Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:6](=O)[C:5]2=[CH:13][CH:14]=1.[N:15]1([CH2:20][CH:21]([CH3:24])[CH2:22][NH2:23])[CH:19]=[CH:18][N:17]=[CH:16]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:23]([CH2:22][CH:21]([CH3:24])[CH2:20][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[C:9](=[O:12])[N:10]2[CH3:11])=[CH:13][CH:14]=1
Reactant: CC(CN)Cn1ccnc1
Reactant: Cn1c(=O)oc(=O)c2ccc(Cl)cc21
Solvent: CCO
Product: CC(Cn1ccnc1)Cn1c(=O)c2ccc(Cl)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2.12 g of 4-chloro-N-methylisatoic anhydride, 1.39 g of 3-(1H-imidazol-1-yl)-2-methylpropanamine and 20 ml of ethanol was stirred at room temperature for 20 hours and concentrated. Ethyl chloroformate (10 ml) was added and the mixture was heated in an oil bath at 90°-105° C. for 2 hours, dissolved in ethanol and concentrated. Ethanol (25 ml) and 2.0 g of potassium hydroxide was added and the mixture was heated at reflux for 3 hours and concentrated. Water was added, and the pH was adjusted to 6-7 with acetic acid. The product was extracted into methylene chloride. Concentration and recrystallization from ethyl acetate resulted in the desired product, mp 206°-209° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH3:20])=[O:18])=[N:15][CH:16]=3)=[CH:9][N:8](COCC[Si](C)(C)C)[C:6]=2[N:7]=1.[NH2:36][C:37]1[CH:47]=[CH:46][C:40]([C:41]([N:43]([CH3:45])[CH3:44])=[O:42])=[CH:39][C:38]=1[CH3:48].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:44][N:43]([CH3:45])[C:41]([C:40]1[CH:46]=[CH:47][C:37]([NH:36][C:2]2[N:3]=[C:4]([O:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:5]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH3:20])=[O:18])=[N:15][CH:16]=4)=[CH:9][NH:8][C:6]=3[N:7]=2)=[C:38]([CH3:48])[CH:39]=1)=[O:42]
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cn1
Reactant: Cc1cc(C(=O)N(C)C)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2c[nH]c3nc(Nc4ccc(C(=O)N(C)C)cc4C)nc(OC4CCOCC4)c23)cn1
Temperature: 150 °C
Yield: 21 %

Procedure:
5-(2-Chloro-4-(tetrahydro-2H-pyran-4-yloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylpicolinamide (1 equiv), 4-amino-N,N,3-trimethylbenzamide (1 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.2 equiv), cesium carbonate (2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv) and 1,4-dioxane (0.2 M) were combined in a microwave vial and irradiated heated at 150° C. for 30 min. The mixture was concentrated and purified by flash chromatography 0-55% (Hex:EtOAc-800 mL), followed by 5-15% B (DCM:MeOH-800 mL) in the same run. Fractions were combined, concentrated and the compound was deprotected according to General Procedure A. The reaction mixture was concentrated and purified to give the title compound (21% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.92 (d, J=1.95 Hz, 1 H), 8.20 (dd, J=7.81, 1.56 Hz, 1 H), 8.07 (dd, J=16.59, 8.39 Hz, 2 H), 7.22-7.31 (m, 3 H), 5.49 (s, 1 H), 3.78-3.88 (m, 2 H), 3.52-3.61 (m, 2 H), 3.07 (s, 6 H), 2.96 (s, 3 H), 2.35 (s, 3 H), 2.08 (d, J=13.28 Hz, 2 H), 1.73-1.84 (m, 2 H). MS (ESI) m/z 530.0 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:13]([OH:15])=O)([O-:3])=[O:2].[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>ClC1C=CC=CC=1Cl>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([N:24]2[C:13](=[O:15])[C:5]3[C:6](=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:9])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
In a 25 mL round bottomed flask, 3-nitrophthalic acid (1 g, 4.7 mmol) was suspended in 1,2-dichlorobenzene (3 mL). To this was added 4-tert-butylaniline (3 mL, 18.8 mmol). The reaction was heated to 150° C., resulting in a blood red solution. The reaction was held at 150° C. for 2.5 h, then poured into a 125 mL Erlenmeyer flask. Precipitation began to occur and 50 mL of Et2O was added to the flask. The suspension was stirred for 15 h and filtered. The filtered cake was washed copiously with Et2O and dried in vacuo at 30° C. for 4 h to afford a white brittle powder. No further purification was performed on this compound. MS (ES+): 325.1(M+H)+. Calc'd for C18H16N2O4-324.33.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1ccc2c(n1)CCCC2
Product: Fc1ccccc1-c1ccc2c(n1)CCCC2

Procedure:
Subsequently, Suzuki-Miyaura conditions were applied as in FIG. 8 using 2-bromo-5,6,7,8-tetrahydroquinoline and 2-fluorophenylboronic acid to obtain the 2-(2-fluorophenyl)-5,6,7,8-tetrahydroquinoline precursor as depicted in FIG. 10. After isolation and purification by flash chromatography, this viscous yellow-orange liquid solidifies at room temperature. In general, 2-(2-fluorophenyl)-pyridine derivatives wore prepared in high yields (over 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][CH2:25]Br)=[CH:23][C:18]=2[O:17][C:16]1=[O:27]>O1CCOCC1>[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[CH:23][C:18]=2[O:17][C:16]1=[O:27]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cn1c(=O)oc2cc(CCBr)ccc21
Solvent: C1COCCO1
Product: Cn1c(=O)oc2cc(CCN3CCN(c4ccc(F)cc4)CC3)ccc21
Yield: 64.7 %

Procedure:
0.025 mol (4.5 g) of 1-(4-fluorophenyl)-piperazine and 0.02 mol (5.12 g) of 3-methyl-6-(2-bromoethyl)-benzoxazolinone, dissolved beforehand in 50 cm3 of dioxane, were introduced into a 100 cm3 flask with a ground glass neck, fitted with a reflux condenser, and the mixture was then heated under reflux for 72 hours, with stirring. After cooling, filtration and drying, 100 cm3 of a 3% strength aqueous solution of sodium hydroxide were added to the precipitate obtained, and the mixture was stirred for 30 minutes. Filtration, drying and recrystallisation from toluene gave 4.6 g of the title product having a melting point of 161°-164° C.
Reaction SMILES: [ClH:1].[NH:2]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C@H:3]1[C:11]([O:13]CC)=[O:12].Cl>O>[ClH:1].[NH:2]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C@H:3]1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Agent: Cl
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Temperature: 95 °C
Yield: 87 %

Procedure:
In a 500 mL reaction flask equipped with a distillation head was added 33.5 g (0.143 mol, 1.0 equiv.) of (2S,3aR,7aS)-Ethyl octahydro-1H-indole-2-carboxylate hydrochloride (16), 102 g of water, and 102 g of conc. hydrochloric acid. The contents were heated to 94-96° C. temperature with mixing for NLT 6 h while collecting about 9 mL of distillate at atmospheric pressure. The reaction mixture was cooled to room temperature and concentrated to dryness on a rotary evaporator. To the resulting crude product, 255 mL of acetonitrile was added and heated for 1 h at reflux with mixing to break up and dissolve the solids. The mixture was cooled gradually to 0-5° C. temperature at a rate of 10-15° C. per h, and held at 0-5° C. for NLT 2 h under nitrogen atmosphere. The solids were collected via filtration and washed with 10-20 mL of chilled (0-5° C.) acetonitrile. The product was dried at 45° C. under vacuum for 16 h to afford 25.6 g of (2S,3aR,7aS)-Octahydro-1H-indole-2-carboxylic acid hydrochloride (5) in 86.9% yield as a white solid. 1H NMR (D2O, 400 MHz): δ 4.42 (dd, 1H, J=11.1, 2.7 Hz), 2.93, (dt, 1H, J=11.8, 3.6 Hz), 2.36 (ddd, 1H, J=12.9, 6.7, 2.7 Hz), 2.31-2.16 (m, 1H), 2.11-2.01 (m, 2H), 1.92-1.90 (m, 1H), 1.79-1.75 (m, 1H), 1.68-1.53 (m, 2H), 1.34-1.13 (m, 3H); LC-MS (m/z): 170.1 (M+H)+. The isolated product (5) correlates to the material prepared according to U.S. Pat. No. 487,932 and Tetrahedron Lett., 1992, 33, 4889.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH3:30][C:31]1([CH3:40])[CH2:36][NH:35][CH2:34][C:33]2[S:37][CH:38]=[CH:39][C:32]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][C:31]1([CH3:40])[CH2:36][N:35]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[CH:21]=2)=[O:28])[CH2:34][C:33]2[S:37][CH:38]=[CH:39][C:32]1=2
Reactant: CC1(C)CNCc2sccc21
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5sccc5C(C)(C)C4)ncn3)CC1)C(=O)N2

Procedure:
84 mg (0.21 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 40 mg (0.24 mmol) 4,4-dimethyl-4,5,6,7-tetra-hydro-thieno[2,3-c]pyridine, 34 μL (0.24 mmol) TEA and 77 mg (0.24 mmol) TBTU were stirred in 1 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9]C#N)[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[SH:9][C:6]1[CH:5]=[C:4]([CH3:12])[C:3]([OH:13])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1cc(SC#N)c(C)c(C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(S)c(C)c(C)c1O
Temperature: 0 °C
Yield: 80.2 %

Procedure:
A solution of 2,3,6-trimethyl-4-thiocyanato-phenol (45.7 g, 237 mmol) in anhydrous THF (300 mL) was added to a suspension of LiAlH4 (9.09 g) in anhydrous THF (600 mL) stirred at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. It was subsequently quenched with THF, followed by H2O and 0.5 M aq. HCl. Extraction with EtOAc (3×) was followed by washing the collected organic fractions with brine, drying over Na2SO4 and solvent evaporation. Column chromatography (SiO2: hexane:EtOAc, 9:1 v/v) yielded 4-mercapto-2,3,6-trimethyl-phenol as a white solid (32 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:21]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:39]>O1CCOCC1>[ClH:39].[ClH:39].[F:38][C:35]([F:36])([F:37])[C:32]1[CH:31]=[CH:30][C:29]([C:22]2[N:21]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]4)[CH:19]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc4nccn34)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc4nccn34)cn2)CNC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-(4-(7-(4-(trifluoromethyl)phenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (400 mg; 0.764 mmol) in 1,4-dioxane (5 mL) was added, in two equal portions, a solution of hydrogen chloride (31 mmol; 4M in 1,4-dioxane). The resulting suspension was stirred in a sealed vial for 2 days at ambient temperature. The solvent was evaporated under a stream of nitrogen and the resulting solid was dried under vacuum to give an off white solid (370 mg). MS (apci) m/z=424.1 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C@H:25]([N:28]5[CH2:32][CH2:31][CH2:30][C@@H:29]5[CH3:33])[CH2:24]4)=[CH:19][C:18]=3[CH3:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:34][C:18]1[CH:19]=[C:20]([N:23]2[CH2:27][CH2:26][C@H:25]([N:28]3[CH2:32][CH2:31][CH2:30][C@@H:29]3[CH3:33])[CH2:24]2)[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:13][CH2:12][C:11]2([CH2:10][CH2:9][NH:8][CH2:36][CH2:35]2)[C:15]1=[O:16]
Reactant: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCNCC2)C1=O
Reaction time: 1 h

Procedure:
2-[2-Methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (150 mg) was treated with 1 mL (excess) of 4M HCl in dioxane at 0° C. The stirring was continued at rt for 1 h. The solvent was evaporated and the solid was further dried under high vacuum at rt for 2 h to obtain the title compound as a tan solid.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9]Br)[CH3:6]>C(O)C>[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9][S:4][CH2:2][CH3:3])[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: CCS
Agent: [Na]
Solvent: CCO
Product: CCOC(CSCC)OCC
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
Sodium (10.7 g, 0.463 mole) was dissolved in ethanol (500 ml) and ice cooled. Ethanethiol (34.4 ml, 0.463 mole) was added, followed after 15 mins. by bromoacetaldehyde diethylacetal (83.8 g, 0.421 mole). The mixture was refluxed 3 hours and the volume reduced to 200 ml by distillation of some of the ethanol at atmospheric pressure. Ether (500 ml) was added and the solution washed with water (3×200 ml), dried over MgSO4 and evaporated at atmospheric pressure. The residue was distilled to provide title compound (70.46 g, 99%) bp 96°-100° C./20 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N+:18]([O-])=O.Cl[Sn]Cl.O.Cl>CCO>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH2:18]
Reactant: Cc1ccc(OCCCN2CCOCC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(OCCCN2CCOCC2)cc1N

Procedure:
A solution of the 4-[3-(4-methyl-3-nitro-phenoxy)-propyl]-morpholine V-i (350 mg, 1.25 mmol) in 90% EtOH (15 mL) was treated with SnCl2.H2O (1.58 g, 6.24 mmol) and conc. HCl (1.04 mL, 12.5 mmol) and heated to reflux for 1 h. The cooled solution was concentrated under reduced pressure and taken to pH=8 with a saturated solution of NaHCO3 then extracted with EtOAc. The combined organics were dried (MgSO4), filtered and evaporated to the desired product V-g as a viscous yellow oil (306 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 6.92 (d, J=8.8 Hz, 1H), 6.30-6.24 (m, 2H), 3.96 (t, J=6.3 Hz, 2H), 3.76-3.69 (m, 4H), 3.58 (s, 2H), 2.57-2.42 (m, 6H), 2.09 (s, 3H), 1.93 (dt, J=13.3, 6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[C:31]#[N:32])=[CH:4][C:5](=[O:23])[N:6]([CH:8]([CH2:16][CH2:17][O:18][C:19]([F:22])([F:21])[F:20])[C:9]([O:11]C(C)(C)C)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[C:31]#[N:32])=[CH:4][C:5](=[O:23])[N:6]([CH:8]([CH2:16][CH2:17][O:18][C:19]([F:20])([F:21])[F:22])[C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(CCOC(F)(F)F)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(CCOC(F)(F)F)C(=O)O)cc1Cl

Procedure:
244 mg (purity 92%, 0.46 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 237 mg (purity 84%, quant.)
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[S:15]1[CH2:20]CC(=O)[CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:17][CH2:16][S:15][CH2:20][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: O=C1CCSCC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CSCC2
Yield: 99.5 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (0.6 g, 3.0 mmol), tetrahydrothiopyran-4-one (0.35 g, 3.0 mmol) and ammonia solution in methanol (2.0 M, 30 mL) was refluxed for 6 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (0.586 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[N:9]=[C:10](I)[C:3]=12.[F:23][C:24]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C(OCC)(=O)C.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.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[N:9]=[C:10]([C:25]3[CH:26]=[CH:27][C:28]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][C:24]=3[F:23])[C:3]=12
Reactant: C[C@H](Cn1nc(I)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1F
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: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 130.5 %

Procedure:
To a microwave tube was added tert-butyl N-[(1R)-2-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-ethyl]carbamate (1.7 g, 4.1 mmol), (2-fluoro-4-phenoxy-phenyl)boronic acid (1.4 g, 6.1 mmol), K2CO3 (1.27 g, 9.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (213 mg, 0.18 mmol) and 1,4-dioxane (12 mL) and water (3 mL). The mixture was capped and heated under microwave conditions for 140° C. for 10 minutes. The reaction was cooled and diluted with ethyl acetate (50 mL) and washed with water (50 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to obtain 2.56 g of crude tert-butyl N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]carbamate. This was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18]C)[C:12]=2[C:11]([C:20]2[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:23][CH:24]=2)=[N:10]1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:20]2[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:23][CH:24]=2)=[N:10]1
Reactant: COC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cs1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: COC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of methyl 4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (42.5 mg) in acetonitrile (4 mL) were added sodium iodide (39.7 mg) and chloro(trimethyl)silane (0.134 mL), and the mixture was stirred at 50° C. for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate to ethyl acetate) to give the title compound (37.2 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].Br[CH2:9][CH2:10][O:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH2:10]([O:11][CH2:12][CH2:13][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH3:9]
Reactant: CCOCCBr
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCn1ccnc1C=O
Temperature: 110 °C
Yield: 17 %

Procedure:
To a solution of imidazole-2-carboxaldehyde (2.00 g, 21 mmol) in DMF (1 mL) was added 1.1 eq. of 1-bromo-2-ethoxyethane (3.51 g, 22 mmol), potassium carbonate and a catalytic amount of potassium iodide. The reactions were heated at 110° C. for 18 hrs followed by evaporation to dryness and purified utilizing a Biotage SP4 with a gradient method of 5-50% methanol in DCM to yield the desired compound (580 mg, 3.56 mmol, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, H), 7.6 (s, H), 7.21 (s, H), 4.45 (dd, 2H), 3.62 (dd, 2H), 3.38 (m, 2H), 1.05 (t, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]21[CH2:11][CH2:10][CH:9]1[CH:7]([O:8]1)[CH2:6]2.[CH3:12][NH:13][CH3:14].[OH-].[Na+]>>[CH3:12][N:13]([CH3:14])[C@H:7]1[C@H:9]([OH:8])[CH2:10][CH2:11][C:2]2([O:3][CH2:4][CH2:5][O:1]2)[CH2:6]1
Reactant: C1COC2(CCC3OC3C2)O1
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Product: CN(C)[C@@H]1CC2(CC[C@H]1O)OCCO2

Procedure:
A mixture of 25.0 g (0.16 mol) of spiro[7-oxabicyclo[4.1.0]-heptane-3,2'-[1,3]-dioxolane] from Example 1, Part D, and 87.0 ml (0.05 mol) of of 40% aqueous dimethylamine was heated in an oil bath at 90° for four hours. The reaction mixture was cooled to 0° and treated with NaOH pellets until two phases separated. Methylene chloride (CH2Cl2) was added, the phases were separated, the aqueous phase was extracted twice with CH2Cl2, the combined organic phases were dried (MgSO4) and the solvent removed in vacuo leaving 31.0 g of a yellow liquid. The crude yellow liquid product thus obtained was distilled at reduced pressure through a short path to give 28.0 g (88%) of the subtitled amino-alcohol: bp 83°-87° (0.2 mm); IR (nujol) 3460 (OH) cm-1, 2780 (N--C--H), 1134, 1090, 1050, 1040, 925 (C-O); mass spec. m/e 201 (M+). nmr (CDCl3); 54.7 (S, 1H, OH), 3.95 (S, 4H, O(CH2CH2O), 3.1-3.5 (m, 1H, CH-OH), δ2.3-2.7 (m, 1H, CH--N), 2.25 (S, 6H, N(CH3)2)2, 1-2 (m, 6H, ring CH2). The IR and nmr spectra were in agreement with the structure assignment.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]#[N:13])=[N:9][C:10]=1[CH3:11]>C(O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:12](=[NH:13])[NH:2][NH2:3])=[N:9][C:10]=1[CH3:11]
Reactant: NN
Reactant: Cc1nc(C#N)ccc1Br
Solvent: O
Solvent: CCO
Product: Cc1nc(C(=N)NN)ccc1Br
Temperature: 50 °C

Procedure:
Hydrazine monohydrate (2 equiv) was added to a stirring 1.2 M suspension of 5-bromo-6-methylpicolinonitrile (1 equiv) in ethanol. The reaction mixture was heated to 50° C. for 24 h. The reaction was cooled to room temperature and filtered. The collected solid was washed with ethanol and t-butyl methyl ether. The solid was dried under vacuum to provide the title compound, as a solid. MS (ESI) m/z 228.9 [M]+, 230.9 [M+2]+.