Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:33][O:32][C:3]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:7]2[CH2:24][CH:25]=[O:26])[O:2]1.Br[C:35]([F:49])([F:48])[C:36]#[C:37][CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>C1COCC1.[Zn].[Hg]Cl>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[O:11][C@@H:10]1[CH2:9][C@H:8]([O:18][SiH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C@H:7]([CH2:24][CH:25]([OH:26])[C:35]([F:49])([F:48])[C:36]#[C:37][CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:43])[CH3:42])[C@H:6]1[CH2:5][CH2:4][C:3]1([O:2][CH2:1][CH2:33][O:32]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCC#CC(F)(F)Br
Reactant: CCCCCC1(CC[C@@H]2[C@H](CC=O)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1
Agent: Cl[Hg]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCCC1(CC[C@@H]2[C@@H](CC(O)C(F)(F)C#CCCO[Si](C)(C)C(C)(C)C)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1

Procedure:
To a solution of 2-[(1S,2R,3R,5S)-2-(3,3-ethylenedioxyoctyl)-3-(tetrahydropyranyloxy)-5-(t-butylsiloxy)cyclopentyl]acetaldehyde (64) (1.00 g) in THF (25 ml) was added activated zinc powder (2.54 g), and while cooling on ice, the solution of 1-bromo-1,1-difluoro-5-(t-butyl-dimethylsilyloxy)-2-pentyne (i) (0.92 g) in THF (5 ml) was added dropwise to the resultant mixture. To the resultant solution was added mercury chloride (0.11 g) and the resultant mixture was stirred under ultrasonic irradiation. The reaction mixture was treated in the conventional manner and the obtained crude product was subjected to silica gel column chromatography to give the title compound (65).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][C:31]#[C:32][CH3:33])[CH:15]=2)=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+].Cl>C(O)C>[CH2:30]([O:29][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=2)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=1)[C:31]#[C:32][CH3:33]
Reactant: CC#CCOc1cc(C#CCN2CCOCC2)cc(Sc2ccc(OCC(=O)OCC)c(C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC#CCOc1cc(C#CCN2CCOCC2)cc(Sc2ccc(OCC(=O)O)c(C)c2)c1
Reaction time: 1 h

Procedure:
{4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 140 mg. HPLC-MS: m/z: 466.0 (M+); Rt: 1.60 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:36]4[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=4)[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and 4-trifluoromethoxyphenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4 (s, 1H), 8.4 (s, 1H), 8.2 (m, 1H), 8.05 (d, 1H, J=7.2 Hz), 7.9 (m, 3H), 7.4-7.7 (m, 7H), 7.0 (d, 1H, J=10.1Hz), 4.3 (m, 2H), 3.6 (m, 4H), 2.9 (m, 2H), 2.6 (m, 4H).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:23]=[CH:24][C:10]=13)[CH2:2]2.Cl[C:30](Cl)([O:32][C:33](=O)[O:34]C(Cl)(Cl)Cl)Cl.CO.C(N1C2=NC(C3C=CC(N=C=O)=CC=3)=NC(N3CC4OC(CC4)C3)=C2C=N1)(C)(C)C>ClCCl.O1CCCC1>[CH3:30][O:32][C:33](=[O:34])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Agent: CC(C)(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N=C=O)cc3)nc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C(C)(C)C)c3n2)cc1

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (65 mg, 0.17 mmol) in a mixture of dichloromethane (2 mL) and tetrahydrofuran (2 mL) was treated with triphosgene (26 mg, 0.09 mmol) as a solution in dichloromethane (1 mL). After the passage of 10 minutes, the appropriate nucleophile—in the case, methanol (excess)—was added to the 3-(1-tert-butyl-6-(4-isocyanatophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide methyl{4-[1-tert-butyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate. MS (ES+): 437.2 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-:18])=[O:17])=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]([CH3:19])[C:4]1=[O:20])[CH3:2]>CC(O)C.Cl.O>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[N+:16]([O-:18])=[O:17])[N:5]([CH3:19])[C:4](=[O:20])[C:3]2([CH2:21][CH3:22])[CH2:1][CH3:2]
Reactant: CCC1(CC)C(=O)N(C)c2cc([N+](=O)[O-])c(NC(C)=O)cc21
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCC1(CC)C(=O)N(C)c2cc([N+](=O)[O-])c(N)cc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
A suspension of N-(3,3-diethyl-1-methyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1,38 g) in 2-propanol (5 ml) and hydrochloric acid (6 N; 20 ml) is stirred at 100° C. for 2 h. After cooling the mixture is diluted with water and extracted with CH2Cl2. The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired compound (1.12 g).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9]OC>>[CH3:9][C:3]1[CH:4]=[C:5]([OH:6])[CH:7]=[CH:8][C:1]=1[OH:2]
Reactant: Oc1ccc(O)cc1
Reactant: COC
Product: Cc1cc(O)ccc1O
Yield: 45 %

Procedure:
In the same microreactor with the previous procedures there are charged 8.0 g amorphous BPO4 calcined at 170° C., 8.0 g hydroquinone and 7.9 g dimethylether, at a weight ratio 1/1/1. The hydroquinone conversion is 52% by moles, the yield to methyl hydroquinone 45% by moles and the selectivity to methyl hydroquinone 87% by moles. The gas-chromatographic analysis of the products gave the following result:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=2)[O:3]1.C(O)(=O)C.[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[Br:22][C:5]1[C:6](=[O:7])[C:2]([CH3:17])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=1
Reactant: BrBr
Reactant: CS(=O)c1ccc(C2=CC(=O)C(C)(C)O2)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)c1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2,2-dimethyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone (135 mg) in 25 ml of CCl4, were added 1 ml acetic acid and 0.1 ml bromine. The reaction mixture was stirred at room temperature for 2.5 hr. Then the reaction was quenched by adding 10 ml of saturated aqueous sodium thiosulfate. The volatile materials were removed in vacuo, which was followed by extraction with dichloromethane (50 ml×3). The organic layer was dried over anhydrous magnesium sulfate and the magnesium sulfate was filtered off. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography (hexane/ethylacetate=1:1) to give 68 mg of 4-bromo-2,2-dimethyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone. mp: 117-118° C. NMR: δ1.55 (s, 6H), 2.79 (s, 3H), 7.81 (d, J=8.2 Hz, 2H), 8.38 (d, J=8.2 Hz, 2H). IR (cm−1): 1706, 1601,1555, 1191, 1052.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6]Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:2][N:3]([CH2:4][CH2:5][CH2:6][S:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=1)[CH3:8]
Reactant: Sc1ccc(Br)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCSc1ccc(Br)cc1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
3-(Dimethylamino)propyl chloride hydrochloride (3.48 g, 22 mmol) was added in portions to a suspension of 4-bromothiophenol (3.78 g, 20 mmol) and potassium carbonate (5.52 g, 40 mmol) in DMF (40 ml) and the reaction mixture heated to 60° C. for 15 minutes. The mixture was allowed to cool to ambient temperature and poured into water (100 ml) and extracted with EtOAc (2×100 ml). The extracts were combined, washed with brine (3×100 ml), dried (Chemelut column 1010) and evaporated to give the title compound (5.25 g, 96%) as a pale yellow oil. NMR 1.76 (m, 2H), 2.20 (s, 6H), 2.35 (t, 2H), 2.93 (t, 2H), 7.18 (d, 2H), 7.38 (d, 2H); m/z 276.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:27]([CH3:28])=[CH:26][S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:27]([CH3:28])=[CH:26][S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)[CH3:14].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH3:13][C:14]1[O:12][C:11]2[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=2)[N:2]=1
Reactant: CC(=O)Cl
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc2c(C(=O)O)cccc2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.35 g, 1.50 mmol) and acetyl chloride (0.11 mL, 1.50 mmol) in dichloromethane (10 mL) was added triethylamine (0.84 mL, 6.0 mmol) dropwise, then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (263 mg, 1.38 mmol). The reaction mixture was then heated to reflux for 1.5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated then washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford 2-methylbenzoxazole-4-carboxylic acid (0.17 g, 64%) as an off-white solid: MS (ESI+) m/z 178 (M+H).
Reaction SMILES: [CH:1]1([C:4]2([OH:14])[CH2:13][CH2:12][C:7]3(OCC[O:8]3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.O.Cl>CC(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2([OH:14])[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: OC1(C2CC2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1CCC(O)(C2CC2)CC1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
8-Cyclopropyl-1,4-dioxaspiro[4.5]decan-8-ol (1.8 g) was dissolved in acetone (30 mL). A solution of water (15 mL) and conc. HCl was added. The reaction mixture was stirred overnight. The reaction mixture was taken in ethyl acetate and washed with sat. NaHCO3. Purification by silica chromatography produced 4-cyclopropyl-4-hydroxycyclohexanone (0.5 g, 27%). 1H NMR (400 MHz, CDCl3): δ 2.80-2.69 (m, 2H), 2.50-2.42 (m, 2H), 1.99-1.78 (m, 4H), 1.01-0.99 (m, 1H), 0.50-0.47 (m, 4H); MS (ESI) m/z: Calculated for C9H14O2: 154.1. found: 155.1 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=4)[O:8][CH2:7][C:6]([OH:42])=[O:5])[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC(C)(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
A solution of tert-butyl 5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was stirred in CH2Cl2 (2 mL) and TFA (2 mL) for 1 h. The volatiles were removed in vacuo and the residue was triturated with ethyl ether. The crude product was purified using prep HPLC (method 10-35—90 mins) to afford to give 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid. (0.43 mg, 0.10 mmol)
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][N:22]=1)[CH2:13][C:14](=O)[CH2:15][C:16](=O)C)#[N:9].Cl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1>C(O)C>[C:8]([C:10]1[CH:11]=[C:12]([C:13]2[N:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[N:32]=[C:15]([CH3:16])[CH:14]=2)[CH:20]=[CH:21][N:22]=1)#[N:9]
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)CC(=O)Cc1ccnc(C#N)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccnc(C#N)c2)n(-c2ccc(F)cc2)n1
Yield: 52.8 %

Procedure:
Triethylamine (4.6 mL, 0.033 mol) was added dropwise to a mixture of 1-(2-cyanoisonicotinyl)-1,3-butanedione (6.0 g, 0.032 mol) and 4-fluorophenylhydrazine hydrochloride (5.37 g, 0.033 mol) in 100 mL of ethanol. The reaction mixture was heated at reflux overnight (about eighteen hours). The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by recrystallization from ether/hexane to give 4.7 g (53% yield) of product as a yellow solid: mp: 94-95° C.; Anal. Calc'd. for C16H11FN4: C, 69.06; H, 3.98; N, 20.13. Found: C, 68.52; H, 3.89; N, 19.73.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:18][N:17]=[N:16][C:15]=1[NH:27][NH2:28]>C1COCC1>[Cl:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:28][N:27]=2)[N:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of triphosgene (30.4 g, 102.4 mmol) in THF (300 mL), 1-[4-chloro-5-(4-chloro-phenyl)-pyridazin-3-yl]-hydrazine (6.52 g, 25.61 mmol) was added in portions over 15 min at room temperature. The mixture was stirred at room temperature for 4 h. After this time, the solution was poured into ice/water (500 mL), and the resulting light yellow solid was collected by filtration. The solid was rinsed with aqueous 0.5N HCl and water. It was then dried under vacuum to give the title compound, 2.81 g of 8-chloro-7-(4-chlorophenyl)-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one as a light yellow solid. HPLC: 2.78 min; MS, M+H=281.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]([CH2:26][NH2:27])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:12]([CH2:26][NH:27][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
1H-NMR (300 MHz, CDCl3): δ 7.27 (d, 2H, J=9 Hz), 6.88 (d, 2H, J=9 Hz), 6.01 (s, 2H), 3.81 (s, 3H), 3.78 (d, 1H, J=14 Hz), 3.62 (d, 1H, J=14 Hz), 3.46 (m, 1H), 3.12-2.70 (m, 5H), 2.60 (m, 1H), 1.55 (s, 9H). 2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (70% pure, 0.2 g, 0.347 mmol) was dissolved in a mixture of anhydrous dichloromethane (5 ml) and triethylamine (72 μl) and cooled in an ice-bath and stirred under nitrogen. Benzoyl chloride (40 μl, 1.0 eq) was added dropwise and the reaction was stirred for 5 minutes, then warmed to ambient temperature and stirred for an additional 16 hours. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (20 ml) and washed with 0.5 N hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo, which afforded 0.15 g of crude 7-(benzoylamino-methyl)-2-amino-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:29][NH2:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([NH:30][CH3:29])=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (75 mg) was coupled to methylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 38.8 mg of 171. MS (Q1) 395.1 (M)+.
Reaction SMILES: [N:1]([CH:4]([C:7]1[N:8]=[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:10]2[C:11](=[O:14])[C:12]=1[I:13])[CH2:5][CH3:6])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[NH2:1][CH:4]([C:7]1[N:8]=[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:10]2[C:11](=[O:14])[C:12]=1[I:13])[CH2:5][CH3:6]
Reactant: CCC(N=[N+]=[N-])c1nc2cccc(C)n2c(=O)c1I
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(N)c1nc2cccc(C)n2c(=O)c1I
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(1-azidopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.10 g, 8.40 mmol) in tetrahydrofuran (20 mL) and water (6.06 mL) was added a 1.0 M solution of trimethylphosphine in tetrahydrofuran (0.1 mmol) at room temperature and stirred for 1 hour. To the mixture was added EtOAc and the mixture was extracted twice with 1 N HCl. The combined extracts were neutralized with solid sodium bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step (2.58 g, 89.5%). LCMS calculated for C12H15IN3O (M+H)+: m/z=344.0. Found: 344.2.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=1[O:21][CH3:22]>ClCCl.C(OCC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][C:14]=1[O:21][CH3:22]
Reactant: COc1cc(CO)ccc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C=O)ccc1Cl
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A suspension of pyridinium chlorochromate (1.37 g, 6.34 mmol) in dichloromethane (35 mL) was treated with Celite (2.0 g) and stirred at rt. A solution of (4-chloro-3-methoxyphenyl)methanol (730 mg, 4.23 mmol) in dichloromethane (5 mL) was added in one portion, and the resulting mixture was stirred at rt for 3 h. After this time, the mixture was diluted with diethyl ether, and stirred vigorously. The mixture was then filtered through a pad of silica gel and the collected solids were rinsed with additional diethyl ether. The combined filtrates were concentrated under vacuum to provide 4-chloro-3-methoxybenzaldehyde as a pale tan-yellow solid (630 mg, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 3.98 (s, 3 H) 7.41 (dd, J=7.9, 1.8 Hz, 1 H) 7.45 (d, J=2.0 Hz, 1 H) 7.55 (d, J=7.6 Hz, 1 H) 9.95 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]>>[CH:22]1([O:21][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)OC1CCCC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)OC4CCCC4)cc23)CC1
Yield: 93 %

Procedure:
Beginning with 13 mg (0.0567 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.27 mg (0.062 mMol) cyclopentyl chloroformate, 18.1 mg (93% of the title compound were recovered.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCOCC.Cl.[N:27]([O-])=[O:28].[Na+]>O>[N:27]([N:8]([CH2:7][C:6]1[CH:19]=[CH:20][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:11][CH:10]=1)=[O:28]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1ccc(NCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(N(Cc2ccc(Cl)cc2)N=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 50 q of the hydrochloride salt from Step 1, 500 mL water, 250 mL ether and 170 mL of 1 N hydrochloric acid was treated with a solution of 12.3 q sodium nitrite in 50 mL of water. After stirring for 2 h at room temperature the reaction mixture was extracted twice with ether. The combined extracts were washed with water and dried over MgSO4. Filtration and concentration gave N-nitroso-N-(p-chlorobenzyl)-4-t-butylaniline.