Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[CH3:9][C:10]1([CH3:31])[C:14]([CH3:16])([CH3:15])[O:13][B:12](/[CH:17]=[CH:18]/[CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:11]1>ClCCl>[CH3:16][C:14]1([CH3:15])[C:10]([CH3:31])([CH3:9])[O:11][B:12]([CH:17]2[CH2:1][CH:18]2[CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:13]1
Reactant: CC[Zn]CC
Reactant: CC1(C)OB(/C=C/CNC(=O)OCc2ccccc2)OC1(C)C
Solvent: ClCCl
Solvent: ICI
Product: CC1(C)OB(C2CC2CNC(=O)OCc2ccccc2)OC1(C)C
Temperature: -15 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
A solution of diethylzinc (7.57 mL, 7.57 mmol) in dichloromethane (10 mL) was stirred at −78° C. under nitrogen as a solution of diiodomethane (1.22 mL, 15.1 mmol) in dichloromethane (10 mL) was added. The resulting mixture was stirred at −15° C. under nitrogen for 1 h to give a white milky suspension. A solution of (E)-benzyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate (1.2 g, 3.78 mmol) in dichloromethane (10 mL) was added. The reaction mixture was stirred at rt for 1 h. and was then quenched with 1HCl. The dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 mL) and brine (20 mL), dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-30% EtOAc/hexane as the eluent to give benzyl ((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methyl)carbamate as a colorless oil (0.84 g, 60%). 1H NMR (400 MHz, METHANOL-d4) d 7.42-7.22 (m, 5H), 5.07 (s, 2H), 3.12-2.84 (m, 2H), 1.20 (s, 12H), 1.17-1.12 (m, 1H), 0.71-0.60 (m, 1H), 0.58-0.44 (m, 1H), −0.28 (dt, J=9.5, 5.8 Hz, 1H). M+1=332.2.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH2:17]2)=[O:15])[CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:38]1[CH:43]=[CH:42][C:41]([C:44](=[O:49])NCCC)=[CH:40][CH:39]=1)=O)C2>>[C:44]([N:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH2:17]2)=[O:15])[CH2:6]1)(=[O:49])[C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(NCCCCC1CNC1)N1Cc2ccncc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(NCCCCC1CN(C(=O)c2ccccc2)C1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(4-(azetidin-3-yl)butyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.46 (d, J=5.0 Hz, 1H), 7.67-7.55 (m, 2H), 7.55-7.34 (m, 4H), 6.37 (t, J=5.5 Hz, 1H), 4.60 (d, J=2.3 Hz, 4H), 4.35 (t, J=8.3 Hz, 1H), 4.11 (t, J=9.1 Hz, 1H), 3.96-3.83 (m, 1H), 3.65 (dd, J=9.7, 5.7 Hz, 1H), 3.07 (dd, J=12.8, 6.7 Hz, 2H), 2.65-2.53 (m, 1H), 1.59 (dd, J=15.2, 7.6 Hz, 2H), 1.43 (dd, J=14.4, 7.2 Hz, 2H), 1.34-1.09 (m, 2H); MS (ESI(+)) m/e 379 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(C(C)C)C(C)C)C.[CH3:44][O:45][CH2:46]Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:33])([CH3:34])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:44][O:45][CH3:46])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COCCl
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCO[C@H]1CC[C@H](N(c2cc(C3=CCC(C)(C)CC3)sc2C(=O)OC)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (406 mg, 0.83 mmol), i-Pr2EtN (218 μL, 1.25 mmol) and DMAP (15 mg, 0.12 mmol) in dry CH2Cl2 (20 mL) was added chloromethyl methyl ether (95 μL, 1.25 mmol), and the mixture was stirred at room temperature overnight. Then the mixture was diluted with CH2Cl2, washed with brine, organic fraction was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 0-30% EtOAc in hexanes to give 286 mg (65%) of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:3]=1.C1C(=O)N(Br)C(=O)C1.C1CCN2C(=NCCC2)CC1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:3]=1
Reactant: O=C1CCc2c(cc(Br)nc2-c2ccccc2Cl)N1c1ccccc1Cl
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1ccccc1Cl

Procedure:
7-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]naphthyridin-2(1H)-one (30 mg, 0.067 mmol) in carbon tetrachloride (5 ml) was treated with NBS (15 mg) and AlBN (1.1 mg) and heated under reflux for 1.5 h. DBU (10 μl) was added, the mixture cooled, and dichloromethane (5 ml) added, followed by 8% sodium bicarbonate (10 ml). The mixture was passed through a hydrophobic frit and evaporated in vacuo to give the product as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[O:16])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])=[O:16])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1ccccc1F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCc4ccccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(2-fluoro-benzyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.Br[CH2:38][CH2:39][OH:40].C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH2:38][CH2:39][OH:40])[CH2:26]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(CCO)C1
Temperature: 60 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (300 mg, 0.74 mmol, chiral intermediate from Example 212) in tetrahydrofuran (14 mL) was treated with triethylamine (260 μL, 1.8 mmol) followed by 2-bromoethanol (63 μL, 0.89 mmol) dropwise and stirred at 60° C. for 6 h. The reaction mixture was treated with additional 2-bromoethanol (26 μL, 0.37 mmol) and stirred at 60° C. for another 6 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was concentrated and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.15 g, 44%). The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.56 (s, 1H), 6.36-6.25 (m, 1H), 4.48 (br s, 1H), 4.19-4.07 (m, 1H), 4.04-3.94 (m, 2H), 3.91-3.82 (m, 1H), 3.81-3.72 (m, 1H), 3.20-3.08 (m, 2H), 2.62 (s, 2H), 2.57 (s, 3H), 1.79 (d, J=6.8 Hz, 3H), 1.40 (t, J=6.6 Hz, 3H). LCMS for C22H27ClN7O2 (M+H)+: m/z=456.2; Found: 456.1.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[CH:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH2:1]([NH:4][C:17]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:18])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)C1CCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
Dissolve propargylamine (1.5 g, 28.07 mmol) in DCM (50 mL), add triethylamine (7.83 mL, 56.15 mmol) and cool the mixture to 0° C. Add cyclopentanecarbonyl chloride (2.5 g, 18.72 mmol) and warm to room temperature. Stir the reaction mixture for 18 h. Wash the mixture with water (3×50 mL) and hydrochloric acid (2N, 50 mL) and dry the organic phase over MgSO4. Remove the solvent in vacuo and triturate the solid with iso-hexane to give the title compound as a fine white powder (1.51 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[CH2:25]1COCC1>>[O:14]=[C:13]1[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH2:9][CH3:25])=[O:7])=[CH:4][C:3]=2[O:12]1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(N)c(O)c1
Product: CCOC(=O)c1ccc2[nH]c(=O)oc2c1

Procedure:
Methyl 4-amino-3-hydroxybenzoate (1.23 g, 7.36 mmol) (commercially available from Pfaltz & Bauer Chemicals Catalog (Order Number A22677)) and 1,1′-carbonyldiimidazole (1.19 g, 7.36 mmol) in 20 mL THF were heated by microwave at 100° C. for 10 minutes. The reaction mixture was used directly for next step. LCMS (API-ES) m/z: 194 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:31][CH2:30][C:18]4([CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:31][CH2:30][C:18]4([CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2nccc(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)C4)n2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cn1cc(Nc2nccc(NC3CCC4(CCNC4)CC3)n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
To a solution of tert-butyl 8-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (0.51 g, 1.19 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (5 mL, 2.83 M) and the mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (10 mL) and adjusted to pH=8 with saturated Na2CO3 solution, then extracted with DCM (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a yellow solid (0.17 g, 44%).
Reaction SMILES: Cl[O-].[Na+].[CH:4]1([CH:7]([O:11][CH2:12][CH:13]=[N:14][OH:15])[CH2:8][CH:9]=[CH2:10])[CH2:6][CH2:5]1.C(N(CC)CC)C>ClCCl.O>[CH:4]1([C@@H:7]2[O:11][CH2:12][C:13]3=[N:14][O:15][CH2:10][C@@H:9]3[CH2:8]2)[CH2:6][CH2:5]1
Reactant: C=CCC(OCC=NO)C1CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C1O[C@@H](C2CC2)C[C@H]2CON=C12

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 27.1 mL, 22.4 mmol) was added drop-wise over 24 minutes to a solution of 2-[(1-cyclopropylbut-3-en-1-yl)oxy]-N-hydroxyethanimine (C51) (1.85 g, 10.9 mmol) and triethylamine (0.114 mL, 0.818 mmol) in dichloromethane (64 mL) that was immersed in a room temperature water bath. The rate of addition was adjusted to maintain the internal temperature of the reaction between 19.5° C. and 22.8° C. After completion of the addition, the reaction mixture was diluted with water (50 mL) and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo (300 mbar, 40° C.) to provide the product as a pale yellow oil. The indicated relative stereochemistry of compound C52 was assigned based on nuclear Overhauser enhancement studies, which revealed an interaction between the methine protons on carbons 3a and 5. Yield: 1.73 g, 10.3 mmol, 94%. GCMS m/z 167 [M+]. 1H NMR (400 MHz, CDCl3) δ 4.73 (d, J=13.5 Hz, 1H), 4.61 (dd, J=10.2, 8.0 Hz, 1H), 4.14 (dd, J=13.5, 1.0 Hz, 1H), 3.80 (dd, J=11.5, 8.0 Hz, 1H), 3.36-3.48 (m, 1H), 2.83 (ddd, J=11.0, 8.0, 1.8 Hz, 1H), 2.31 (ddd, J=13.0, 6.5, 1.5 Hz, 1H), 1.64 (ddd, J=12.8, 11.4, 11.3 Hz, 1H), 0.89-0.98 (m, 1H), 0.51-0.64 (m, 2H), 0.38-0.45 (m, 1H), 0.21-0.28 (m, 1H).
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH2:38][CH3:39])[C:35](=[O:40])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH2:45]>O>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:40])[NH:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH3:42])[CH2:38][CH3:39])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)(C)CN
Agent: Oc1ccccn1
Solvent: O
Product: CC[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
24 mg of 2-hydroxypyridine (0.26 mmol) was added to a solution of 250 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (106i) (0.51 mmol) in (2,2-dimethylpropyl)amine (1.20 ml) (10.2 mmol), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/acetone=3/1-2/1) to obtain 246 mg of the title compound (yield: 83%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:10])=[C:5]([C:7](O)=[O:8])[N:6]=1.Cl.C([N:14]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:1][C:2]1[NH:3][C:4]([CH3:10])=[C:5]([C:7]([NH2:14])=[O:8])[N:6]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nc(C(=O)O)c(C)[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(N)=O)c(C)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 115.1 %

Procedure:
A solution of 2,5-dimethyl-4-imidazolecarboxylic acid (1.4 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.93 g), and N-hydroxybenzotriazole (1.49 g) in N,N-dimethylformamide (14 ml) was stirred at 0° C. for 15 minutes. A solution of (2E,4E)- and (2Z,4E)-4-methyl-2,4-heptadien-1-ylamine (1.79 g) in N,N-dimethylformamide (6 ml) was added dropwise to the solution over a period of 10 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 24 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (3% methanol-chloroform) to give N-[(2E,4E)- and (2Z,4E)-4-methyl-2,4-heptadien-1-yl]-2,5-dimethyl-4-imidazolecarboxamide (1.6 g) as an oil.
Reaction SMILES: N.[Na].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1.Br[CH2:22][CH2:23][CH2:24][Cl:25]>CCCCCCC>[Cl:25][CH2:24][CH2:23][CH2:22][N:8]1[C:7]2[CH:6]=[C:5]([C:4]([F:3])([F:19])[F:20])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: ClCCCBr
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Agent: N
Agent: [Na]
Solvent: CCCCCCC
Product: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Temperature: -40 °C
Yield: 157.1 %

Procedure:
Into a 5 liter reactor fitted with stirring and cooling means and maintained at about -40° C., there were poured 1 liter of liquid ammonia, 11.5 g (0.5 mole) of metallic sodium, 0.5 g of ferric acetate and then, slowly, 133.5 g (0.5 mole) of 2-trifluoromethyl-phenothiazine. The mixture was stirred for one hour and there were added 78.8 g (0.5 mole) of 1-bromo-3-chloropropane. After stirring for some minutes, the mixture was allowed to warm slowly up to room temperature, with elimination of the liquid ammonia. There were then added 2 liters of heptane and stirring was maintained for 12 hours. The mixture was then refluxed for one hour and filtered, washed with heptane, evaporated to dryness and recrystallized from heptane to give 270 g (yield 81%) of N-(γ-chloropropyl)-2-trifluoromethyl-phenothiazine.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24]>O.O1CCCC1.[OH-].[Na+]>[CH3:21][N:22]([CH3:26])[C:23](=[S:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CN(C)C(=S)Cl
Reactant: O=C(c1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=S)Oc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
1.4 g (0.025 mol) of potassium hydroxide pellets are added to a suspension of 5.4 g (0.0224 mol) of 4-hydroxyphenyl 4-nitrophenyl methanone in 60 ml of water. The reaction mixture is heated at 50° C. for two hours, with vigorous stirring. The mixture is then cooled to 0° C. and a solution of 3.5 g (0.029 mol) of dimethylthiocarbamoyl chloride in 15 ml of tetrahydrofuran (THF) is added dropwise. When the addition is complete, the reaction mixture is stirred for 15 minutes at 0° C. and then for one hour at 20° C. The reaction medium is then hydrolyzed in 25 ml of 1N NaOH at 0° C. The precipitate obtained is filtered off and washed with water until the pH of the washings is neutral. After drying, it is recrystallized from a methylene chloride/hexane mixture to give 5.9 g (yield: 84%) of the expected product melting at 168° C.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH2:12]([C:15]([NH:21][CH2:22][CH:23]=[O:24])([CH2:18][CH2:19][CH3:20])[C:16]#[CH:17])[CH2:13][CH3:14]>C1C=CC=CC=1>[CH2:18]([C:15]([N:21]([CH2:22][CH:23]=[O:24])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11])([CH2:12][CH2:13][CH3:14])[C:16]#[CH:17])[CH2:19][CH3:20]
Reactant: C#CC(CCC)(CCC)NCC=O
Reactant: CS(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C#CC(CCC)(CCC)N(CC=O)C(=O)Nc1nnc(S(C)=O)s1

Procedure:
A mixture of 5-methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 2-(1,1-dipropylprop-2-ynylamino)acetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the diethyl acetal of 2-[1-(1,1-dipropylprop-2-ynyl)-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)O1>C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc2ccc(-c3ccc(O)cc3)cc2c1
Temperature: 70 °C
Yield: 101.8 %

Procedure:
A solution of methyl 7-{[(trifluoromethyl)sulfonyl]oxy}-2-naphthalenecarboxylate (100 mg, 0.3 mmol), tetrakistriphenylphosphine palladium (14 mg, 0.012 mmol) and 4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl-) phenol (79 mg, 0.36 mmol) in a mixture of dimethoxyethane (1.6 mL) and 2 M aqueous Na2CO3 (1.3 mL) was heated in a 70° C. oil bath for one hour. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by chromatography on silica gel, (hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.085 g, 95.5% as 0.20 ethyl acetate). 1H NMR (DMSO-d6): δ 9.64 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.03-7.99 (m, 2H), 7.93-7.90 (m, 2H), 7.66 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 3.90 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:11][CH2:12][O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: C1=COCCC1
Reactant: CCN(CCO)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCN(CCOC1CCCCO1)c1ccc(Br)cc1
Temperature: 70 °C

Procedure:
14.7 g (60.3 mmols) of N-ethyl-N-(2-hydroxyethyl)-4-bromoaniline, 90 ml of chloroform, 10.68 ml (2.0-fold equivalent weight) of 3,4-dihydro-2H-pyran and 0.76 g (0.05-fold equivalent weight) of pyridine p-toluenesulfonate were mixed, and the mixture obtained was heated at 70° C. for 1.5 hours in an atmosphere of argon. Thereafter, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution obtained, which was then extracted with chloroform (200 ml×2). The organic layer thus formed was washed with a saturated aqueous sodium hydrogencarbonate solution, which was then dried with anhydrous magnesium sulfate and thereafter concentrated. The residue thus obtained was purified by silica gel column chromatography (developing system: chloroform) to obtain 18.90 g of N-ethyl-N-[2-(tetrahydropyran-2-yl)oxyethyl]-4-bromoaniline (yield: quantitative; a colorless oily liquid).