Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[N:3]=1
Reactant: Clc1ccccc1CBr
Reactant: O=C1Cc2ccccc2C(=S)N1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Oc1cc2ccccc2c(SCc2ccccc2Cl)n1
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a 50 mL round bottom flask was added 1-thioxo-1,4-dihydro-2H-isoquinolin-3-one (0.8 g, 4.51 mmol), K2CO3 (1.9 g, 13.5 mmol), and absolute EtOH (15 mL) followed by 1-(bromomethyl)-2-chlorobenzene (0.88 g, 4.29 mmol). Upon completion of addition, the reaction mixture was stirred for 18 h. At the conclusion of this period, the reaction mixture was acidified with a solution of citric acid (100 mL, 10% w/v), extracted with EtOAc (100 mL), washed with brine (75 mL) and then dried over Na2SO4. The solvent was removed under vacuum to yield a residue. The residue was purified via silica gel chromatography (20% EtOAc:Hex) to yield the title compound as a pale yellow solid (1.1 g, 3.64 mmol, 81%). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.05 (d, J=8.35 Hz, 1H), 7.59-7.64 (m, 1H), 7.50-7.57 (m, 2H), 7.37-7.42 (m, 1H), 7.31 (ddd, J=8.46, 6.92, 1.32 Hz, 1H), 7.16-7.23 (m, 2H), 6.71 (s, 1H), 5.92 (br. s., 1H), 4.67 (s, 2H). LC/MS m/z 302 [M+H].
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][C:9]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: OCc1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CCl)ccc1CC1CCCCC1
Temperature: 75 °C
Yield: 100 %

Procedure:
To a solution of (4-(cyclohexylmethyl)-3-(trifluoromethyl)phenyl)methanol (0.060 g, 0.220 mmol) in toluene (2 mL) was added thionyl chloride (1.32 mmol). The reaction was heated to 75° C. for 3 h and quenched with water at 0° C. The mixture was extracted with hexanes (twice). The combined organics were washed with saturated NaHCO3(aq), dried over MgSO4, and concentrated to give the title compound as an oil (0.220 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 0.91-1.06 (m, 2H), 1.12-1.23 (m, 3H), 1.61-1.74 (m, 6H), 2.66 (d, J=6.95 Hz, 2H), 4.59 (s, 2H), 7.30 (d, J=7.96 Hz, 1H), 7.47 (d, J=7.96 Hz, 1H), 7.63 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 121.1 %

Procedure:
A solution of 1-bromo-4-(trifluoromethyl)benzene (1.0 g, 4.44 mmol, 1.00 equiv), pyridin-4-ylboronic acid (820 mg, 6.67 mmol, 1.50 equiv), PCy3 (156 mg, 0.56 mmol, 0.14 equiv), Pd2(dba)3 (220 mg, 0.24 mmol, 0.06 equiv), and K3PO4 (2.5 g, 11.79 mmol, 3.00 equiv) in 1,4-dioxane (10 mL) was placed in a 20-mL sealed tube under inert atmosphere stirred overnight at 100° C. in an oil bath, and then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:20)) yielded 1.2 g (crude) of 4-(4-(trifluoromethyl)phenyl)pyridine as a yellow solid.
Reaction SMILES: [CH2:1]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1>>[CH2:1]([S:8](/[CH:11]=[CH:12]/[C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Cc1ccccc1
Yield: 78 %

Procedure:
A solution of benzyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 78% yield.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][CH:13]=[C:9]3[N:8]=[C:7]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH:6]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.CN([CH:31]=[O:32])C>>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:31]=[O:32])=[C:9]3[N:8]=[C:7]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: N#Cc1cccc(Cc2cc(NC3CC3)n3nccc3n2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(Cc2cc(NC3CC3)n3ncc(C=O)c3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To 3-((7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile (69 mg, 0.24 mmol) in DMF (0.6 mL), POCl3 (130 μL, 1.4 mmol) was added at room temperature. After the addition was complete, the reaction was stirred for 1 hour at room temperature. Then, the reaction was quenched by addition to ice cold 6N NaOH. The mixture was diluted with water and the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, 3-((7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile, was collected as a solid in 37% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][Li]>>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=2[C:7](=[O:8])[CH3:26])=[CH:17][CH:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [Li]C
Reactant: O=C(O)c1cc(Cl)ccc1Nc1ccc(OCc2ccccc2)cc1
Product: CC(=O)c1cc(Cl)ccc1Nc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
[II; R=5-Cl, R' and R"=H, OR°=4-OCH2C6H5, Alk=CH3 ] was prepared from 5-chloro-2-(4-benzyloxyphenylamino)benzoic acid and methyllithium according to the procedure of Example 1, part (a), and obtained in about 80% yield as a yellow solid, m.p. 74°-75° C. when recrystallized from cyclohexane.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[N:24][N:23]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:27]([C:25]1[S:26][C:22]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)=[N:23][N:24]=1)(=[O:28])=[O:29])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(-c2nnc(S(=O)(=O)Cl)s2)cc1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(4-nitrophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (400 MHz; DMSO-d6) δ 8.42 (d, 2H), 8.27 (d, 2H), 6.40 (brs, 2H), 4.05 (q, 2H), 3.35 (s, 2H), 3.21 (t, 2H), 2.71 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1COCC1.C[Mg]I.[NH4+].[Cl-]>CCOCC>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][C:10]([C:11]([OH:12])([CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C(=O)c1ccc(-c2ccccc2)cc1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)c1ccc(-c2ccccc2)cc1
Temperature: -25 °C

Procedure:
To a flame dried 500 mL flask flushed with N2, was added 24 g (100 mmol) of ethyl 4-phenylbenzoylformate and 300 mL of anhydrous THF. The solution was cooled with stirring to -25° C. and 37 mL (110 mmol) of a 3.0 M solution of methylmagnesium iodide was added at a rate to maintain the reaction temperature below -10° C. The reaction progress was monitored by TLC and upon disappearance of starting material, 100 mL of saturated NH4Cl solution and 200 mL of ether were added. The organic layer was separated and washed with 2×50 mL of brine, dried (MgSO4) and concentrated leaving racemic ethyl 2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionate as an oil.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][OH:12])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:11][OH:12])[C:8]([NH:22][O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NOCc1ccccc1
Reactant: O=C(O)[C@@H](CO)CC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)[C@@H](CO)CC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a mixture of (2R)-3-cyclopentyl-2-(hydroxymethyl)propanoic acid (18.3 g, 106 mmol), O-benzyl hydroxyamine hydrochloride (18.62 g, 117 mmol) and 4-(dimethylamino)pyridine (28.5 g, 233 mmol) in dichloromethane (110 mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (22.3 g, 117 mmol). The mixture was maintained at 0° C. for 3 h. After this time, 500 mL of 1N cold, aqueous HCl solution was added, and the mixture was stirred for another 30 min. The resulting white solid precipitate was collected by filtration. The precipitate was washed with 1N HCl, with water, and with cold DCM. Drying overnight in a vacuum dessicator provided (2R)-3-cyclopentyl-2-(hydroxymethyl)-N-[(phenylmethyl)oxy]propanamide (19.1 g, 65%). LCMS: (M+H)+: 278.1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([NH2:11])=[N:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2cc(Br)ccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(-c2ccc3c(N)n[nH]c3c2)cc1

Procedure:
A commercial “Miniblock” reactor was charged with trityl-resin bearing 6-bromo-1H-indazol-3-amine (95 mg, 0.066 mmol); 4-methoxyphenylboronic acid (0.3 mmol); Pd2dba3 (5 mg). Subsequently the reactor was sealed and the reaction mixture was put under inert atmosphere (N2 or Ar).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:7]([NH:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=O)Nc1ccsc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCNc1ccsc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of N-3-thienylpentanamide (13.4 g, 73.0 mmol) in THF (200 mL) was added LiAlH4 (3.50 g, 100 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h and at 60° C. for 1 h. After cooling down to ambient temperature, the reaction was quenched by the addition of saturated sodium sulfate dropwise until the color change from green to white and diluted with THF (200 mL). The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to yield the title compound (9.70 g, 79%): MS (ES+) m/z 170.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([NH2:21])=[S:20])#[N:17]>>[NH2:21][C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=1)/[C:16]#[N:17])=[S:20]
Reactant: N#CCC(N)=S
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Product: COc1cc(/C=C/C=C(\C#N)C(N)=S)cc(OC)c1O
Yield: 47.8 %

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.15 g, 0.72 mmol) to 2-cyanothioacetamide (0.073 g, 0.72 mmol). After refluxing for 1 h the residue was purified on a TLC-plate in hexane-ethyl acetate, 1:1 to give a red solid (0.10 g, 52%). The product gave the following analytical data:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:37][C:38]1[C:46]2[C:45]([N:47]3[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]3)=[N:44][CH:43]=[N:42][C:41]=2[NH:40][CH:39]=1>CC#N>[CH3:37][C:38]1[C:46]2[C:45]([N:47]3[CH2:52][CH2:51][CH:50]([NH:53][C:12](=[O:14])[C:11]4[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH:10]=4)[CH2:49][CH2:48]3)=[N:44][CH:43]=[N:42][C:41]=2[NH:40][CH:39]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: O=C(O)c1cccc(OCCN2CCCC2)c1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: Cc1c[nH]c2ncnc(N3CCC(NC(=O)c4cccc(OCCN5CCCC5)c4)CC3)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-{[2-(1-pyrrolidinyl)ethyl]oxy}benzoic acid D38 (200 mg) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (171 mg, 0.98 mmol) was dissolved under argon in MeCN (20 ml) and cooled down to 0° C. Then N-methylmorpholine (0.3 ml) was added and the mixture was stirred at 0° C. for 2 hours. To this mixture was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (240 mg) in small portions, afterwards the reaction was then warmed up to room temperature. After stirring for 16 hours, the reaction was filtered and concentrated to give crude product. This product was purified by prep-HPLC (A 0.01% NH4HCO3/Water, B: ACN, 0˜8 min 25-50%, 50%˜60% 8-12 min, 60%˜95% 12-15 min, 95˜95% 15-18 min) to give 50 mg of white solid of desired product E43. LCMS [MH+] 449.2@1.52 min (5 min run)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccccc3)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and phenylboronic acid (122 mg, 1.0 mmol) to afford after chromatographic purification the title compound (74 mg, 20%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]2[O:16][CH3:17])=O.[OH:18][CH2:19][C@H:20]([NH:27][C:28]1[S:29][CH2:30][C:31](=[O:33])[N:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:18][CH2:19][C@H:20]([NH:27][C:28]1[S:29]/[C:30](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]3[O:16][CH3:17])/[C:31](=[O:33])[N:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1c(C(N)=O)cnc2ccc(C=O)cc12
Reactant: O=C1CSC(N[C@@H](CO)c2ccccc2)=N1
Product: COc1c(C(N)=O)cnc2ccc(/C=C3\SC(N[C@@H](CO)c4ccccc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-methoxy-quinoline-3-carboxylic acid amide (example 2b) and 2-((R)-2-hydroxy-1-phenyl-ethylamino)-thiazol-4-one (example 3a) to give 6-[2-((R)-2-hydroxy-1-phenyl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-methoxy-quinoline-3-carboxylic acid amide. LC-MS m/e 449 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[O:8][C:7](=[O:12])[NH:6][C:5]=2[S:4][CH:3]=1.[CH2:13](N1C2SC=CC=2C(=O)OC1=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:6]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:10]=2[C:9](=[O:11])[O:8][C:7]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2sccc12
Reactant: Cc1csc2[nH]c(=O)oc(=O)c12
Product: Cc1csc2c1c(=O)oc(=O)n2Cc1ccccc1

Procedure:
This compound was prepared from 5-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (57) by applying the same method as described for the preparation of 1-benzyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (58). Yield 4.2 g (56%); MP 183° C. 1H-NMR (DMSO-d6) δ 2.31 (s, 3H), 5.10 (s, 2H), 6.85 (s, 1H), 7.37 (m, 5H) ppm; EIMS m/z 274 (M+1).
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10](=[O:12])[CH3:11])[CH:6]=1.[N+:13]([C:16]1[CH:20]=[N:19][NH:18][N:17]=1)([O-:15])=[O:14].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[N+:13]([C:16]1[CH:20]=[N:19][N:18]([CH2:4][C:5]2[O:9][N:8]=[C:7]([C:10](=[O:12])[CH3:11])[CH:6]=2)[N:17]=1)([O-:15])=[O:14]
Reactant: CC(=O)c1cc(CCl)on1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cn2ncc([N+](=O)[O-])n2)on1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-hydroxymethyl-isoxazol-3-yl)-ethanone (262 mg, 1.86 mmol) in dry CH2Cl2 (2.6 mL) was treated at 0° C. with Et3N (0.34 mL, 2.41 mmol) followed by DMAP (23 mg, 0.19 mmol) and Ms-Cl (0.17 mL, 2.23 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure to give crude 1-(5-chloromethyl-isoxazol-3-yl)-ethanone as a pale yellow oil. In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 1-(5-chloromethyl-isoxazol-3-yl)-ethanone in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (210 mg, 1.84 mmol) in DMF (3.0 mL) pre-treated for 30 min with DIPEA (0.63 mL, 3.68 mmol) and the reaction mixture was stirred for 16 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (2:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.90 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:18][C:9]2=[N:10][C:11]([Cl:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@H:35]([CH3:37])OS1(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[N:18]([C@H:35]([CH3:37])[CH2:36][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:9]2=[N:10][C:11]([Cl:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to example 3, intermediate j) from 6-chloro-5-ethoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium tert-butoxide and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1](=[C:3]1[CH2:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[CH2:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[OH:2].C([BH3-])#N.[Na+].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl>CO>[NH:1]([CH:3]1[CH2:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[CH2:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[OH:2]
Reactant: C=C1c2ccccc2C(=NO)Cc2sccc21
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: C=C1c2ccccc2C(NO)Cc2sccc21

Procedure:
9-Hydroximino-4-methylene-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene (5.7 g), sodium cyanoborohydride (5.4 g) and methyl orange (0.05 g) are stirred in methanol (150 ml). A solution of concentrated HCl in methanol (1:1 v/v) is added dropwise at a rate sufficient to maintain the mixture at the indicator turning point until thin layer chromatography (silica gel plate, methylene chloride elution) indicates the starting oxime has been consumed (2-3 hours). The mixture is evaporated to dryness in vacuo and the residue is treated with water (250 ml) and adjusted to pH 8 with concentrated ammonia. The mixture is extracted with ether (3×80 ml) and the combined ether layers are washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo to give 9-hydroxamino-4-methylene-9,10-dihydro-4H-benzo[4,5]cyclohepta-[1,2-b]thiophene.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[CH2:10][NH:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:13])[CH2:10][N:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: CNCC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CN(CC(=O)OCc1ccccc1)C(=O)CCC(=O)O
Yield: 86.3 %

Procedure:
A mixture of sarcosine benzyl ester (3.0 g, 30.7 mmol) and succinic anhydride (5.5 g, 30.7 mmol) in toluene (75 mL) was heated to reflux for 3 h, cooled, filtered, and the filtrate was concentrated. The residue was taken up in 5% aqueous sodium carbonate and extracted with ethyl acetate. The aqueous phase was adjusted to pH 3 with concentrated hydrochloric using Congo Red paper and extracted with ethyl acetate. The organic phase was washed with water, dried (magnesium sulfate) and concentrated to yield the title compound (7.4 g, 67.5%): TLC Rf 0.48 (silica, 9:1:1 dichloromethane:methanol:formic acid).
Reaction SMILES: [C:1](=[O:3])=[O:2].[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[CH:5]>>[C:6]1([C:4]#[C:5][C:1]([OH:3])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: O=C=O
Product: O=C(O)C#Cc1ccccc1
Yield: 52 %

Procedure:
The longer reaction time for the P1 catalysed reaction may be due to the heterogeneous reaction behavior in this solid catalyst system. A reaction intermediate Poly(NHC—CO2)0.5(NHC—Cu)0.5 was synthesized by reaction of Poly(NHC)0.5(NHC—Cu)0.5 (P1) with CO2. This intermediate was directly used to react with stoichiometric amount 1-ethynylbenzene (1 eq. to NHC—CO2) under standard condition without an additional CO2 source. 52% yield of phenylpropiolic acid was obtained in 24 hours. With these experiment results, it is believe that the unique structure of P1 catalyst is the key to the high activities. The free carbene species in the structure are randomly located around copper center and act as an organo catalyst to activate CO2. This essential step may reduce the activation energy barrier for CO2 insertion.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]([OH:13])[C:11]([C:14]([F:17])([F:16])[F:15])=[N:10][C:7]2=[N:8][CH:9]=1)([O-])=O.C(O)C.Cl.[H][H]>[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]2[N:12]([OH:13])[C:11]([C:14]([F:15])([F:17])[F:16])=[N:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2nc(C(F)(F)F)n(O)c2c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cnc2nc(C(F)(F)F)n(O)c2c1

Procedure:
6-Nitro-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (4.9 grams) was mixed with 100 milliliters of ethanol and 3 milliliters of concentrated hydrochloric acid, and 1 gram of 5 percent palladium on carbon was added to the mixture. The mixture was hydrogenated to a 3 mole-equivalent uptake of hydrogen. The reaction mixture was then filtered and evaporated, yielding a gummy solid residue which was taken up in 150 milliliters of water and used directly in the reaction reported in the following example.