Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]1[CH2:13][C:12]2[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)[CH:16]=[N:17][C:11]=2[NH:10][C:9]1=[O:23])=[O:6])[CH3:3].Cl.[CH3:25][N:26]1[CH2:32][C:31]2[CH:33]=[C:34](/[CH:37]=[CH:38]/[C:39](O)=O)C=N[C:30]=2[NH:29][C:28](=O)[CH2:27]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[CH2:2]([O:4][C:5](=[O:6])[CH2:7][N:8]1[CH2:13][C:12]2[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20](=[O:22])[N:29]([CH3:30])[CH2:28][C:27]3[N:26]([CH3:25])[C:32]4[C:38]([CH:39]=3)=[CH:37][CH:34]=[CH:33][CH:31]=4)[CH:16]=[N:17][C:11]=2[NH:10][C:9]1=[O:23])[CH3:3]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2NC1=O
Yield: 89 %

Procedure:
According to the procedure of Example 1 (a), except substituting (E)-3-(3-ethoxycarbonylmethyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (1.20 g, 89%) was prepared as a tan solid and as a mixture of amide rotomers: 1H NMR (300 MHz, CDCl3) δ 8.34-8.28 (m, 1H), 7.66-7.34 (m, 2H), 7.60-7.53 (m, 2H), 7.33-7.21 (m, 2H), 7.11 (t, J=7.5 Hz, 1H), 6.83 (d, J=15.0 Hz, 1H), 6.50-6.40 (m, 1H), 4.93-4.30 (m, 2H), 4.59-4.52 (m, 2H), 4.27-4.19 (m, 4H), 3.71 (s, 3H), 3.13-3.06 (m, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (ESI) m/e 462 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@:8]([CH3:29])([CH2:11][CH2:12][C:13]1[O:14][C:15]([C:18]#[C:19][CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:17]=1)[CH2:9][OH:10])=[O:6])[CH:2]=[CH2:3].N1C=NN=N1.C(N(C(C)C)[P:39]([O:44][CH2:45][CH:46]=[CH2:47])[O:40][CH2:41][CH:42]=[CH2:43])(C)C.ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[P:39]([O:40][CH2:41][CH:42]=[CH2:43])([O:44][CH2:45][CH:46]=[CH2:47])([O:10][CH2:9][C@@:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])([CH3:29])[CH2:11][CH2:12][C:13]1[O:14][C:15]([C:18]#[C:19][CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:17]=1)=[O:59]
Reactant: C=CCOP(OCC=C)N(C(C)C)C(C)C
Reactant: C=CCOC(=O)N[C@@](C)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: C=CCOC(=O)N[C@](C)(CCc1ccc(C#CCCOC2CCCCC2)o1)COP(=O)(OCC=C)OCC=C
Yield: 81.2 %

Procedure:
To a solution of (2R)-2-allyloxycarbonylamino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)furan-2-yl]butan-1-ol (0.6202 g, 1.54 mmol) obtained in Example (26a) in dichloromethane (15 ml) were added successively 1H-tetrazole (0.7220 g, 10.31 mmol) and diallyl diisopropylphosphoramidite (0.81 ml, 3.06 mmol) with stirring under ice-cooling, and then the reaction mixture was stirred at room temperature for 2 hours. After stirring, to the reaction mixture was added m-chloroperbenzoic acid (content: 70%) (0.7556 g, 3.07 mmol) with stirring under ice cooling, and the resulting mixture was stirred at the same temperature for 10 minutes. After stirring, to the reaction mixture was added 10% aqueous sodium thiosulfate solution to quench the reaction, and the resulting mixture was extracted with dichloromethane. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:2) as the eluent to afford the title compound (0.7049 g, yield: 81%).
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].N1C=CC=CC=1.[Cl:36][C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:37]([Cl:36])=[O:39])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCNC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2-(2-ethylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (19.9 mg, 0.05 mmol) and pyridine (20 μL, 0.15 mmol) in CH2Cl2 (2 mL) at 0° C. was added triphosgene (22.7 mg, 0.08 mmol) in CH2Cl2 (0.5 mL). The resulting solution was warmed to rt, and stirred for 1 h. The completion of reaction was confirmed by LC-MS, and the product was used for next step without workup.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[OH:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=1.N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2](/[N:1]=[C:20]2\[CH:21]=[CH:22][C:17](=[O:16])[CH:18]=[C:19]\2[NH:23][C:24](=[O:26])[CH3:25])[C:3](=[O:15])[N:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)NC1=CC(=O)C=C/C1=N\c1c(C)n(C)n(-c2ccccc2)c1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of N-(3-hydroxyphenyl)acetamide in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][CH3:24])[CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH2:23]([C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[C:13]=1[CH3:22])(=[O:10])=[O:11])[CH3:24]
Reactant: OB(O)c1ccncc1
Reactant: CCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
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: COCCOC
Solvent: CCO
Product: CCc1cc(-c2ccncc2)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 25.1 %

Procedure:
This product was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-ethyl-phenyl)-amide (0.10 g) and 4-pyridineboronic acid (0.043 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.25 ml) and 2 M aqueous sodium carbonate solution (0.9 ml) with tetrakis(triphenylphosphine)palladium (0.013 g) to obtain the title compound (0.025 g) as a yellowish foam. MS (ISP): 427.3 (M+H)+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C(=C)C(O)=O.[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]O)[CH3:12].[OH2:20]>>[C:2]([O:1][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[CH2:14][CH:13]([CH2:11][CH3:12])[CH2:16][CH2:17][CH2:18][CH3:19])(=[O:20])[CH:3]=[CH2:4]
Reactant: CCCCC(CC)CO
Reactant: C=C(C(=O)O)c1ccco1
Reactant: O
Product: C=CC(=O)Oc1occc1CC(CC)CCCC
Temperature: 190 °C
Yield: 92.6 %

Procedure:
Furylacrylic acid (23 g, 0.135 mol), 2-ethylhexanol (87.5 g, 0.67 mol) and 0.5 ml Tyzor® (DuPont tetraisopropyltitanate) were mixed in a 3-neck round bottom flask equipped with a thermometer, condenser and high speed stirrer. The mixture was heated to 190° C. and held there with stirring until the theoretical 2.4 ml of water was distilled off at atmospheric pressure. The residual product was distilled at 134° C./0.5 torr yielding 33.0 g (92.6%) of 2-ethylhexylfuryl acrylate. A gas chromatagraphic analysis indicated the product was 97.1% pure. The material has peak absorption at 300.1 nm and a K of 98.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCOc1ccc(CCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)CCCOc1ccc(CCCO)cc1

Procedure:
After the method of Preparation 3, 4.13 g (15.51 mmol) of 4-[4-(3-hydroxypropyl)phenoxy]butanoic acid, ethyl ester is saponified with potassium carbonate to produce a solid. This is recrystallized from an ethyl acetate-hexane mixture giving 2.45 (66%) of 4-[4-(3-hydroxypropyl)phenoxy]butanoic acid as white crystals: m.p. 92°-94° C.; IR (KBr) 3420 (br.), 1710 cm-1 ; 1 H-NMR (CDCl3) is consistent with the desired product; MS (CI) m/e 239 (M+ +H). Analysis calculated for C13H18O4 : C, 65.53; H, 7.61; O, 26.86. Found: C, 65.75; H, 7.87; O, 26.38.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].[NH2:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:31]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:30]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:5]([NH:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:41])[F:42])[N:31]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:30]1)=[O:6])=[N+:2]=[N-:3]
Reactant: COc1ccc([C@@H](c2ccccc2)[C@H](N=[N+]=[N-])C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc([C@@H](c2ccccc2)[C@H](N=[N+]=[N-])C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (151 mg, 0.45 mmol) and the product from step 4 of Example 99 (200 mg, 0.42 mmol) were dissolved in pyridine (5 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.04 mL, 0.45 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (5 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×15 mL). The combined dichloromethane extracts were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-N2)+=764.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:65][CH:64]=1)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:62][C:63]3[CH:64]=[CH:65][C:66]([C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)=[CH:67][CH:68]=3)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(N)nc3cc(C(=O)N[C@@H](Cc4ccc(-c5ccccc5)cc4)C(=O)N(C)C)ccc23)CC1
Reaction time: 0.17 h
Yield: 18.6 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (26 mg, 0.070 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (12 uL, 0.070 mmol). The reaction was stirred for 10 min., and the (2S)-2-amino-3-biphenyl-4-yl-N,N-dimethylpropanamide (19 mg, 0.070 mmol) was added. The reaction was stirred for 2 h. at r.t., and was purified by RP-HPLC (pH=10) to afford the desired product (3 mg, 20%) as a white solid. Analytical LCMS (M+H)+: m/z=538.0.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[CH:20]=1.O>CCCCCC.C1(C)C=CC=CC=1>[CH3:18][C:8]1[CH:9]=[C:10]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]2=[N:12][C:7]=1[CH:25]([C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[OH:26]
Reactant: Cc1cc2c(nc1Br)CCCCC2
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c(nc1C(O)c1cccnc1)CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 ml) in toluene (20 ml) at -20° C., under nitrogen, was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyridine (6 g, 0.025 m) in toluene (30 ml) and kept at -20° C. for 0.25 hours. This was blown over into a solution of 3-pyridine carboxaldehyde (2.7 g) in toluene (30 ml) kept at -20° C. The solution was allowed to warm up to room temperature and water added. The organic phase was separated, dried (MgSO4) and evaporated. The solid was recrystallised from ether (twice) to give 1-(6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyrid-2-yl)-1-(pyrid-3-yl)methanol (4.32 g, 64%) m.p. 124°-6° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].C1(O)C=CC=CC=1>C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:22][C:14]3[S:15][C:16]4[C:21]([N:13]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)[C:3]=2[N:11]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Nc1nc2cccnc2s1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: Clc1ccc2ncnc(Nc3nc4cccnc4s3)c2n1
Yield: 49.3 %

Procedure:
4,6-Dichloro-pyrido[3,2-d]pyrimidine (100 mg; 0.503 mmol) and 76 mg (0.503 mmol) of thiazolo[5,4-b]pyridin-2-yl-amine in 0.3 mol of phenol were heated at 140° C. for 2 hours with stirring. Ethyl acetate was added to the reaction solution and the resulting solid was purified by a thin layer silica gel column chromatography (chloroform:methanol=10:1) to give 78 mg (yield: 45%) of (6-chloro-pyrido[3,2-d]pyrimidin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH2:10][C:9](=[O:18])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:19]I>CN(C=O)C.C(Cl)Cl.O>[CH3:19][CH:10]1[C:9](=[O:18])[NH:8][C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]1=2
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC1C(=O)Nc2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A round bottom flask was charged with sodium hydride (0.295 g, 7.46 mmol) in 9.0 mL of DMF and treated with 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.3 g, 6.22 mmol) (CAS #20011-90-9, prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein, which are incorporated herein by reference). After stirring at 60° C. for 1 hour, the solution was treated with methyl iodide (1.16 mL, 18.6 mmol) and stirring continued for 17 hours with the exclusion of light. After cooling, the reaction was diluted with CH2Cl2/H2O, washed with NaHSO4 solution, H2O, and dried over Na2SO4. Evaporation and flash chromatography (SiO2, CHCl3) gave 0.885 g (63%) of the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][CH3:18])[CH3:14].N1CCCCC1>CN(C=O)C.CCOC(C)=O.[Cu](I)I>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[C:17]1[O:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[CH:18]=1)[CH3:14]
Reactant: CCOC(CC)OCC
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCOC(OCC)c1cc2ccc(C(=O)OC)cc2o1
Temperature: 45 °C
Reaction time: 6 h
Yield: 32.2 %

Procedure:
A dried flask under nitrogen is charged with methyl 3-hydroxy-4-iodobenzoate (10.0 g, 35.9 mmol), propioaldehyde diethyl acetal (5.72 ml, 40.0 mmol), bistriphenylphosphine palladium diacetate (538 mg, 0.72 mmol), copper iodide (273 mg, 1.4 mmol) and piperidine (3.94 ml, 40.0 mmol) in DMF (50 ml). The mixture is stirred at 45° C. for 6 h, then at RT overnight. The reaction is diluted with EtOAc (250 ml) and washed with 50% saturated 1:1 NaCl/NaHCO3 solution (4×100 ml). The organic layer is dried (Na2SO4), filtered and concentrated to a brown oil. The crude material is chromatographed over 500 g slurry-packed silica, eluting with 15% EtOAc/hexane. The appropriate fractions are collected and concentrated, affording 3.22 g (32%) of methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate as an orange oil. 1H NMR (400 MHz, CDCl3): δ 1.29, 3.72, 3.96, 5.70, 6.88, 7.61, 7.95, 8.20 ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH2:12].[CH3:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23](Cl)=[O:24])[CH:18]=[C:19]([CH3:21])[CH:20]=1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:23](=[O:24])[CH2:22][C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Reactant: Cc1cc(C)cc(CC(=O)Cl)c1
Product: COC(=O)c1cc(I)c(Cl)cc1NC(=O)Cc1cc(C)cc(C)c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-4-chloro-5-iodo-benzoic acid methyl ester (2.26 g in 25 mL dichloroethane) was added (3,5-dimethylphenyl) acetyl chloride (1.2 g in 15 mL dichloroethane) and the mixture heated to 75° C. on an oil bath. After 3 hours, the reaction was cooled and the solvent removed in vacuo. The title compound was isolated by crystallization from methanol (2.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][NH:23][C@@H:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2].Cl[C:35]([O:37][CH3:38])=[O:36]>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][N:23]([C:35]([O:37][CH3:38])=[O:36])[C@@H:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)Cc1cccc(Oc2ccc([N+](=O)[O-])cc2CN[C@@H](C)Cc2ccccc2)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc([N+](=O)[O-])cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: (3-{2-[((S)-1-methyl-2-phenyl-ethylamino)-methyl]-4-nitro-phenoxy}-phenyl)-acetic acid ethyl ester and methyl chloroformate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)[C:9]2[CH:22]=[CH:21][C:20]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(O)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N:30]([C:38]5[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=5)[C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)[CH:17]=4)[C:12]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)(O)[C:11]=3[CH:10]=2)=[CH:4][CH:3]=1.[I-].[Na+].O.[PH2]([O-])=O.[Na+].O>C(O)(=O)C>[CH3:44][C:41]1[CH:40]=[CH:39][C:38]([N:30]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:16]2[CH:15]=[CH:14][C:13]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]4[C:11]([C:12]=3[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[CH:10][C:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)=[CH:22][CH:21]=4)[CH:17]=2)=[CH:43][CH:42]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c(c2)C(O)(c2ccccc2)c2ccc(N(c4ccc(C)cc4)c4ccc(C)cc4)cc2C3(O)c2ccccc2)cc1
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c(-c4ccccc4)c4cc(N(c5ccc(C)cc5)c5ccc(C)cc5)ccc4c(-c4ccccc4)c3c2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
The crude N,N,N′,N′-tetrakis(4-methylphenyl)-2,6-diamino-9,10-dihydro-9,10-diphenyl-9,10-anthracenediol was dissolved in 65 ml acetic acid. Sodium iodide (10 g), and sodium hypophosphite hydrate (10 g) were added with stirring. The mixture was heated to reflux for 60 minutes, cooled to room temperature and poured into water. The precipitated solid was collected by filtration, washed with water, washed with a small amount of methanol (˜5 ml) and then dried. Purification by column chromatography yielded 2.3 g (76% yield) of pure N,N,N′,N′-tetrakis(4-methylphenyl)-9,10-diphenyl-2,6-anthracenediamine (Inv-B73) as an orange solid. At a pressure of 600 mTorr, Inv-3 sublimed at 290° C. using train sublimation. FD-MS (m/z): 720.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][C:13](=C)[CH2:12][C@@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:24]>>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH2:12][C:13](=[O:24])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Reactant: CO
Product: O=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(S)-benzyloxymethyl-2-(S)-(3-fluorophenyl)-4-methylenecyclopentane from Step A (7.1 g, 25.5 mmol) in methanol (300 mL) was cooled in a dry ice/acetone bath and ozone was bubbled into the solution until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (10 mL) was added. After 10 min, the bath was removed and the reaction was allowed to warm to room temperature over 2 h. The mixture was treated with 10 drops of sulfuric acid (c) in water (2 mL) for 1 h before most of the methanol was removed in vacuo. The mixture was diluted with water and extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (15% ethyl acetate in hexanes) to give the title compound (4.74 g).