Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([CH2:24][CH:25]([CH3:27])[CH3:26])([CH:13]([C:21]([CH3:23])=[CH2:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]1=[O:28])=O)(C)(C)C.C[O-].[Mg+2].C[O-]>CO>[CH3:26][CH:25]([CH3:27])[CH2:24][C:10]1([CH:13]([C:21]([CH3:23])=[CH2:22])[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:11][CH2:12][NH:8][C:9]1=[O:28]
Reactant: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(C(=O)OC(C)(C)C)C1=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCNC1=O
Yield: 117.4 %

Procedure:
A solution of tert-butyl N-tert-butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-α-(propen-2-yl)-3-pyrrolidineacetate (5.40 g, 13.7 mmol) in MeOH (70 mL) is treated with magnesium methoxide (74.7 mL, 68.5 mmol, 10.3 wt % in MeOH). The resultant solution is stirred under N2 at room temperature for 16 hours. The solution is quenched with 1:1 glacial AcOH/H2O (100 mL). The solution is reduced to a minimal volume under reduced pressure, and the unprotected lactam is extracted into CH2Cl2 (3×100 mL). The organic layers are combined, washed with saturated NH4Cl (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4.75 g of a gold oil. The oil is purified by silica gel chromatography (100 g SG, 25% EtOAc/hexane) to yield 3.85 g (96%) of the title compound as an off-white, low-melting solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20](=O)[O:21]C2C=CC([N+]([O-])=O)=CC=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].CN1CCOCC1>C(Cl)Cl>[C:20](=[O:21])([O:19][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=1)[O:9][CH2:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(CO)CC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 90 h
Yield: 73.6 %

Procedure:
(1-Methylpiperidin-4-yl)methanol (2.50 g, 19.3 mmol) in DCM (50 mL) was added to a solution of bis-(4-nitrophenyl)carbonate (7.06 g, 23.2 mmol) in DCM (100 mL), followed by NMM (1.70 mL, 15.5 mmol). The reaction mixture was stirred for 90 hours and then washed sequentially with aliquots of 1 M aq Na2CO3 solution until the aqueous layer was colourless. The organic layer was dried (MgSO4) and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (4.18 g, 73%) as a yellow solid.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[C:20]1([CH2:30]Br)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][CH2:30][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:10]1
Reactant: BrCc1cccc2ccccc12
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3cccc4ccccc34)[C@@H](CO)O2)cc1F
Yield: 17.8 %

Procedure:
The general procedures of Examples 4 and 5 were followed using 1.3 g of potassium hydroxide, 1.00 g of 2'-deoxy-5-fluorouridine and 2.7 g of 1-naphthylmethyl bromide, thereby producing 0.28 g of the title compound in a yield of 18%.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15]CC)=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Agent: Cl
Solvent: CO
Product: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
35 ml of 5N NaOHaq was added to a solution of 15.15 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate in MeOH and the mixture was stirred at 60° C. for 8 hrs. The mixture was cooled to 0° C. and 35 ml of 5N HCl was added thereto. The precipitate was filtered and dried in vacuo to give 13.8 g of 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylic acid as a colorless solid.
Reaction SMILES: NC1C(N)=C(C2C=CC(C)=CC=2)C=CC=1C.N[C:18]1[C:19]([N+:25]([O-:27])=[O:26])=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1.[I-:28].[K+].N(O)=O>>[I:28][C:18]1[C:19]([N+:25]([O-:27])=[O:26])=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1
Reactant: [I-]
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Agent: Cc1ccc(-c2ccc(C)c(N)c2N)cc1
Agent: O=NO
Agent: [K+]
Product: Cc1cccc(I)c1[N+](=O)[O-]

Procedure:
The diaminodimethylbiphenyl from which the present synthesis is initiated is not commercially available, however, the compound can be prepared by the method reported by Carlin and FOltz wherein aminonitrotoluene is reacted with potassium iodide in the presence of nitrous acid to give iodonitrotoluene. Two moles of the iodonitrotoluene are reacted then in the presence of copper powder to produce dinitrodimethylbiphenyl. Subsequent reduction with hydrogen in the presence of a catalyst produces the corresponding amino compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[C:4]([O:14]C)[C:3]=1[C:16]1[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[CH:18][CH:17]=1.FC1C=CC=C(OC)C=1C1N=NC(N(C)C2CC(C)(C)NC(C)(C)C2)=C(C2C=NN(C)C=2)C=1.B(Br)(Br)Br.Cl>C(Cl)Cl.CO>[F:1][C:2]1[C:3]([C:16]2[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]3[CH2:24][C:25]([CH3:31])([CH3:32])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]3)=[CH:18][CH:17]=2)=[C:4]([OH:14])[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: COc1cc(-c2cnn(C)c2)cc(F)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: BrB(Br)Br
Agent: COc1cccc(F)c1-c1cc(-c2cnn(C)c2)c(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CN(c1ccc(-c2c(O)cc(-c3cnn(C)c3)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h
Yield: 15 %

Procedure:
A mixture of 6-(2-fluoro-6-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine and 6-(2-fluoro-6-methoxyphenyl)-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (0.03 g, 0.07 mmol, total amount of the 2 regioisomers) was dissolved in CH2Cl2 (0.2 M). A 1 M solution of BBr3 in CH2Cl2 (0.3 mL, 3.5 mmol) was rapidly added. The reaction mixture was stirred for 3 h. MeOH was added to the reaction at 0° C. then the solvent was concentrated under reduced pressure. The crude material was purified via reverse phase preparative HPLC (15 to 45% acetonitrile in water, 5 mM ammonium hydroxide as modifier). The solvent was concentrated in vacuo and the resulting solid was suspended in CH3CN/H2O (4/1 mL). 1 M aqueous HCl (3 equivalents) was added and the volatiles were concentrated in vacuo to afford the hydrochloride salt of 3-fluoro-2-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol as a yellow solid (5 mg, 15%). LCMS Rt=0.50 min [Method Q]; [M+H]: 439.4; 1H NMR (400 MHz, DMSO) δ 9.20 (d, J=12.0 Hz, 1H), 8.29 (d, J=12.0 Hz, 1H), 8.23 (s, 1H), 8.04 (d, J=9.5 Hz, 1H), 7.92 (s, 1H), 7.79 (bs, 1H), 7.09 (dd, J=12.0, 1.5 Hz, 1H), 7.04 (s, 1H), 4.92 (bs, 1H), 3.88 (s, 3H), 3.03 (s, 3H), 2.05 (t, J=13.0 Hz, 2H), 1.81 (dd, J=13.0, 3.5 Hz, 2H), 1.53 (s, 6H), 1.49 (s, 6H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:25]3[S:24][C:23]([NH:26][C:27]([C:29]4[S:30][C:31]([CH3:34])=[CH:32][CH:33]=4)=[O:28])=[N:22][C:21]=3[C:20]([O:35][CH3:36])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.B(F)(F)F.CCOCC.C(S)C>ClCCl>[CH3:36][O:35][C:20]1[C:21]2[N:22]=[C:23]([NH:26][C:27]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[O:28])[S:24][C:25]=2[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCS
Product: COc1ccc(N2CCNCC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Reaction time: 36 h
Yield: 58 %

Procedure:
To a solution of 4-{4-methoxy-2-[(5-methyl-thiophene-2-carbonyl)-amino]-benzothiazol-7-yl}-piperazine-1-carboxylic acid benzyl ester (300 mg, 0.57 mmol) in dichloromethane (5 ml) were added boron trifluoride diethyl etherate (0.72 ml, 5.7 mmol) and ethane thiol (1.2 ml, 17 mmol) and the mixture stirred for 36 h. The volatile components are evaporated and the residue codistilled twice with toluene. The residue was dissolved in dichloromethane (25 ml), extracted with 1N aqueous sodium carbonate and the organic phase dryed with Na2SO4. Removal of the solvent and flash chromatography (silica, eluent CH2Cl2/MeOH/aqu. NH4OH 100:10:1) afforded the title compound as light yellow solid (58%), MS: m/e=389 (M+H+).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24].C(Br)(Br)[Br:28].N(OCCCC)=O>C(#N)C>[Br:28][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: BrC(Br)Br
Agent: CCCCON=O
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Temperature: 70 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-trimethylsilylethynylpyrazole (30 mg, the compound of Example A2) in acetonitrile (0.5 ml) and bromoform (0.5 ml) was added dropwise over five minutes n-butyl nitrite (0.025 ml). The mixture was heated at 70° C. for 30 minutes, then cooled and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane: hexane (1:4) to provide the title compound as a white solid m.p. 130° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28].C(N(CC)CC)C.C1COCC1.C([O:50][CH2:51][C:52](Cl)=[O:53])(=O)C>C(OCC)(=O)C>[OH:53][CH2:52][C:51]([N:32]1[CH2:33][CH2:34][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:31]1)=[O:50]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1c(C(=O)NC2CCNC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1c(C(=O)NC2CCN(C(=O)CO)C2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
To a mixture of the thus-obtained 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-pyrrolidin-3-yl-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxamide (153 mg, 0.327 mmol), triethylamine (99.7 μL, 0.720 mmol) and THF (3 mL) was added acetoxyacetyl chloride (38.7 μL, 0.360 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). The obtained oil was dissolved in THF (4 mL) and ethanol (12 mL), 8N aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with water, acidified with 1N hydrochloric acid (8.5 mL), and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=10/0-9/1). Recrystallization of the obtained solid from ethyl acetate-THF gave the title compound (121 mg, 72%) as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:32][C:31]2[C:12](=[CH:13][C:14]3[N+:19]([O-:20])=[N:18][C:17]([CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:16][C:15]=3[CH:30]=2)[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[N:24]1([CH2:23][CH2:22][CH2:21][C:17]2[N:18]=[N+:19]([O-:20])[C:14]3[CH:13]=[C:12]4[C:31]([CH2:32][CH:10]([CH2:9][OH:8])[CH2:11]4)=[CH:30][C:15]=3[N:16]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2cc3nc(CCCN4CCOCC4)n[n+]([O-])c3cc2C1
Agent: Cl
Solvent: CO
Product: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CC(CO)C3
Yield: 96.9 %

Procedure:
A solution of silyl ether 139 (488 mg, 1.07 mmol), and 1 M HCl (1.18 mL) in MeOH (30 mL) was stirred at 20° C. for 3 h. The solvent was evaporated and the residue was crystallised from MeOH/EtOAc to give alcohol 140 (357 mg, 88%) as the hydrochloride salt: mp (MeOH/EtOAc) 210-212° C.; 1H NMR [(CD3)2SO] δ 11.19 (s, 1H, HCl), 8.16 (s, 1H, H-9), 7.80 (s, 1H, H-5), 4.70 (br s, 1H, OH), 3.75-3.99 (m, 4H, 2×CH2O), 3.41 (d, J=6.6 Hz, 2H, CH2O), 3.33-3.51 (m, 2H, CH2N), 3.11-3.27 (m, 4H, CH2N, H-8), 2.87-3.11 (m, 6H, 2×CH2N, CH2), 2.59-2.71 (m, 1H, H-7), 2.22-2.32 (m, 2H, CH2); 13C NMR [(CD3)2SO] δ 163.6, 154.2, 148.4, 146.7, 131.8, 122.5, 113.8, 63.5, 63.0 (2), 55.0, 50.9 (2), 41.6, 35.4, 35.1, 33.1, 20.8. Anal. calcd for C18H24N4O3.HCl.¼CH3OH: C, 56.4; H, 6.7; N, 14.4. Found: C, 56.3; H, 6.4; N, 14.6%.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>CN(C=O)C>[CH:39]1([C:42]([N:22]2[CH2:23][C:18]3[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])=[N:16][C:15]([C:12]4[CH:13]=[CH:14][C:9]([NH:8][C:6]([NH:5][CH:2]5[CH2:3][CH2:4]5)=[O:7])=[CH:10][C:11]=4[F:31])=[N:20][C:19]=3[CH2:21]2)=[O:43])[CH2:41][CH2:40]1
Reactant: O=C(Cl)C1CC1
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)C1CC1)C2
Temperature: 20 °C
Reaction time: 0.03 h

Procedure:
To a stirring solution of (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) (112 mg, 0.25 mmol) in DMF (2 ml), was added Et3N (70 μL, 0.5 mmol). Reaction mixture was stirred at room temperature (20° C.) for 2 minutes followed by the addition of cyclopropanecarbonyl chloride (23 μL, 0.25 mmol) followed by stirring at room temperature for two hours. The reaction mixture was concentrated in vacuo before partitioning between water (10 ml) and DCM (10 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at high pH to afford the title compound as an off white solid (25 mg, 0.052 mmol, 21%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[S:26])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1cccc(F)c1)c1ccccn1
Solvent: Cc1ccccc1
Product: Fc1cccc(NC(=S)c2ccccn2)c1
Yield: 48.4 %

Procedure:
N-(3-Fluorophenyl)-2-pyridinecarboxamide (13.0 g, 60 mmol) and Lawesson's reagent (29.2 g, 72 mmol) were refluxed in toluene (180 mL) for 3 hours. The residue obtained after evaporating the solvent was flash chromatographed on silica gel (eluted with 2% ethyl acetate in petroleum ether) and then recrystallized from a mixture of dichloromethane and hexanes to yield a N-(3-fluorophenyl)-2-pyridinecarbothioamide as a yellow solid (6.75 g, 48%) m.p. 72°-76° C.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]#[N:13])[NH:9]2)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[C:23]3[CH:30]=[C:29]([CH2:31][C:32]([F:35])([F:34])[F:33])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:17][CH2:16]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]#[N:13])[NH:9]2)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22]2[C:23]3[CH:30]=[C:29]([CH2:31][C:32]([F:34])([F:35])[F:33])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:19][CH2:20]1
Reactant: COc1cc2[nH]c(C#N)cc2cc1CN1CCC(Nc2ncnc3sc(CC(F)(F)F)cc23)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)c(O)cc2[nH]1
Yield: 61.7 %

Procedure:
500 mg of 6-methoxy-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (1 mmol) was slowly added to 5 mL of 1M BBr3 in DCM at 0 degrees and reaction mixture was brought to RT. After 4days ice was added to reaction mixture in the presence of sodium bicarbonate. Volatile organic was evaporated and the residue was partitioned between water and ethyl acetate-methanol 10:1. Organic layer was evaporated with silica gel and loaded on the column. The product was eluted with hexane-ethyl acetate-methanol 1:1:0.1, evaporation of fractions produced 300 mg of 6-hydroxy-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (Compound 182). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. Monohydrochloride salt exists as a mixture of rotomers in approximate ratio 10:1, NMR is described for the major one: 1H NMR (600 MHz, MeOD-d4): 8.70 (s, 1H), 7.81 (s, 1H), 7.77 (s, 1H), 7.21 (s, 1H), 6.98 (s, 1H), 4.64 (m, 1H), 4.48 (s, 1H), 4.01 (q, 2H, J=10.3 Hz), 3.66 (m, 2H), 3.35 (m, 2H), 2.37 (m, 2H), 2.12 (m, 2H). 13C NMR (150 MHz, MeOD-d4): δC 157.64, 156.62, 153.92, 141.09, 130.54, 127.75, 127.48, 125.65, 121.96, 121.59, 118.27, 115.23, 114.85, 113.98, 107.11, 97.45, 57.78, 52.88, 47.29, 35.54 (q, J=33 Hz), 29.95. ESI MS [MH+]: 487.1519.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[CH2:11]([N:13]([CH2:18][CH3:19])[C:14](=[O:17])[CH2:15][OH:16])[CH3:12].[OH-].[K+].C(O)(C)C>O>[CH2:11]([N:13]([CH2:18][CH3:19])[C:14](=[O:17])[CH2:15][O:16][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1)[CH3:12]
Reactant: CCN(CC)C(=O)CO
Reactant: FC(F)(F)c1nsc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCN(CC)C(=O)COc1nc(C(F)(F)F)ns1
Temperature: -10 °C
Reaction time: 10 h
Yield: 47.1 %

Procedure:
5.6 g (0.03 mol) of 5-chloro-3-trifluoromethyl-1,2,4-thiadiazole are added to a mixture which comprises 4 g (0.03 mol) of hydroxyacetic acid diethylamide, 1.9 g (0.03 mol) of potassium hydroxide powder and 80 ml of isopropanol and has been cooled to -10° C. The reaction mixture is stirred for 10 hours at -10° C. and poured into water, and the product is filtered off under suction. 4 g (47% of theory) of (3-trifluoromethyl-1,2,4-thiadiazol-5-yl)-oxyacetic acid diethylamide are obtained in the form of white crystals of melting point 60° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[N+:22]([O-])=O)[C:13]2=[O:25])[C:6]1=[O:26].[H][H]>[Pd].C1COCC1>[NH2:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:20](=[O:21])[N:12]([CH:7]1[CH2:8][CH2:9][C:10](=[O:11])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]1=[O:26])[C:13]2=[O:25]
Reactant: [H][H]
Reactant: COCCN1C(=O)CCC(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: COCCN1C(=O)CCC(N2C(=O)c3cccc(N)c3C2=O)C1=O
Yield: 91.4 %

Procedure:
10% Pd/C (50 mg) was added to a THF solution of 2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (260 mg). The reaction vessel was pressurized with hydrogen gas at 5 times the atmospheric pressure. After 6 hrs of reaction time, the catalyst was filtered off and solvent was removed by rotary evaporation in vacuo yielding 218 mg of light-yellow solid. MS (m/e): 332 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=1[N+:21]([O-:23])=[O:22].[NH4+].[Cl-]>CN(C=O)C>[F:13][C:14]1[C:15]([N+:21]([O-:23])=[O:22])=[C:16]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Nc2cccc(F)c2[N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-nitro-phenylamine (1.82 g, 0.013 mol) in DMF (8 ml) at 0° C. is added NaH (60% dispersion in mineral oil, 0.53 g, 0.013 mol). The reaction is stirred at this temperature for 15 min. Subsequently, a solution of 1,3-difluoro-2-nitro-benzene (0.70 g, 4.4 mmol) in DMF (2 ml) is added slowly. After stirring for additional 30 min, it is poured into a saturated aqueous solution of NH4Cl. The precipitate therefore formed is collected by vacuum filtration. The desired compound is obtained after flash column chromatography purification of the precipitate (silica gel, eluted by hexanes-ethyl acetate). 1H NMR (CDCl3) δ 6.77 (dd, 1H, J=10 Hz, J2=10.6 Hz), 7.11 (d, 1H, J=8.8 Hz), 7.35-7.41 (m, 1H), 7.49-7.59 (m, 2H), 7.99 (dt, 1H, J1=8.0 Hz, J2-2.0 Hz), 8.09 (t, 1H, J=2.0 Hz), 8.35 (bs, 1H); LC-MS: 278.0 (MH+).