Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH2:12]1[O:22][C:21]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:13]1.[Cl-].[NH4+]>O1CCCC1>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:21]2[O:22][CH2:12][O:13][C:14]=2[CH:15]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A solution of 5 ml (60 mmol) of methyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 37.5 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 9 g 60 mmol) of 3,4 -methylenedioxybenzaldehyde in 60 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 80 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-[3,4-(methylenedioxy) phenyl]-2-butynoate as a brown oil.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:15]=1[C:16](O)=[O:17]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: COc1cccc(C(F)(F)F)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: COc1cccc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, off-white solid, MS: m/e=357.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methoxy-6-trifluoromethylbenzoic acid.
Reaction SMILES: Cl[C:2]1[N:29]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[CH2:18][CH2:17]4)=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])[CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:30][N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:38]=[C:39]([NH:40][C:2]3[N:29]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([N:16]6[CH2:21][CH2:20][CH:19]([N:22]7[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]7)[CH2:18][CH2:17]6)=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:41]=[CH:42][CH:43]=2)[CH2:35][CH2:36]1
Reactant: CN1CCN(C2CCN(c3ccc(-c4cccn5nc(Cl)nc45)cc3)CC2)CC1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(N6CCC(N7CCN(C)CC7)CC6)cc5)cccn4n3)c2)CC1

Procedure:
206 a) 2-Chloro-8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-(4-bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3241 mmol) and 1-methyl-4-piperidin-4-yl-piperazine (66.0 mg, 0.360 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow solid (0.023 g, 17%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (d, J=6.7 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.64 (d, J=7.4 Hz, 1H), 7.10 (t, J=6.8 Hz, 1H), 7.03 (d, J=8.3 Hz, 2H), 3.87 (d, J=12.5 Hz, 2H), 2.82 (t, J=12.6 Hz, 2H), 2.70-2.35 (m, 9H), 2.30 (s, 3H), 1.95 (d, J=11.9 Hz, 2H), 1.75-1.60 (m, 2H). MS=411 (MH)+. 206 b) [3-(4-Methyl-piperazin-1-yl)-phenyl]-(8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 2-chloro-8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridine (23.0 mg, 0.0560 mmol) and 3-(4-methylpiperazin-1-yl)aniline (12.0 mg, 0.0627 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (5.0 mg, 0.0091 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.014 g, 44%). MP=222-225° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.33 (d, J=6.6 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.52 (d, J=7.7 Hz, 1H), 7.48 (s, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.03 (d, J=7.9 Hz, 2H), 6.95-6.89 (m, 2H), 6.82 (s, 1H), 6.57 (d, J=8.4 Hz, 1H), 3.86 (d, J=13.2 Hz, 2H), 3.31-3.26 (m, 4H), 2.81 (t, J=12.2 Hz, 2H), 2.70-2.38 (m, 13H), 2.37 (s, 3H), 2.30 (s, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.75-1.63 (m, 2H). MS=566 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]2[CH:14]([OH:15])[C:13]([CH3:17])([CH3:16])[O:12][C:11]3[CH:18]=[CH:19][S:20][C:10]2=3)=[O:7])=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].[K+].[Br-]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]2[CH:14]([OH:15])[C:13]([CH3:17])([CH3:16])[O:12][C:11]3[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[S:20][C:10]2=3)=[O:7])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Oc2ccsc2C(NC(=O)c2ccc(Cl)cc2)C1O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(NC(=O)c2ccc(Cl)cc2)C1O

Procedure:
The title compound was prepared as described in Example 9 starting with 7-(4-chlorobenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.23 g, 3.64 mmol) and 90% nitric acid (1.5 mL) in acetic acid (20 mL) to give the product, 0.384 g (28%), as a yellow solid: mp 226°-229° C. dec; IR (KBr): 3315, 1655, 1535 and 1503 cm-1 ; MS: m/z 383 (MH+); 1H NMR (DMSO-d6): δ1.25(s, 3H), 1.44(s, 3H), 3.90(m, 1H, simplifies to d, J=8.9 Hz with D2O), 4.95(m, 1H, simplifies to d, J=8.9 Hz, with D2O), 5.94(d, J=6.0 Hz, 1H exchanges with D2O), 7.60(d, J=8.6 Hz, 2H), 7.72(s, 1H), 7.94(d, J=8.6 Hz, 2H) and 9.11(d, J=7.6 Hz, 1H, exchanges with D2O).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]([O:31][C:32]([O:34][CH:35](I)[CH3:36])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:35]([O:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH3:36])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(I)OC(=O)OC(C)(C)C
Agent: [Na+]
Product: CC(OC(=O)OC(C)(C)C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 42.7 %

Procedure:
In the same manner as in Example 81, 89 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 162 mg of 1-(t-butoxycarbonyloxy)ethyl iodide.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH:13]=O)([CH3:3])[CH3:2].[CH3:15][NH2:16].C(O)C.[BH4-].[Na+]>CO>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:13][NH:16][CH3:15])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)c1c(C=O)oc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNCc1oc2ccccc2c1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 3-isopropylbenzofuran-2-carbaldehyde (250 mg, 1.33 mmol) in anhydrous methanol (8 mL) is added a solution of n-methylamine in ethanol (0.281 mL, 5.32 mmol) and the reaction is stirred at room temperature overnight under an atmosphere of argon. The solution is then concentrated, and re-solvated in methanol (8 mL) and cooled in an ice bath. Sodium borohydride (0.152 g, 4 mmol) was added portion wise and the reaction was stirred at room temperature under argon for 6 h. The solution is concentrated, and re-solvated in 1.3N NaOH (5 mL) and ether (5 mL) and stirred for 1 h. The ether layer was collected. The aqueous layer was washed with ether (2×10 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica gel, 9:1 DCM:MeOH) yielded the title compound as a yellow oil (228 mg, 85%): 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J=4.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.25-7.16 (m, 2H), 3.75 (s, 2H), 3.15-3.22 (m, 1H), 2.25 (s, 3H), 1.36-1.34 (2s, 6H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].[C:9](Cl)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O.[OH-].[Na+]>C(Cl)Cl>[C:9]([NH:6][CH:5]([CH3:7])[C:4]([OH:3])=[O:8])(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(=O)Cl
Reactant: COC(=O)C(C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(=O)NC(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 g (291 mmol) of D,L-alanine methyl ester hydrochloride and 64.77 g (640 mmol) of triethyl)amine are initially charged in 300 ml of dry methylene chloride at 0° C. 43.24 g (291 mmol) of heptanoyl chloride in 50 ml of methylene chloride are added dropwise. The mixture is allowed to warm to RT and stirred at this temperature for 2 h. The precipitate is filtered off and the methylene chloride phase is extracted with saturated sodium bicarbonate solution and wraith saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is dissolved in 300 ml of methanol. 300 ml of water, in which 46.55 g (1164 mmol) sodium hydroxide are dissolved, are added to this solution, and the mixture is stirred at RT for 2 h. The mixture is filtered, the methanol is evaporated using a rotary evaporator and the aqueous phase that remains is acidified to pH 1–2 using conc. Hcl. The precipitated product is filtered off and dried. Extraction of the aqueous phase with ethyl acetate gives a second product fraction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](Br)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1.C(O)C.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=3)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2Br)c1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2-c2cccc(F)c2)c1
Yield: 7.6 %

Procedure:
5-Amino-3-bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridine (1.2 g, 29 mmol) was dissolved in toluene (16 ml) and ethanol (18 ml) under argon atmosphere. To the solution Pd(PPh3)4 (157 mg, 0.14 mmol), 3-fluorophenylboronic acid (0.50 g, 35.8 mmol) and 2M solution of Na2CO3 (14 ml) was added. The reaction mixture was refluxed for 1 hour then it was filtered through celite and washed with toluene. The filtrate was tightened in vacuum; water (13 ml) and ethyl acetate (13 ml) were added to the residue. It was separated and the water phase was extracted with ethyl acetate (2×5 ml). The organic phase was washed with water (5.0 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (Kieselgel 60, ethyl acetate:hexane=2:1) to yield 0.94 g (76%) of the title compound. The crude product can be purified by stirring with methanol to give a yellow amorphous material. LC-MS: (M+H)+ 428.2. 1H NMR (500 MHz, DMSO-d6, 25° C.): 5.67 (s, 2H); 6.81 (d, J=2.6 Hz, 1H); 7.00-7.07 (m, 2H); 7.35-7.43 (m, 1H); 7.50-7.60 (m, 2H); 7.60-7.64 (m, 1H); 8.20-8.25 (m, 1H); 8.27 (d, J=2.6 Hz, 1H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O[CH2:10][C:11]1[C:17](O)=[C:16]([CH2:19][CH3:20])[CH:15]=[C:14]([CH2:21]O)[C:12]=1[OH:13].Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH2:21][C:14]1[CH:15]=[C:16]([CH2:19][CH3:20])[CH:17]=[C:11]([CH2:10][C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[C:12]=1[OH:13]
Reactant: CCc1cc(CO)c(O)c(CO)c1O
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: O
Product: CCc1cc(Cc2ccc(O)cc2O)c(O)c(Cc2ccc(O)cc2O)c1
Reaction time: 8 h
Yield: 46.6 %

Procedure:
To a 2 liter round bottom flask was added 800 ml of de-mineralized water, 825.0 g resorcinol and 45.58 g of 2,6-bis(hydroxymethyl)-4-ethylresorcinol. 6.5 ml of concentrated hydrochloric acid was added and the mixture stirred overnight at ambient conditions. The reaction mixture was then added to 12 L of de-mineralized water and slowly stirred at room temperature for 24 hours. The precipitate was isolated by vacuum filtration and washed with de-mineralized water. It was air dried for 24 hours and then vacuum oven dried at 60° C. for 18 hours. About 39.3 g of product was obtained having a purity of about 91% as determined by HPLC analysis.
Reaction SMILES: [N:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[C:10]([CH2:20][CH3:21])=[N:11][N:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][CH3:29])[CH3:25]>C(#N)C.CCOC(C)=O.[Cu]I>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[C:28]1[N:3]=[N:2][N:1]([C:4]2[CH:23]=[CH:22][C:7]([CH2:8][C:9]3[C:10]([CH2:20][CH3:21])=[N:11][N:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=34)=[CH:6][CH:5]=2)[CH:29]=1)[CH3:25]
Reactant: CCOC(CC)OCC
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N=[N+]=[N-])cc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(OCC)c1cn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)nn1

Procedure:
A solution of 3-(4-azido-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (20) (2 g, 6.53 mmol), propionaldehyde diethylacetal (1.294 g, 9.79 mmol) and copper(I) iodide (1.492 g, 7.83 mmol) in 33 ml of acetonitrile was stirred at r.t. for 24 h. The reaction was diluted in EtOAc and washed with sat aq Na2 CO3, water and brine. The organic layer was dried over anhydrous Na2 SO4, filtered and concentrated under HV. The crude product was purified by flash chromatography (silica gel, EtOAc/DCM 0% to 50%) to give a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:23]3[O:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 95 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (2 g, 0.0061 mol), 5-methyl-2-furanboronic acid pinacol ester (1.1 g, 0.0091 mol), sodium carbonate (0.969 g, 0.0092 mol), DMF (80 mL) and water (20 mL) were added and degassed the reaction vessel with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.213 g, 0.0003 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 0-20% ethyl acetate in hexane) to yield the desired product [1.4 g, 70%]. 1H NMR: (400 MHz, CDCl3): δ 8.01 (d, J=1.6 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68 (dd, J′=8.8 Hz, J″=1.6 Hz, 1H), 6.78 (d, J=3.2, 1H), 6.14-6.45 (m, 1H), 3.88 (m, 8H), 2.42 (s, 3H); LC-MS (ESI): Calculated mass: 329.1; Observed mass: 330.0 [M+H]+ (RT: 1.71 min).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.S(Cl)([Cl:15])=O>>[CH2:6]1[O:7][C:8]2[CH:9]=[CH:10][C:2]([C:1]([Cl:15])=[O:12])=[CH:3][C:4]=2[O:5]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: O=C(Cl)c1ccc2c(c1)OCO2

Procedure:
20 g (0.12 mole) of piperonylic acid are suspended in 170 ml of thionyl chloride and refluxed for 2 hours. The solution is concentrated under reduced pressure. The residual oil crystallizes immediately after the addition of petroleum ether. The crystals are spun and washed with petroleum ether.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:20]=[CH:21][C:22]([N+:27]([O-:29])=[O:28])=[C:23]([CH:26]=1)[C:24]#[N:25]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:19]3[CH:20]=[CH:21][C:22]([N+:27]([O-:29])=[O:28])=[C:23]([CH:26]=3)[C:24]#[N:25])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Sc1cccc2cnccc12
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Sc2cccc3cnccc23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 1.20 g (7.4 mmol), DMF 40 ml, potassium carbonate 2.00 g (14.5 mmol) and 5-chloro-2-nitrobenzonitrile 1.30 g (7.1 mmol) was stirred at room temperature for 2 hours, and 5-(5-isoquinolylsulfanyl)-2-nitrobenzonitrile 2.14 g (97.8%) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)=[O:22]>>[C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:20]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(C(C)=O)c3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-aminoacetophenone gave the title compound as an off-white solid, mp 191-194° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1(C(OC)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16].Cl.[OH-:24].[Na+]>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1([OH:24])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16]
Reactant: COC(=O)C1(CCC(C)(C)C)C(=O)CC(=O)c2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)CCC1(O)C(=O)CC(=O)c2ccccc21
Yield: 56 %

Procedure:
A solution of Example 8C (0.28 g, 0.93 mmol) in 1 N NaOH (11.2 mL) was stirred at 45° C. for 2 days. The solution was neutralized to PH 3 with 1 N HCl, extracted with ethyl acetate, and the organic layer was concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound as a white solid (0.135 g, 56%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and-saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (532 mg, 87%).
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][CH:6]([N:8]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)C)C.[C:25](O)(=O)C>[Fe]>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:4](=[O:24])[CH:5]([CH3:25])[CH2:6][N:8]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)[C:14]=2[N:15]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Product: CC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reaction time: 0.17 h

Procedure:
To a solution of 1.07 g (0.030 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butanoic acid ethyl ester in 20 mL of acetic acid was added 1.0 g (0.018 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hrs and then filtered while hot. 50 mL of water and 50 mL of ethyl acetate were added and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-96:4) gave 0.584 g of (rac)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1) as a white solid.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl>O1CCCC1>[OH:15][C@@H:14]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:17][CH:16]=1
Reactant: COP([O-])OC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Product: COP(=O)(OC)[C@H](O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Dimethyl phosphite (37 μl, 0.40 mmol) was added to the solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -78° C., and it was maintained at this temperature for 15 minutes. Then p-nitrobenzaldehyde (0.40 mmol) was added thereto. After the temperature was raised to room temperature, the stirring was continued for 12 hours. Hydrochloric acid (1N) was added thereto to stop the reaction, and the mixture was extracted with ethyl acetate (10 ml×three times). The combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy(p-nitrophenyl)methylphosphonate as a final product in a yield of 81%. The chemical reaction in this Example is shown in chemical formula 31.