Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[N:10][C:11]([Cl:16])=[CH:12][C:13]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si:22](Cl)([CH3:24])[CH3:23].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[N:10][C:11]([Cl:16])=[C:12]([Si:22]([CH3:24])([CH3:23])[CH3:21])[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C(C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(Oc2ccccc2C(C)(C)C)nnc(Cl)c1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
In dry tetrahydrofuran (15 mL) was dissolved 498 mg (1.70 mmol) of 3-(2-tert-butylphenoxy)-6-chloro-4-methoxypyridazine obtained in Example 31 (1), the solution was cooled to −78° C., 1.10 mL (1.87 mmol) of a n-butyl lithium-hexane solution (1.70M) was added to the solution and the resulting mixture was stirred for 20 minutes. To the mixture was added 0.370 mL (2.91 mmol) of trimethylsilyl chloride, and the resulting mixture was stirred at the same temperature for 10 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, extracted with ether. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography to obtain 596 mg (1.63 mmol, Yield: 95.9%) of 3-(2-tert-butylphenoxy)-6-chloro-4-methoxy-5-(trimethylsilyl)pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[C:15]([O:25][CH2:26][CH3:27])=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:14]([Cl:13])[C:15]([O:25][CH2:26][CH3:27])=[CH:16][C:17]=2[O:23][CH3:24])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: CCOc1cc(OC)c(C(=O)O)cc1Cl
Product: CCOc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)cc1Cl

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-chloro-4-ethoxy-2-methoxybenzoic acid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[S:22][C:23]([CH2:26][NH:27][CH2:28][CH3:29])=[CH:24][N:25]=1.O>CN(C)C=O>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([N:27]([CH2:26][C:23]2[S:22][C:21]([Cl:20])=[N:25][CH:24]=2)[CH2:28][CH3:29])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCOc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CCNCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])c(N(CC)Cc2cnc(Cl)s2)n1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
1.36 g of 2-chloro-6-ethoxy-3-nitropyridine, 10 mL of N,N-dimethylformamide (DMF), and 2.00 g of potassium carbonate were added to a 100 mL single neck flask, under stirring at room temperature, 1.20 g of 2-chloro-5-ethylaminomethylthiazole prepared in the example 1 in 5.0 mL of DMF was added dropwise. After that, the reaction solution was heated to 40-80° C. and reacted for 3-6 hr. After cooling down, the resulting mixture was added to water (50 mL), then treated by the method according to the example 1 to obtain 1.01 g of 6-ethoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridin-2-amine, a viscous liquid, with 98.6% purity, a yield of 43.2%, and the structure was confirmed by GC-Mass and 1H NMR.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:16][N:17](CC)CC.C[Si](C#N)(C)C>C(#N)C.C(Cl)Cl>[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:16]#[N:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1ccc(Cc2ccccc2)cc1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1cc(Cc2ccccc2)ccn1
Yield: 77.2 %

Procedure:
To a solution of 4-benzylpyridine-N-oxide (8.8 g, 48 mmol) in acetonitrile (50 mL) was added Et3N (9.9 mL, 71.2 mmol). Neat trimethylsilyl cyanide (15.8 mL, 118 mmol) was added dropwise. The resulting solution was heated at reflux for 10 h under nitrogen then after cooling, diluted with CH2Cl2 (150 mL). The resulting solution was washed with NaHCO3 (2×150 mL), dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by filtration on silica gel using EtOAc/n-hexane as eluant to afford the title compound as a pale yellow oil (7.2 g, 78%): 1H NMR (CDCl3) δ4.03 (s, 2H), 7.16 (d, J=7.2 Hz, 2H), 7.20-7.40 (m, 4H), 7.49 (s, 1H), 8.59 (d, J=5.1 Hz, 1H); IR (film) 2240, 1600, 1500 cm−1.
Reaction SMILES: CO[C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:27]2[O:31]C3C=CC=CC=3[CH:28]=2)[C:14](=[O:26])[CH:15]=[CH:16][CH2:17][O:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:6][CH:5]=1.[NH2:37][OH:38].CO.[ClH:41]>C1COCC1.O.[OH-].[Na+]>[ClH:41].[O:31]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:28]=[C:27]1[N:13]([C:14](=[O:26])[CH:15]=[CH:16][CH2:17][O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:37][OH:38])=[O:36])=[CH:5][CH:6]=1
Reactant: NO
Reactant: COC(=O)c1ccc(OCCN(C(=O)C=CCOCCN2CCCC2)c2cc3ccccc3o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NO)c1ccc(OCCN(C(=O)C=CCOCCN2CCCC2)c2cc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{2-[3-benzofuran-2-yl-4-(2-pyrrolidin-1-ylethoxy)but-2-enoyl-amino]ethoxy}benzoic acid methyl ester (90 mg, 0.182 mmol) in THF (1 ml), a solution of hydroxylamine in 50% water (1 ml) and 1N NaOH (0.050 ul) were added. Methanol was added dropwise until a homogeneous solution was obtained and the reaction mixture was stirred overnight at rt. After cooling the mixture at 0° C., 6 N HCl was added until pH 7 was reached. The crude solid was filtered and purified by HPLC to give the title compound (17 mg) as white solid. LC/MS, M+1: 494.3; M−1: 492.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1C=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.I([O-])(=O)(=O)=[O:22].[Na+]>[Ru](=O)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:8]2[CH:12]=[N:13][N:14]=[CH:7]2)=[C:4]([CH:3]=1)[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22]
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)cc1nncn12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1

Procedure:
In the manner given in Example 3, 7-chloro-5-phenyl-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-chloro-2-(4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C[Al](C)C.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[C:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])[CH:16]=1.S([O-])([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[CH3:28][C:27]1[O:26][N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]=1[C:22]#[C:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][N:18]=1)[C:14]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:13]
Reactant: Cc1csc(N)n1
Reactant: COC(=O)c1ccnc(C#Cc2c(-c3ccccc3)noc2C)c1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc(NC(=O)c2ccnc(C#Cc3c(-c4ccccc4)noc3C)c2)n1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
To a solution of 2-amino-4-methylthiazole (57 mg, 0.50 mmol) in dioxane (1.2 mL) was added trimethylaluminium (2 M in heptane, 251 μl, 0.50 mmol). The resulting red-brown solution was stirred for 1 h at ambient temperature before 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid methyl ester (40 mg, 0.13 mmol) was added. The reaction mixture was heated for 2.25 h at 110° C. before cooling to ambient temperature. Water (29 μL) was added and the mixture was stirred for 10 min at ambient temperature. Magnesium sulfate was added and the mixture was filtered over Hyflo®. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) was followed by separation between hydrochloric acid (1 M, 30 mL) and ethyl acetate (100 mL). The organic layers were washed with brine, dried over sodium sulfate and were concentrated affording the title compound (48 mg, 96%) as an off-white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:23])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:22])/[CH2:9][CH2:10][C:11](=[O:21])[CH:12]([CH3:20])[CH2:13][S:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([O:1][CH2:2]/[CH:3]=[C:4](/[CH3:23])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:22])/[CH2:9][CH2:10][C:11](=[O:21])[CH:12]([CH3:20])[CH2:13][S:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 300 mg (0.00088 mol) of methyl [[(6E, 10Z)-12-hydroxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]acetate in 5 ml of methylene chloride is treated with 0.5 ml of pyridine and 0.4 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from solvent each time on a rotary evaporator. The residue is chromatographed on silica gel with ether. There is obtained (2Z,6E)-12-[[(methoxycarbonyl)methyl]thio]-3,7,11-trimethyl-10-oxo-2,6-dodecadienyl acetate which exhibits the following bands in the IR spectrum: 1710 cm-1, 1657 cm-1, 1552 cm-1, 1445 cm-1, 1375 cm-1, 1290 cm-1, 1235 cm-1.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=1)[N:7]=3.C(=O)([O-])[O-].[K+].[K+].C(#N)C.O.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][N:46]([CH2:48][CH2:49][O:50]C(=O)C)[CH:47]=2)O1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:22][C:16]1[N:15]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:43]5[CH:44]=[N:45][N:46]([CH2:48][CH2:49][OH:50])[CH:47]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC(=O)OCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(-c3cnn(CCO)c3)cc1OCC2
Temperature: 140 °C
Yield: 17.8 %

Procedure:
To a microwave vial was added 5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine (0.180 g, 0.000462 mol) and potassium carbonate (0.1917 g, 0.001387 mol) in acetonitrile (2.0 mL, 0.038 mol) and water (2.0 mL, 0.11 mol). The reaction was thoroughly degassed and purged with N2 for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.05344 g, 4.624E-5 mol) and Acetic acid 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl ester (0.1554 g, 0.0005549 mol) were added and the vial was sealed immediately. The reaction was heated to 140° C. for 20 minutes in the microwave. The mixture was diluted with methylene chloride and filtered through celite. Saturated NH4Cl was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to give 211 (34.6 mg) as a colorless solid. MS (ESI+) 421.1. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.4, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 7.38 (dd, J=8.4, 1.8, 1H), 7.27 (d, J=1.7, 1H), 5.84-5.69 (m, 1H), 5.19 (s, 2H), 4.93 (t, J=5.3, 1H), 4.50 (s, 4H), 4.16 (t, J=5.6, 2H), 3.77 (q, J=5.6, 2H), 1.42 (d, J=6.6, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].O1CCCC1.C([Li])(CC)C.[C:56](#[N:59])[CH:57]=[CH2:58]>CO.O>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:58][CH2:57][C:56]#[N:59])[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: C=CC#N
Agent: [Li]C(C)CC
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCC#N)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine (0.145 g, 0.23 mmol) and tetrahydrofuran (5 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of s-butyl lithium (0.22 mL, 1.3 M in hexane, 0.28 mmol). After 30 minutes, add acrylonitrile (0.015 g, 0.28 mmol). Allow to warm to ambient temperature and then heat to reflux. After 12 hours, add water and separate the layers. Extract the aqueous layer three times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3/0.5/96.5 methanol/concentrated ammonium hydroxide/dichloromethane to give the title compound: Rf=0.61 (silica gel, 5/0.5/94.5 methanol/concentrated ammonium hydroxide/dichloromethane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1.ClC1N=C(NC2C=CC=CC=2C2N(C)C=CN=2)C(Cl)=CN=1.Cl[C:36]1[N:41]=[C:40]([NH:42][C@@H:43]2[C@@H:48]3[CH2:49][C@@H:45]([CH:46]=[CH:47]3)[C@@H:44]2[C:50]([NH2:52])=[O:51])[C:39]([Cl:53])=[CH:38][N:37]=1.[N+](C1C=CC2CCC(=O)CCC=2C=1)([O-])=O>>[Cl:53][C:39]1[C:40]([NH:42][C@@H:43]2[C@@H:48]3[CH2:49][C@@H:45]([CH:46]=[CH:47]3)[C@@H:44]2[C:50]([NH2:52])=[O:51])=[N:41][C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:13]=2)=[N:37][CH:38]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: Nc1ccc2c(c1)CCC(O)CC2
Agent: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3ccc4c(c3)CCC(O)CC4)ncc2Cl)[C@H]2C=C[C@@H]1C2

Procedure:
Prepared analogously to Example 216d replacing 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine with 2-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol and (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine was replaced with (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide. 2-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol is a byproduct from the reductive amination of 2-Nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one with various amines. The reaction was carried out in the presence of the desired reductive amination product to provide a crude mixture of amino and alcohol products. The crude mix was then reduced and a mixture of amino and alcohol products were used in the synthesis of target compounds. The mixture was then purified by prep HPLC to afford the desired amino compound as well as (1S,2S,3R,4R)-3-[5-Chloro-2-(7-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide. LC/MS (ESI): 440.22. 1H NMR (400 MHz, DMSO, d6) δ 9.12 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.69 (m, 1H), 7.46 (m, 2H), 7.26 (s, 1H), 6.97 (d, 1H, J=8.08 Hz), 6.35 (m, 1H), 6.27 (m, 1H), 4.58 (m, 1H), 4.15 (m, 1H), 3.72 (m, 1H), 3.31 (s, 2H), 2.88 (s, 1H), 2.78 (m, 3H), 2.11 (d, 1H, J=8.59 Hz), 1.89 (m, 2H), 1.41 (d, 1H, J=8.09 Hz), 1.33 (m, 2H).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:35]=[CH:34][C:25]4[C@H:26]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:27][O:28][C:24]=4[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2].CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:36])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:35]=[CH:34][C:25]4[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=4[CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCSCCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)OC)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCSCCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)O)c2)c(C)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
To a solution of methyl [(3S)-6-({4′-[2-(ethylthio)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.358 g, 0.707 mmol) in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (3 mL) was added 2 M aqueous sodium hydroxide solution (0.750 mL), and the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.309 g, yield 89%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][N:9]([S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:29])=[O:28])[CH:10]2[CH:15]3[CH:11]2[CH2:12][N:13]([C:16]2[N:21]=[CH:20][C:19]([C:22]([O:24]CC)=O)=[CH:18][N:17]=2)[CH2:14]3)[CH:4]=[CH:5][N:6]=1.Cl.[NH2:41][OH:42].[O-]CC.[Na+].O>CCO>[OH:42][NH:41][C:22]([C:19]1[CH:20]=[N:21][C:16]([N:13]2[CH2:14][CH:15]3[CH:11]([CH:10]3[N:9]([CH2:8][CH2:7][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[S:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)(=[O:28])=[O:29])[CH2:12]2)=[N:17][CH:18]=1)=[O:24]
Reactant: NO
Reactant: CCOC(=O)c1cnc(N2CC3C(C2)C3N(CCn2ccnc2C)S(=O)(=O)c2ccc3ccccc3c2)nc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nccn1CCN(C1C2CN(c3ncc(C(=O)NO)cn3)CC21)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 50 °C
Yield: 19.7 %

Procedure:
To a solution of ethyl 2-{6-[[2-(2-methylimidazol-1-yl)ethyl](naphthalene-2-sulfonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxylate (0.211 g, 0.38 mmol) in EtOH (6 ml) in a sealed tube, was added hydroxylamine hydrochloride (0.460 g, 6.6 mmol) and sodium ethoxide (0.358 g, 5.3 mmol). The mixture was heated at 50° C. for 18 h, then water (20 ml) was added, and the product extracted with DCM (3×100 ml) and EtOAc (2×100 ml). The combined organic extracts were dried (MgSO4) and concentrated and the product purified by recrystallisation (MeOH) to give the title compound as a white solid (40 mg, 20%). LCMS Purity >98%, m/z 534 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.71 (1H, m), 1.82 (2H, m), 2.34 (3H, s), 3.43-3.55 (4H, m), 3.71 (2H, d, J=11.9 Hz), 4.14 (2H, t, J=6.5 Hz), 6.76 (1H, d, J=1.2 Hz), 7.08 (1H, d, J=1.2 Hz), 7.66-7.76 (2H, m), 7.88 (1H, dd, J=1.8, 10.5 Hz), 8.06 (1H, dd, J=2.0, 7.1 Hz), 8.18 (1H, d, J=8.7 Hz), 8.25 (1H, dd, J=2.0, 8.9 Hz), 8.57-8.62 (3H, m), 8.98 (1H, br s), 11.02 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28](OCC)[O:29]CC)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.03 g) in acetone (50 ml) was added 6 N-hydrochloric acid (5 ml), and the mixture was stirred for 2 hours at room temperature. After adding water (30 ml), the reaction mixture was neutralized with an aqueous sodium bicarbonate solution and acetone was distilled off under reduced pressure. The resultant oily precipitates were extracted with ethyl acetate. The ethyl acetate extracts were washed with water, saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give reddish oil of crude diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.26 g), which was used in a succeeding reaction without further purification.
Reaction SMILES: [H-].C([Al+]C[CH:8]([CH3:10])[CH3:9])C(C)C.[OH2:11].[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[O:11]1[CH2:9][CH2:8][CH2:10][CH2:15][CH:16]1[OH:12].[CH3:14][CH2:13][O:12][CH2:16][CH3:15]
Reactant: C1CCOC1
Reactant: CC(C)C[Al+]CC(C)C
Reactant: O
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOCC
Product: OC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 18.5 g. of the reaction product of part D in 200 ml. of toluene is cooled to -78° C. under a nitrogen atmosphere. Dropwise treatment over 30 min. with 155 ml. of a 0.56 molar solution of diisobutylaluminum hydride and toluene is followed by stirring at -78° C. for an additional 30 min. The resulting mixture is then treated with 45 ml. of water and 70 ml. of tetrahydrofuran, added dropwise. The reaction mixture is then diluted with an additional 300 ml. of toluene and allowed to warm to ambient temperature. Stirring is continued for 2 hrs. at 25° C. The mixture is then filtered through diatomaceous earth. The solids are then washed with benzene and ethyl acetate and the combined filtrate washed with brine, dried over magnesium silfate, and concentrated under reduced pressure to yield crude 3α,5α-dihydroxy-2β-(3α-hydroxy-4-phenyl-trans-1-butenyl)-1α-cyclopentaneacid acetaldehyde γ-lactol, bis(tetrahydropyranol ether). Silica gel TLC R f is 0.55 in ethyl acetate.