Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2][C:3]1[C:4]([C:24]([O-])=[O:25])=[CH:5][C:6]2[O:10][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:23]=1.C[N+](C)=C(N(C)C)O[N:31]1[C:35]2C=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C)C=O>[CH3:2][C:3]1[C:4]([C:24]([N:31]2[CH2:37][CH2:38][CH2:39][CH2:34][CH2:35]2)=[O:25])=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:7]=2[CH:23]=1
Reactant: Cc1cc2c(cc1C(=O)[O-])OC(c1ccccc1)(c1ccccc1)O2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C(=O)N1CCCCC1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 20 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 6-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxylic acid lithium salt (101.5 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)-uronium-hexafluorophosphate (114 mg, 0.3 mmol, 1.0 eq.). The reaction mixture was stirred 1 h at 20° C. Piperidine (26 mg, 0.3 mmol, 1.0 eq.) was added and the reaction mixture was stirred 20 h at 20° C. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine and then dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography afforded the title compound (73 mg, 61%) as a light yellow solid.
Reaction SMILES: [Ge:1](Cl)([Cl:4])([Cl:3])[Cl:2].C[SiH2]O[Si](C)(C)C.[C:13]([OH:17])(=[O:16])[CH:14]=[CH2:15].Cl>CCCCCC>[C:13]([OH:17])(=[O:16])[CH2:14][CH3:15].[Cl:2][GeH:1]([Cl:4])[Cl:3]
Reactant: C=CC(=O)O
Reactant: Cl[Ge](Cl)(Cl)Cl
Agent: C[SiH2]O[Si](C)(C)C
Agent: Cl
Solvent: CCCCCC
Product: CCC(=O)O
Product: Cl[GeH](Cl)Cl
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a 2 L round bottom flask purged with argon was added successively: germanium tetrachloride (200 g [0.9346 mol]), tetramethyl disiloxane (125 g[0.93 mol]), and acrylic acid (70.0 g[0.97 mol]). The reaction flask was purged with argon then sealed by placement of a ground glass stopper with a teflon sleeve and secured via teflon tape. The slightly cloudy mixture changed to a clear, colorless homogeneous solution within about 2 hours, and this was stirred for seven days at ambient temperature. The volatile components were removed via vacuum (0.5 to 5 mmHg) while the product mixture was heated to an internal temperature of 70° C.-80° C., where it was a homogeneous, clear and colorless viscous solution (melt). Evacuation was continued until no more distillate was observed (ca. 2 hours). This was cooled to an ambient temperature to yield a white amorphous solid. To this was added 950 mL of concentrated HCl. The resulting heterogeneous mixture was warmed to an internal temperature of 60° C.-70° C., and stirred for four hours. The cooled mixture was extracted 3 times with 500 mL of dichloromethane. The combined extracts were evaporated under reduced pressure via rotary evaporator to give a while amorphous solid. This was dissolved in ca. 1 L boiling hexane (until a clear colorless homogeneous hot solution was obtained), and let cool gently to ambient temperature. The product, trichlorogermane propionic acid, was isolated via suction filtration, washed once with hexane to give fine prisms, mp 75° C.-79° C. This was immediately taken up (vigorous reaction), with careful addition of 850 mL of ammonium hydroxide (29% ammonia). The resulting turbid mixture was stirred for 4 days at ambient temperature (the mixture changes to a clear, colorless homogeneous solution within 3 hours). To this homogeneous solution was added dropwise over two hours through a reflux condenser 400 mL of concentrated sulfuric acid. NOTE: This is a very vigorous reaction and should be handled with extreme care. A white precipitate formed after addition of ca. 375 mL of acid. The pot was stirred for 48 hours, and then the white solid was isolated via suction filtration, washed successively with 2×150 mL water, 1×150 mL acetone, and 1×200 mL of diethyl ether, then this brilliant white solid was air dried overnight, and then taken up with 150 mL hot water, then cooled and filtered to yield 78.84 g (50%) of analytically pure carboxyethyl germanium sesquioxide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cncnc1N
Product: CCOC(=O)c1cncnc1NC(C)=O
Yield: 59 %

Procedure:
Compound 21 (0.72 g, 4.3 mmol) was mixed with 8 mL of acetic anhydride and the reaction mixture was stirred under reflux for 2 h until no starting material was observed by TLC (4:1 EtOAc/hexanes). The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography (CH2Cl2/EtOAc) to yield 0.53 g of compound 22 in 59% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CC(N(C)C)=O.C1(C)C=CC=CC=1.[CH:24]12[CH2:30][CH:27]([CH:28]=[CH:29]1)[CH:26]1[C:31]([O:33][C:34](=O)[CH:25]21)=[O:32]>O>[O:32]=[C:31]1[CH:26]2[CH:25]([CH:24]3[CH2:30][CH:27]2[CH:28]=[CH:29]3)[C:34](=[O:33])[N:1]1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)c1ccc(N2C(=O)C3C4C=CC(C4)C3C2=O)cc1
Temperature: 165 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To 4-aminobenzoic acid (800 g, 5.83 mol) is added dimethylacetamide (2.5 l), toluene (1 l), and slowly with stirring bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (956 g, 5.83 mol). After the addition the mixture is stirred for 1 hour, raised to 140° C. with removal of water (100 ml) azeotropically and then raised to 165° C. to remove the toluene. The mixture is cooled and the product precipitated into water (3 l). Filtration, washing with water, drying in an oven at 80° C. and recrystallisation from ethanol yields a white crystalline solid (1.56 kg, 94%). M.p.: 224°-228° C.
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1O.[C:10](=[O:13])([O-])[O-].[K+].[K+].[CH3:16]I>CC(C)=O>[CH3:16][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:3]([O:13][CH3:10])[C:2]=1[F:1]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(O)c1F
Reactant: CI
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(OC)c1F
Temperature: 0 °C
Yield: 90.9 %

Procedure:
2-fluoro resorcinol (prepared according to Patrick, T. B., et al., J. Org. Chem (1986), 51, 3242-4) (12.8 g, 100 mmol), potassium carbonate (42 g, 0.3 mol), and methyl iodide (25 mL, 0.4 mol) were mixed with acetone (300 mL) and refluxed for 6 hrs. The reaction was poured into ice-water (500 mL) and extracted in ethyl acetate (500 mL). The ethyl acetate was washed with water (200 mL×2), and brine (200 mL×1), dried over sodium sulfate, filtered, and solvent was removed to yield 14.2 grams (91%) of 1,3-dimethoxy 2-fluoro benzene. This fluoro-benzene intermediate (23.19 g, 148.5 mmoL), N-bromo succinimide (26.52 g, 149 mmol), and 300 uL of 70% aqueous perchloric acid (Aldrich Chemical, 3.4 mmoL) were mixed in carbon tetrachloride (100 mL) and stirred at room temperature for 1 hour. The mixture was filtered, and solvent was removed to obtain a yellow oil. The oil was subjected to silica-gel chromatography (silica gel, hexane mobile phase) to yield 33.28 grams (95%) of the 1,3-dimethoxy-4-bromo-2-fluorobenzene 12 compound as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16](=C(O)C)[C:17](=O)[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=O.C(NC(C)C)(C)C.[Li]>>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16]2[C:29]([C:28]([F:27])([F:34])[F:35])=[N:3][N:2]([CH3:1])[C:17]=2[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNN
Reactant: CC(O)=C1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]
Solvent: CC(C)NC(C)C
Product: Cn1nc(C(F)(F)F)c2c1CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using methylhydrazine and 9-(4-chlorophenylsulfonyl)-2-(1-hydroxyethylidene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 using ethyl trifluoroacetate and lithium diisopropylamine. See also: Ferrer, Leticia Oliveira; Margaretha, Paul. Chemical Communications 2001, (5), 481-482.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[CH:16][C:15]=2[F:33])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:35][OH:36])=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[CH:16][C:15]=2[F:33])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NO
Reactant: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCOc1nc(Br)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Compound A (4.7 g, 9.0 mmol), hydroxylamine hydrochloride (943 mg, 13.6 mmol), pyridine (60 mL, 740 mmol), and water (30 mL, 1.7 mol) were combined and stirred at room temperature overnight. Additional water (30 mL) was added, and the solids were filtered, washed with water, and dried to yield compound B (4.4 g) as a white solid, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7]O)[CH:6]=1.S(Cl)([Cl:11])=O>ClCCl>[ClH:11].[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][Cl:11])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCn1cc(Br)cn1
Solvent: ClCCl
Product: Cl
Product: ClCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.97 g of 4-bromo-1H-pyrazole-1-ylmethanol was dissolved to 100ml of dichloromethane. 5 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 3.27 g of 4-bromo-1-(chloromethyl)-1H-pyrazole hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:27])[CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:28])=[CH:4][N:3]=1.Cl.[CH3:30][N:31]1[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:28][C:5]1[C:6]([N:8]([CH3:27])[CH:9]2[CH2:26][CH2:25][C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[N:3][CH:4]=1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a suspension of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (241 mg, 0.56 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (172.32 mg, 1.29 mmol) in butan-1-ol (5 mL) was added DIPEA (217.14 mg, 1.68 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight, then cooled down to rt, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the title compound as a white solid (198 mg, 72%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][CH2:24][CH2:25][N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:29]=2[CH2:28][CH2:27]1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:37][C:34]2[CH:35]=[CH:36][C:29]3[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:32][CH2:31][C:30]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(OC)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cccc(O)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-3-hydroxy-N-methyl-benzamide was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methoxy-N-methyl-benzamide and 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (preparation in Example 34b) in an analogous manner to Example 1221d. Title product isolated as a white foam (10 mg, 15%), HPLC purity 99%. LCMS 497.09 (M+H), 1H-NMR (CDCl3, 400 MHz) δ:10.79 (s, 1H), 8.06 (s, 1H), 7.20-7.09 (m, 5H), 7.01 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.25 (d, J=4.8 Hz, 1H), 3.56 (d, J=5.6 Hz), 3.38 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.97-2.75 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[C:13]([S:16][CH2:17][CH:18]([S:22][CH3:23])[C:19](Cl)=[O:20])(=[O:15])[CH3:14].SCC(SC)C(N1[C@H](C(O)=O)CC2(C(=O)CCC2=O)C1)=O>>[C:13]([S:16][CH2:17][CH:18]([S:22][CH3:23])[C:19]([N:6]1[CH2:7][C:3]([O:11][CH3:12])([O:2][CH3:1])[CH2:4][C@H:5]1[C:8]([OH:10])=[O:9])=[O:20])(=[O:15])[CH3:14]
Reactant: CSC(CSC(C)=O)C(=O)Cl
Reactant: COC1(OC)CN[C@H](C(=O)O)C1
Agent: CSC(CS)C(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(CSC(C)=O)SC)C1

Procedure:
4,4-Dimethoxy-L-proline is reacted with 3-(acetylthio)-2-(methylthio)propionic acid chloride according to the procedure of Example 3 (d) to yield 1-[3-(acetylthio)-2-methylthio-1-oxopropyl]-4,4-dimethoxy-L-proline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][NH:22][CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].CCN(C(C)C)C(C)C>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][N:22]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCNC4)no2)cc1Cl
Reactant: CCOC(=O)CCBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN1CCOc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2C1
Yield: 93.1 %

Procedure:
A mixture of 8-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (Example 13) (0.036 g, 0.199 mmol), ethyl 3-bromopropanoate (0.084 g, 0.199 mmol) and DIPEA (0.097 ml, 0.557 mmol) was stirred and heated at 80° C. for 4 hours when a further portion of ethyl 3-bromopropanoate (0.084 g, 0.199 mmol) and DIPEA (0.097 ml, 0.557 mmol) were added and heated overnight when a further portion of ethyl 3-bromopropanoate (0.084 g, 0.199 mmol) and DIPEA (0.097 ml, 0.557 mmol) were added and heated for 3 more hours when all starting material gone. The cooled reaction mixture was diluted with EtOAc/water (30 ml of each) and the organics dried (magnesium sulphate), evaporated and purified by flash chromatography eluting with 1:1 EtOAc/iso-hexane to give the title compound (90 mgs) as a colourless gum. MS (ES) C25H2835ClN3O5 requires 485; found 486 [M+H]+.
Reaction SMILES: [C:1]1([CH2:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:14].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)Cl>[Br:14][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2ccccc12
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: BrCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-naphthylmethanol (3.2 g) was taken up in CH2Cl2 (10 mL) and cooled to 0° C. Phosphorus tribromide (25 mL, 1 M in CH2Cl2) was added drop wise and allowed to stir at RT for 2 h. Saturated sodium bicarbonate and sodium hydroxide was added slowly until alkaline. The organic layer was separated, dried over sodium sulfate, and evaporated under reduced pressure to give an off-white solid (4.4 g). Proton NMR was sufficient for the next step.
Reaction SMILES: [C:1]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)([O:3][CH3:4])=[O:2].[C:18]1([CH:25]=C[CH:23]=[C:21](O)[CH:20]=1)[OH:19].P(Cl)(Cl)(Cl)=O.O>C1(C)C=CC=CC=1>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]1[C:1](=[O:2])[O:3][C:4]3[CH:25]=[C:18]([OH:19])[CH:20]=[CH:21][C:23]=3[C:6]=1[CH2:7][CH2:8]2
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)C1C(=O)CCc2cc(OC)ccc21
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2c(c1)CCc1c-2c(=O)oc2cc(O)ccc12
Temperature: 80 °C
Yield: 70.8 %

Procedure:
To a solution of 1-carbomethoxy-6-methoxy-2-tetralone (see, Colvin, Martin, and Shroot, Chemistry and Industry, 2130 (1966)) (18.0 g, 76.8 mmol) and resorcinol (8.9 g, 80.7 mmol) stirring at ambient temperature in toluene (450 mL) was added phosphorus oxychloride (12.0 g, 7.3 mL, 18.3 mmol) dropwise, and the mixture warmed to 80° C. for 12 h. After cooling to room temperature, the mixture was poured into water (500 mL) and filtered, rinsing the precipitate with ether. The filtrate layers were separated, the aqueous layer was extracted with ethyl acetate (3×500 mL), and the combined organic layers were dried (sodium aulfate) and concentrated. Recrystallization of the residue from methanol provided 16.0 g of the title compound as a yellow solid, mp 244-249d° C.: 1H NMR (300 MHz, DMSO-d6) d 10.55 (br s, 1H), 8.24 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 6.6-7.0 (m, 4H), 3.76 (s, 3H), 2.8-3.0 (m, 4H); 13C NMR (125 MHz, DMSO-d6) d 170.3, 160.3, 158.3, 158.1, 153.3, 147.7, 137.5, 127.4, 125.8, 122.5, 114.5, 112.6, 112.4, 110.9, 101.4, 54.6, 26.3, 22.7; IR (KBr) 3250, 1676, 1618 cm-1 ; MS (FD+) m/e 294 (M+); Anal. calc'd. for C18H14O4 : C, 73.45; H, 4.80. Found: C, 73.15; H, 4.86.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[C:26]([O:32][CH3:33])[CH:25]=1)[CH:22]=[CH2:23]>>[CH2:21]([C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([Cl:20])[C:6]([NH:9][C@@H:10]4[C@@H:15]5[CH2:16][C@@H:12]([CH:13]=[CH:14]5)[C@@H:11]4[C:17]([NH2:19])=[O:18])=[C:7]3[N:8]=2)=[C:26]([O:32][CH3:33])[CH:25]=1)[CH:22]=[CH2:23]
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: C=CCc1ccc(C=O)c(OC)c1
Product: C=CCc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c(OC)c1
Yield: 12 %

Procedure:
In a similar fashion as for the synthesis of III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-allyl-2-methoxybenzaldehyde were reacted to produce the title compound as a yellow solid (12%). Mp. 123-6° C. 1H NMR (d-chloroform): 10.83 (br s, 1H), 8.32 (d, J=8 Hz, 1H), 8.02 (s, 1H), 7.00 (d, J=7 Hz, 1H), 6.91 (s, 1H), 6.46-6.31 (m, 3H), 6.00 (m, 1H), 5.55 (d, J=10 Hz, 1H), 5.28-5.12 (m, 4H), 4.05 (s, 3H), 3.48 (d, J=7 Hz, 1H), 3.18 (s, 1H), 2.91 (s, 1H), 2.87 (d. J=7 Hz, 1H), 2.35 (d, J=8 Hz, 1H), 1.75 (d, J=8 Hz, 1H). MS: 449.9 (M+H). HPLC retention time: 2.94 minutes (G Method).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C@H:9]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCOCC1.[OH:36][C:37]([CH3:42])([CH3:41])[C:38](=O)[CH3:39].[BH3-]C#N.[Na+]>CO>[CH3:28][O:27][C:25](=[O:26])[C@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH:19][C:17](=[O:18])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][CH:38]([CH3:39])[C:37]([OH:36])([CH3:42])[CH3:41]
Reactant: CC(=O)C(C)(C)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(C)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of TFA-Phe-Leu-OMe (0.56 mmol) in MeOH was added N-methylmorpholine (0.93 mL, pH=7), 3-hydroxy-3-methyl-2-butanone (0.84 mmol), and NaCNBH3 (0.72 mmol) under a N2 atmosphere. The reaction mixture was stirred overnight at room temperature and quenched with 50 mL of saturated NaHCO3. The aqueous layer was extracted 3 times with EtOAc (25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and then flash chromatographed (1-3% MeOH/CH2Cl2 ; SiO2 gel) to yield 0.17 g (80% yield) of N-(2-hydroxy-2-methyl-1-methylpropyl)-L-phenylalanyl-L-leucine methyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].FC(F)(F)C([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=1[CH2:29][CH3:30])=O.C(N(CC)CC)C>ClCCl>[CH2:29]([C:20]1[C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][NH:16][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[CH3:30]
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: CCc1c(CCNC(=O)C(F)(F)F)ccc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1c(CCNC(=O)CCCCC(=O)OC)ccc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.3 %

Procedure:
A solution of 6-chloro-6-oxohexanoic acid methyl ester (10 g) in dry dichloromethane (100 ml) was added dropwise to a stirred, cooled solution of Intermediate 2 (10.4 g) and triethylamine (5.65 g) in dry dichloromethane (100 ml). The reaction mixture was stirred for 1 h at room temperature, the solvent was removed in vacuo and the residue was purified by FCC using ether as eluent to give the title compound (15 g) as a white solid, m.p. 37°-39°.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].[NH2:26][C:27]1[N:28]=[C:29]([CH3:32])[S:30][CH:31]=1>>[CH3:13][S:14]([C:17]1[CH:18]=[C:19]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:26][C:27]3[N:28]=[C:29]([CH3:32])[S:30][CH:31]=3)=[N:3][CH:4]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1nc(N)cs1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Product: Cc1nc(Nc2ncc(-c3cccc(S(C)(=O)=O)c3)c3sc(C)nc23)cs1

Procedure:
The title compound, MS: m/e=417.2 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), (3-methylsulfonylphenyl)boronic acid and 4-amino-2-methylthiazole (Example C).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][C:10](=[CH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>[OH-].[OH-].[Pd+2].CO>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A mixture of the compound from step 3 (21.0 g, 71.7 mmol), Pd(OH)2 (3.0 g, 20% on C), methanol (500 ml) and 2N HCl (37 ml) was hydrogenated on a Parr shake apparatus for 2 h. The catalyst was removed by filtration through celite and the solvents removed under vacuum. Saturated K2CO3 solution was added (50ml) and extracted with CH2Cl2 (2×250 ml). The combined extracts were washed with H2O (250 ml) and brine (100 ml), dried (Na2SO4) and evaporated to give the title-product as a pale yellow oil (19.3 g); δ (360 MHz, CDCl3) 2.58 (2H, d, J=7.3 Hz, CH2), 2.75-2.81 (3H, m, 2 of CH of CH2 and CH), 3.35-3.38 (2H, m, 2 of CH of CH2), 3.62 (3H, s, CO2Me), 4.31 (1H, s, CH), 7.14-7.18, 7.23-7.27 and 7.38-7.40 (total 10H, each m, Ar--H).