracts are dried over sodium sulfate, treated with charcoal, filtered, and evaporated under vacuum affording 1-ethyl-4,6-dimethyl-2(1H)-pyrimidinone as a tan solid (7.6 g., 62%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH2:7].[NH2:9][C:10]1[C:11]([C:18](N2C=CN=C2)=[O:19])=[N:12][C:13]([Cl:17])=[C:14]([NH2:16])[N:15]=1>O1CCCC1>[NH2:9][C:10]1[C:11]([C:18]([NH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH2:7])[CH3:8])=[O:19])=[N:12][C:13]([Cl:17])=[C:14]([NH2:16])[N:15]=1
Reactant: CN(CCN)CCN
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Cl
Solvent: C1CCOC1
Product: CN(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 69354.8 %

Procedure:
To a stirred solution of 84.0 g (0.744 mol) of N-(2-aminoethyl)-N-methyl-1,2-ethanediamine (see U.S. Pat. No. 3,201,472 for a method of obtaining this compound) in 700 ml of tetrahydrofuran was added 88.6 g (0.372 mmol) of 1-(3,5-diamino-6-chloropyrazinoyl)imidazole in 10 portions over 1 5 h. After 1 h at ambient temperature the reaction mixture was filtered and concentrated to 300 ml. The solution was added dropwise to 1.4 liters of ether with vigorous stirring. The solid was filtered, washed with ether and dried. There was obtained 74.3 g (0.258 mol, 70%) of 3,5-diamino-N-[2-[(2-aminoethyl)methylamino]ethyl]-6chloropyrazinecarboxamide. A sample was filtered through a pad of silica gel and eluted with 5:95 (v/v) methanol:methylene chloride saturated with ammonia gas mp 138°-139.5° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=[C:37]2B1OC(C)(C)C(C)(C)O1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:37]3[C:36]4[C:40](=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=4)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and tert-butyl 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (Example 93A) (262 mg, 0.702 mmol) in N,N-dimethylformamide (2.63 mL) was added saturated aqueous bicarbonate solution (880 μL) followed by bis(triphenylphosphine)palladium dichloride (17.26 mg, 0.025 mmol). The mixture was heated to 70° C. for 3 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 689.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cccc(B(O)O)c1C
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4C)c3O2)cc1
Yield: 62.8 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-dimethylphenyl)boronic acid (0.294 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.335 g (62%) of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=[C:10]([O:21][CH3:22])[N:9]=1)=[O:6].C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH3:22][O:21][C:10]1[CH:11]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:13]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[N:9]=1
Reactant: COc1cc(C(=O)OC(C)(C)C)cc(NC(=O)CCCBr)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1cc(C(=O)OC(C)(C)C)cc(N2CCCC2=O)n1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
t-Butyl 2-(4-bromobutyramido)-6-methoxypyridine-4-carboxylate (D56) (0.47 g) was dissolved in dioxan and treated with DBU (0.31 mL; 1 eq.). After stirring for 0.5 h, further DBU (0.31 mL; 1 eq.) was added. Stirring was continued for 2 h and the mixture was poured into citric acid solution (10% aq.) and extracted twice with ethyl acetate. The combined extracts were washed with aq. bicarbonate, water and brine, dried (MgSO4) and evaporated, giving the title compound (D57) as a beige solid (0.275 g).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([C:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].C(O)C.[OH-].[K+]>CCOCC>[C:5]([C:9]1[CH:13]=[CH:12][C:11](=[C:2]([CH3:4])[CH3:1])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)C1=CC=CC1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)=C1C=CC(C(C)(C)C)=C1

Procedure:
Dry acetone (99.3 mmol, 5.77 g, 7.3 mL) and t-butylcyclopentadiene (50.6 mmol, 6.17 g) were mixed in a dropping funnel and added at room temperature to an ethanol solution (10 mL) of KOH (10.3 mmol, 0.58 g) stirring under nitrogen. After stirring overnight, the golden solution was diluted with ether, washed with 2 N HCl, water, and dried over sodium sulfate. A sample of the crude organic fraction (7.4 g) was taken for analysis (GCMS) showing 90% conversion to the title compound. The product was submitted to distillation. 1H-NMR (CDCl3): δ 1.38 (s, 9H), 2.28 (s, 6H), 6.24 (m, 1H), 6.63 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[OH-].[Na+].O.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>COC(C)(C)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
4-Chloroaniline (52.7 kg, 413 mol) was dissolved in a mixture of t-butyl methyl ether (180 kg), 30% aqueous sodium hydroxide (61.6 kg, 463 mol) and water (24.2 kg), then cooled to 15° C. To the resulting slurry was charged trimethylacetyl chloride (52.2 kg, 448 mol) over 1 h, keeping the temperature below 40° C. After stirring 30min at 30° C. the slurry was cooled to -10° C. and held for 2 hours. The product was collected by filtration, washed with a solution of 90/10 water/methanol (175 kg), then dried in vacuo to give 85 kg (97% yield) of the title compound as a crystalline solid: mp 152-153° C.; 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J =9 Hz, 2H) 7.28 (d, J =9 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 176.7, 136.6, 129.1, 128.9, 121.4, 39.6, 27.6.