Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][CH:9]=2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>CN1C(=O)CCC1>[O:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)=[CH:9]1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cc(-c2ccoc2)ccc1F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(Nc2ccc(-c3ccoc3)cc2[N+](=O)[O-])c1
Temperature: 110 °C
Yield: 33.5 %

Procedure:
To a solution of 1d (2.07 g, 10 mmol) in NMP (2 ml) was added ethyl 3-aminobenzoate (1.82 g, 11 mmol) and triethylamine and the mixture was heated to 110° C. in a nitrogen atmosphere overnight. The mixture was diluted with ice-water and extracted with ethyl acetate . The concentrated extract was purified by column-chromatography on silica gel using a mixture of petroleum ether and ethyl acetate (9:1 v/v) to yield ethyl 3-(N-(4-(3-furanyl)-2-nitrophenyl))aminobenzoate (1.18 g, 34%). This ester was hydrogenated in ethanol at ambient pressure using Pd (5% on activated carbon) as the catalyst. The resulting diamine (1.07 g) was treated with triethyl orthoformate (1.11 ml, 6.64 mmol) and a catalytic amount of pTSA in refluxing THF (10 ml). Column-chromatographic work-up of the concentrated reaction mixture using ethyl acetate as the eluent afforded 6c1 (0.66 g, 56%). M.p. 87-89° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]([OH:9])=O)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([O:54][C:55]1[C:64]([CH3:65])=[CH:63][C:58]([C:59]([NH:61][NH2:62])=[O:60])=[CH:57][C:56]=1[CH2:66][CH3:67])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl.CN(C=O)C>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([C:7]([NH:62][NH:61][C:59](=[O:60])[C:58]2[CH:63]=[C:64]([CH3:65])[C:55]([O:54][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:56]([CH2:66][CH3:67])[CH:57]=2)=[O:9])[CH:10]=[C:11]([CH3:13])[N:12]=1)[CH3:15]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(C(=O)NNC(=O)c2cc(C)nc(N(CC)CC)c2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of 2-diethylamino-6-methyl-isonicotinic acid (1.50 g, 6.13 mmol) and DIPEA (2.38 g, 18.4 mmol) in DCM (25 mL), TBTU (2.16 g, 6.74 mmol) is added. The mixture is stirred at rt for 10 min before a solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide (3.32 g, 6.13 mmol) in DMF (10 mL) is added. The mixture is stirred at rt for 1 h before it is diluted with DCM and washed with sat. aq. NaHCO3-solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with a gradient of EA in heptane to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N′-(2-diethylamino-6-methyl-pyridine-4-carbonyl)-hydrazide (2.1 g) as a gum; LC-MS: tR=0.88 min, [M+1]+=not detectable. This material (2.10 g, 4.42 mmol) is dissolved in THF (40 mL) and Burgess reagent (1.16 g, 4.87 mmol) is added. The mixture is stirred at 110° C. for 5 min under microwave irradiation. The mixture is cooled to rt, diluted with diethyl ether and washed with water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give {4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-6-methyl-pyridin-2-yl}-diethyl-amine (1.03 g) as a pale yellow gum; LC-MS: tR=0.99 min, [M+1]+=457.27.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[CH:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>C1COCC1>[C:7](/[CH:9]=[CH:19]/[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CC=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C/C=C/C#N)CC1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a solution of 1 M of potassium tert-butoxide in THF (45.5 mL, 0.0455 mol) at 0° C. was added drop wise a solution of diethyl cyanomethylphosphonate (7.72 mL, 0.0477 mol) in THF (70 mL). The reaction mixture was warmed up to at RT, cooled to 0° C. again, and a solution of tert-butyl 4-(2-oxoethyl)piperazine-1-carboxylate (9.90 g, 0.0434 mol) in THF (10 mL) was added. The reaction mixture was allowed to warm up to RT and stirred for 2 more hours. After being quenched with water, the mixture was extracted with EtOAc. The organic layers were dried and concentrated. The residue was purified by silica gel column eluting with DCM to give the desired product (7.5 g, 69%).
Reaction SMILES: C1(=O)CCC=C1.C(OCC1C=CC=CC=1)C1C=CC=CC=1.[CH:22]([C:25]1[CH2:29][CH2:28][C:27](=[O:30])[CH:26]=1)([CH3:24])[CH3:23]>>[CH:22]([CH:25]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)C1=CC(=O)CC1
Agent: O=C1C=CCC1
Solvent: c1ccc(COCc2ccccc2)cc1
Product: CC(C)C1CCC(=O)C1
Yield: 88 %

Procedure:
Cyclopentenones designed to test the tolerance of the catalyst to functional groups and steric hindrance were subjected to the reduction conditions. A cyclopentenone that contained an isolated olefin was successfully reduced in high ee (entry 5). Substrates with either a benzyl ether (entry 6) or an ester (entry 7) were also reduced with high enantioselectivity. Examination of the tolerance of the catalyst to steric hindrance on the substrate revealed that longer reaction times were necessary as the steric bulk of the substituent on the β-carbon increased. For instance, the reduction of 3-isopropylcyclopentenone (entry 8) proceeded to 90% completion after 3 days to afford 3-isopropylcyclopentanone in 88% yield and 94% ee.13,14 To date, attempted reductions of cyclopentenones with vinyl or alkynyl groups conjugated to the enone gave mixtures of products resulting from competing 1,4- and 1,6-reductions.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][OH:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester, which was directly subjected to the following reaction.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([Br:35])[CH:29]=2)=[CH:24][CH:23]=1)[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:37][C:38]#[N:39])=[C:30]([Br:35])[CH:29]=2)=[CH:24][CH:23]=1)[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Cn1cc(C(=O)N(Cc2ccccc2)Cc2ccc(-c3ccc(O)c(Br)c3)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)N(Cc2ccccc2)Cc2ccc(-c3ccc(OCC#N)c(Br)c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 74.6 %

Procedure:
A mixture of N-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide (1.5 g, 2.85 mmol), prepared in the previous step, bromoacetonitrile (240 μL, 3.44 mmol) and potassium carbonate (1.95 g, 14.1 mmol) in 75 mL of DMF was stirred under nitrogen at room temperature for 23 h. The reaction was partitioned between methylene chloride and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give N-benzyl-N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-1-methyl-1H-indole-3-carboxamide (1.2 g, 75%) as a white solid, MS (ESI) m/z 564 [M+H]+. Elemental Analysis for C32H26BrN3O2: Calc'd: C, 68.09; H, 4.64; N, 7.44; Found: C, 66.78; H, 4.68; N, 7.19.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([F:21])[CH:14]=2)[N:7]=[C:6]1[N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1.[C:37]([O-:40])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:36])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:40][CH3:37])=[CH:15][CH:14]=2)=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([F:21])[CH:14]=2)[N:7]=[C:6]1[N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(-c2ccc(OC)cc2)c1=O
Yield: 48.3 %

Procedure:
A solution of [2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-5-chloro-4-(4-cyano-3-fluoro-phenyl)-6-oxo-6H-pyrimidin-1-yl]-acetic acid methyl ester (2.2 g, 4.2 mmol), p-methoxyboronic acid (1.9 g, 12.7 mmol), Pd-118 (274 mg, 0.42 mmol) and K2CO3 (1.2 g, 8.4 mmol) in DMF (50 mL) was stirred at 145° C. for 6 h under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EA (3×). The combined organics were washed with water, washed brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to give 600 mg of the title product (24%). [M+H] Calc'd for C31H34FN5O6, 592. Found, 592.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10](C=O)=[CH:9][CH:8]=1)[CH3:2].[CH:28]([OH:30])=O.[OH-].[Na+].[CH3:33][NH:34][CH:35]=O>>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:33][N:34]([CH3:35])[CH:28]=[O:30])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=CO
Reactant: CCN(CC)CCNc1ccc(C=O)c2sc3ccc(OC)cc3c(=O)c12
Reactant: CNC=O
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)CCNc1ccc(CN(C)C=O)c2sc3ccc(OC)cc3c(=O)c12
Temperature: 0 °C
Yield: 89.9 %

Procedure:
A solution of 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-carboxaldehyde (3 g, 7.8 mmol) and 1.5 mL of formic acid in 25.5 mL of N-methylformamide was heated to 170° C. for 8 h with stirring under nitrogen. The reaction mixture was poured into 160 mL of ice/water, basified with 35% of NaOH solution, and extracted into chloroform (3x). the organic layer was washed with water (2x) and brine, dried over sodium sulfate, and the sovlent was removed in vacuo affording 3 g (89.9%) of the desired N-[[1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-yl]methyl]-N-methylformamide (Formula IV: R1 =R2 =Et; R4 =Me; R8 =7-OCH3 ; n=2).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([CH2:18][CH2:19][CH3:20])=[CH:17][C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1.Cl[Si](C)(C)C.C(N(CC)CC)C.[N-]1C=CN=C1>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH:34][C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[O:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([CH2:18][CH2:19][CH3:20])=[CH:17][C:3]1=2
Reactant: Nc1nnn[nH]1
Reactant: CCCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1

Procedure:
5.77 g (0.02 mol) of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 3) and 6.49 g (0.04 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 100 ml of dimethylformamide are stirred at 50° C. for one hour. To 2.5 g (0.024 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) in 50 ml of dimethylformamide cooled to 0°-5° C. is added 9.14 ml (0.072 mol) of chlorotrimethylsilane (Aldrich Chemical Company) and 10 ml (0.072 mol) of triethylamine. The mixture is stirred and allowed to reach room temperature. After two hours the mixture is combined with the previous imidazolide mixture and stirred for fourteen hours at room temperature. The resulting precipitate 0.9 g, of 4-oxo-2-propyl-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide is collected; mp 306°-308° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:43]([O:47][C:48]([NH:50][CH2:51][CH2:52][CH:53]([C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=1)[C:54](O)=[O:55])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:54](=[O:55])[CH:53]([C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=3)[CH2:52][CH2:51][NH:50][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(C(=O)Nc1ccc2c(c1)c(N)nn2C(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a stirred solution of 3,5-diamino-indazole-1-carboxylic acid tert-butylester (2.17 g, 8.75 mmol), PyBroP (4.1 g, 8.75 mmol) and 4-tert-butoxycarbonylamino-2-(3,4-dichloro-phenyl)-butyric acid (3 g, 8.75 mmol) in dichloromethane (100 mL) was added diisopropylethylamine (3.0 mL, 17.5 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature over 4 hours then was concentrated and the residue partitioned between EtOAc and ammonium chloride (saturated, aqueous). The organic phase was separated and washed with sodium bicarbonate (saturated, aqueous), then dried (sodium sulfate) and concentrated to a brown foam. Purification by column chromatography (silica, 20% petroleum ether-EtOAc gave the title compound as a light brown solid (2.92 g, 58%); 1H NMR (400 MHz, DMSO) 1.36 (9H, s), 1.56 (9H, s), 1.80–1.90 (1H, m), 2.10–2.20 (1H, m), 2.89 (2H, m), 6.29 (2H, brs), 6.87 (1H, t), 7.38 (1H, d), 7.45 (1H, d), 7.61–7.65 (2H, m), 7.90 (1H, m), 8.19 (1H, s), 10.30 (1H, s); MS (ES+) m/e=578.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=2[O:25]1>>[O:25]1[C:26]2[CH:27]=[CH:28][C:29]([C:6]3[N:7]=[C:8]([N:10]4[C:14]5[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=5[N:12]=[CH:11]4)[S:9][C:5]=3[C:3]([OH:2])=[O:4])=[CH:30][C:31]=2[O:32][CH2:24]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccc5c(c4)OCO5)c(C(=O)O)s3)c2cc1OC
Yield: 24.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,4-methylenedioxybenzeneboronic acid (24.9 mg, 0.15 mmol) gave 4-Benzo[1,3]dioxol-5-yl-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (10.5 mg, 25%) as a white solid. MS m/z 426 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1[CH:7]=[CH:8][C:9]2[C:10](=[CH:12][N:13]=[N:14][C:15]=2O)[CH:11]=1>C(OCC)(=O)C>[ClH:3].[Cl:3][C:15]1[C:9]2[C:10](=[CH:11][CH:6]=[CH:7][CH:8]=2)[CH:12]=[N:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nncc2ccccc12
Solvent: CCOC(C)=O
Product: Cl
Product: Clc1nncc2ccccc12
Temperature: 2.5 °C
Yield: 65 %

Procedure:
A 3-neck 2 L round-bottomed flask was charged with phosphorous oxychloride (306 g, 2 mol. eq.) and cooled to about 0 to 5° C. To this was added 73 g of powdered phthalazinone (0.5 mol eq.). The reaction mass appeared as a suspension and was heated to about 60° C. with stirring. The progress of the reaction was monitored by HPLC. While the reaction mixture was maintained at approximately 50° C., about 65% of the phosphorous oxychloride was distilled out under vacuum. The concentrated reaction mixture was cooled to room temperature, about 375 mL of ethyl acetate was added, and then the mixture was purged with HCl gas for about 30 min; thereafter, the mixture was cooled to a temperature of 0 to 5° C. and stirred for about one hour. The resulting pale yellow material was filtered and washed with 150 mL of cold ethyl acetate. The isolated material was 1-chlorophthalazine hydrochloride, which was dried under vacuum for about 3 hours at 30° C. Yield=65%; purity=99%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH:14]=O)=[CH:4][CH:3]=1.[C:16]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].[C:39]1(C)C=CC=C[CH:40]=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:14]=[CH:19]/[C:16]([O:18][CH2:39][CH3:40])=[O:17])=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ccccc1
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)cc1-c1ccccc1
Product: CCOC(=O)/C=C/c1ccc(O)cc1-c1ccccc1

Procedure:
A solution of 5-hydroxy-[1,1′-biphenyl]-2-carbaldehyde (651) (292 mg, 1.47 mmol) and (carboxymethylene)-triphenylphosphorane (564.5 mg, 1.62 mmol) in toluene (15 mL) was refluxed for 24 hours. The reaction was concentrated in vacuo and was purified by flash column chromatography on silica gel with hexanes and EtOAc (30%) to give (E)-ethyl 3-(5-hydroxy-[1,1′-biphenyl]-2-yl)acrylate (652).
Reaction SMILES: [C:1]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C@@H:2]([C@H:4]([C:6]([O:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[OH:5])[OH:3].[H-].[Na+].Br[C:31](Br)([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Cl-].[Na+]>C(COC)OC.O>[O:5]1[C@@H:4]([C:6]([O:8][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])[C@H:2]([C:1]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:3][C:31]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)OC(c2ccccc2)c2ccccc2)[C@H](C(=O)OC(C)(C)C)O1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
3.92 g of tert-butyl diphenylmethyl L-tartarate was dissolved in 10 ml of dimethoxyethane, and 844 mg of 60% sodium hydride was added at 0° C. , followed by stirring at the same temperature for 45 minutes. Then, a solution of 3.37 g of diethyl dibromomalonate in 5 ml of dimethoxyethane, was added, followed by stirring under heating at 80° C. for 12 hours. The reaction solution was cooled to room temperature and then poured into water. The aqueous layer was saturated with sodium chloride and extracted with ethyl ether. The obtained organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1→5/1) to obtain 1.73 g (yield: 44%) of the above identified compound as white solid.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[N:10]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:11]([CH:13]([N:24]([CH3:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:12].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:67])=[O:66].CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[N:10]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:11]([CH:13]([N:24]([CH3:34])[C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:67])=[O:66])=[O:30])=[CH:32][CH:33]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:12]
Reactant: CN(c1ccc(C(=O)O)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Reactant: NCCS(=O)(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccc(C(=O)NCCS(=O)(=O)O)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
4-{[(4-Benzofuran-2-yl-phenylcarbamoyl)-(4-tert-butyl-phenyl)-methyl]-methyl-amino}-benzoic acid (110 mg, 0.2 mmol), was taken up in 3 mL of DMF followed by addition of HOBt (79 mg, 0.52 mmol) and EDCI (99 mg, 0.52 mmol). The reaction was stirred at RT for 30 min, taurine (103 mg, 0.083 mmol) was added followed by Hunig's base (107 mg, 0.083 mmol) and allowed to stir an additional 16 h at RT. The solution was filtered through a fit and the DMF was subjected to reverse phase HPLC purification. After removal acetonitrile/water under reduced pressure, followed by trituration with methanol, gave a white solid (50 mg, 39%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccn2)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccn5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(pyridin-2-yl)piperidine-1-carboxylate (amine intermediate “N”) were reacted to give the title compound. LC/MS (M+H)+: 636. Ret. time: 1.69 min. (Condition I).