Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:28][C:29]1[CH:38]=[CH:37][C:32]2[C:33](Cl)=[N:34][S:35][C:31]=2[CH:30]=1>C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:33]3[C:32]4[CH:37]=[CH:38][C:29]([Br:28])=[CH:30][C:31]=4[S:35][N:34]=3)[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N)c2)COC1
Reactant: Clc1nsc2cc(Br)ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(Nc3nsc4cc(Br)ccc34)c2)COC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of [5-(3-amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (51 mg, 0.167 mmol) in THF (2 ml) was stirred at −78° C. under nitrogen. Butyllithium (1.6 M solution in hexanes, 0.26 ml, 0.418 mmol) was added at once. After 10 minutes a solution of 6-bromo-3-chloro-benzo[d]isothiazole (WO 2006091858, page 132; 52 mg, 0.209 mmol) in 0.4 ml THF was added rapidly. After stirring for 30 minutes the mixture was quenched with 5% aq. NH4Cl and warmed to rt. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (hexanes/20-35% EtOAc) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:10][CH2:9][CH2:8][O:7][N:6]=1.[Br:15]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]([Br:15])[C:5]1[O:10][CH2:9][CH2:8][O:7][N:6]=1
Reactant: Clc1ccccc1CC1=NOCCO1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1ccccc1C(Br)C1=NOCCO1
Yield: 87 %

Procedure:
4.0 g (19 mmole) of 3-(2-chlorobenzyl)-5,6-dihydro-1,4,2-dioxazine (prepared as described in Preparation 1) were dissolved in 40 ml of carbon tetrachloride, and then 4.1 g (23 mmole) of N-bromosuccinimide and 0.2 g of benzoyl peroxide were added to the solution, which was then stirred, whilst heating, for 8 hours. At the end of this time, 100 ml of ethyl acetate and 100 ml of hexane were added to the solution, and the mixture was stirred at room temperature for 30 minutes; insolubles were then removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, to give 4.8 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH:20]1([NH:25][C:10]2[N:11]=[C:6]([CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([CH3:1])[CH:3]=3)[NH:7][C:8](=[O:16])[C:9]=2[C:14]#[N:15])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCC1
Reactant: CSc1nc(Cc2cccc(C)c2)[nH]c(=O)c1C#N
Solvent: CC#N
Product: Cc1cccc(Cc2nc(NC3CCCC3)c(C#N)c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(3-methylbenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.31 g (3.65 mmol) of cyclopentylamine in 3 ml of acetonitrile at 90° C. under argon overnight. After cooling to room temperature, the crude product is purified by preparative HPLC. 0.03 g (26% of theory) of the title compound is obtained as a colourless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C(=O)c2ccccc2)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 13.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56.5 mg), 2-hydroxy-4-methoxybenzophenone (286 mg), and 4-dimethylaminopyridine (163 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensioon was stirred at 160° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (14.5 mg, yield 14%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[O:11][C:12]2[C:13](=[C:15]([C:27]#[N:28])[C:16]([CH3:26])=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=2F)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][N:37]([CH3:43])[C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1.C(OCC)(=O)C>CS(C)=O.O>[CH2:1]([O:8][CH2:9][C:10]1[O:11][C:12]2[C:13](=[C:15]([C:27]#[N:28])[C:16]([CH3:26])=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=2[N:40]2[CH2:41][CH2:42][C@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(COCc3ccccc3)nc2c1C#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(COCc3ccccc3)nc2c1C#N
Temperature: 90 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
2-[(Benzyloxy)methyl]-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-90) (70 mg, 0.19 mmol) was dissolved in dimethyl sulfoxide (1.4 ml), triethylamine (63 μl, 0.45 mmol) and (3S)-3-(dimethylamino)pyrrolidine (29 μl, 0.23 mmol) were added, followed by stirring at 90° C. for 4 hours under nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away and the resulting residue was subjected to preparative, thin-layer silica gel column, chromatography, eluted with a mixed solvent of chloroform/methanol (10:1, v/v) to obtain the entitled compound (46 mg, 52%) as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[C:4]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[C:3]=1[N+:38]([O-])=O.CO.[Cl-].[NH4+]>C(OCC)(=O)C.[Zn]>[NH2:38][C:3]1[C:4]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])=[C:5]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=4)(=[O:20])=[O:21])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c([N+](=O)[O-])c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c(N)c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of 4-[4-amino-2-(2,4-difluorophenoxy)-3-nitrophenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (108 mg, 0.191 mmol) in ethyl acetate (0.46 mL) was treated with methanol (0.46 mL) and saturated aqueous ammonium chloride solution (0.166 mL, 2.48 mmol) and cooled to 0° C. The reaction mixture was treated with zinc (99.7 mg, 1.52 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, filtered through a pad of Celite, and the solids were washed with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate solution (40 mL). The aqueous layer was separated and re-extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (40% EtOAc/hexanes to 100% EtOAc) gave the desired product (100 mg, 93%) as a brown oil. LCMS calculated for C27H23F2N4O4S (M+H)+: m/z=537.1. found: 537.1.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])[CH2:2][CH2:3]C.N1CCC[C:12]1=O>>[CH3:12][CH:2]([CH3:3])[CH2:1][CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10]
Reactant: CCCCC1CCNC1=O
Reactant: O=C1CCCN1
Product: CC(C)CC1CCNC1=O

Procedure:
3-butyl-2-pyrrolidinone (Sinnerich J, Elad D (1968) "The light-induced addition of 2-pyrrolidinone to olefins" Tetrahedron, 24, 4509-4516);
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:21])[CH:11]=[CH:12][C:13]=1[O:14][C@@H:15]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[F:32])[C:26](Cl)=[O:27].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:21][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([F:32])=[C:23]([F:22])[CH:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][C@@H:15]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16]1
Reactant: CN1CC[C@@H](Oc2ccc(N)cc2-c2c(Br)cnn2C)C1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CC[C@@H](Oc2ccc(NC(=O)c3ccc(F)c(F)c3)cc2-c2c(Br)cnn2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.5 %

Procedure:
A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-1-methyl-pyrrolidin-3-yloxy)-phenylamine (88 mg, 0.25 mmole), 3,4-difluoro-benzoyl chloride (40 μL, 0.30 mmole), and triethylamine (70 μL, 0.5 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 24 mg, 19% yield). 1H NMR (CD3OD, 400 MHz) δ 2.17-2.31 (m, 1H), 2.71-2.84 (m, 2H), 2.87-2.97 (m, 2H), 3.14-3.25 (m, 1H), 3.38-3.48 (m, 1H), 3.72-3.79 (m, 1H), 3.75 (s, 3H), 3.89-3.97 (m, 1H), 5.17-5.24 (m, 1H), 7.17-7.30 (m, 1H), 7.41-7.47 (m, 1H), 7.56-7.62 (m, 1H), 7.63-7.69 (m, 1H), 7.78-89 (m, 1H), 7.88-7.93 (m, 2H). Exact mass calculated for C22BrH21F2N4O2 490.1, found 491.5, 493.5 (MH+).
Reaction SMILES: O=[C:2]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]#[N:5].O.[NH2:16][NH2:17]>CCO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[C:2]2[CH:3]=[C:4]([NH2:5])[NH:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCC(=O)[C@@H]1C[C@H]1c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc([C@@H]2C[C@H]2c2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 6 h
Yield: 127.5 %

Procedure:
To a stirred solution of 39 (28.5 g, 153.87 mmol, 1.00 equiv) in EtOH (300 mL) under N2 was added 85% hydrazine hydrate (5.7 g, 100 mmol, 0.65 equiv), and the reaction mixture was stirred at 80° C. for 6 h. The reaction was cooled to RT, and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/MeOH gradient (1 to 5% MeOH) to afford 25.4 g (83%) of trans-3-(2-phenylcyclopropyl)-1H-pyrazol-5-amine (41) as a light yellow oil: 1H NMR (400 MHz, DMSO-d6): δ 7.30-7.10 (m, 5H), 5.15 (s, 1H), 4.90-4.20 (br s, 2H), 2.10-2.07 (m, 1H), 2.00-1.95 (m, 1H), 1.35-1.31 (m, 2H), 1H not seen; MS (ESI+) m/z=200 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(Cl)(=O)C([Cl:33])=O>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([Cl:33])=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(Oc3ccc(C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C(=O)Cl)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid (16) (0.149 g, 0.388 mmol) in toluene (3 mL) was added oxalyl chloride (0.06 mL, 0.087 g, 0.687 mmol, 1.8 eq) followed by DMF (1 drop). The reaction mixture was stirred at RT under N2 for 45 min. The reaction mixture was concentrated to give crude 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride as a yellow oil. Isonipecotic acid (0.051 g, 0.39 mmol), triethylamine (0.12 mL, 0.087 g, 0.86 mmol) and H2O (2 mL) were combined and the solution was cooled in an ice-water bath under N2. To the cold isonipecotic acid solution was slowly added dropwise a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride in THF (2 mL) with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir for 5 d. The pH of the reaction mixture was adjusted to ˜1 (litmus paper) with 1 N HCl and the acidic reaction mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with H2O (2×), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude title compound. The crude product was purified by flash chromatography over SiO2 with CH2Cl2:MeOH (94:6) to give 0.133 g (69%) of compound 17 as an amorphous solid. 1H NMR (400 MHz; DMSO-d6): δ 1.42 (m, 2H), 1.80 (m, 2H), 2.17 (s, 3H), 2.93 (br s, 2H), 3.87 (s, 3H), 6.59 (d, J=8.6 Hz, 2H), 7.09 (dd, J=2.5 Hz, 9.2 Hz, 1H), 7.15 (m, 4H), 7.25 (m, 3H), 7.35 (d, J=2.4 Hz, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.70 (s, 1H), 12.25 (br s, 1H). AP LRMS m/z 494 (M−H)−.
Reaction SMILES: [CH2:1]([NH:3][NH2:4])[CH3:2].CN([CH:8]=[C:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]1=O)C>>[CH2:1]([N:3]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:9]=2[CH:8]=[N:4]1)[CH3:2]
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CCNN
Product: CCn1ncc2c1CCCC2=O

Procedure:
Prepared analogously to Example 1 starting from ethylhydrazine and 2-(dimethylaminomethylene)-cyclohexane-1,3-dione.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[C:8]([C:19]3[CH:20]=[N:21][NH:22][CH:23]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]#[N:29].O>C1COCC1>[C:28]([CH2:27][N:21]1[CH:20]=[C:19]([C:8]2[C:9]3[C:10]([O:17][CH3:18])=[N:11][CH:12]=[C:13]([C:15]#[N:16])[C:14]=3[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH:23]=[N:22]1)#[N:29]
Reactant: COc1ncc(C#N)c2c1c(-c1cn[nH]c1)cn2C1CCCC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(C#N)c2c1c(-c1cnn(CC#N)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-cyclopentyl-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (152.2 mg) obtained in Step A of Example 98 in THF (2 mL) was added sodium hydride (dispersion in mineral oil, 39.6 mg) at 0° C., and the mixture was stirred for 1 hr. To the reaction mixture was added 2-bromoacetonitrile (38 μL) at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred overnight. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.7 mg).
Reaction SMILES: O.S(=O)(=O)(O)O.[Si:7]([O:17]CC)([O:14]CC)([O:11]CC)[O:8][CH2:9][CH3:10].[CH3:20][Si:21]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>C(O)C.C(O)(C)C>[Si:7]([O-:17])([O-:14])([O-:11])[O:8][CH2:9][CH3:10].[CH3:20][Si:21]([O:22][CH2:23][CH3:24])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CCO[Si](C)(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: CCO[Si]([O-])([O-])[O-]
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A sample of 90% hydrolyzed ethyl silicate/methyltriethoxy silane co-condensate was prepared by adding water (11 grams) containing a trace of sulfuric acid to a solution of tetraethyl orthosilicate (37.5 grams) and methyl triethoxy silane (37.5 grams) in anhydrous ethanol (75 grams). Ethocel (4.5 grams) was added to thicken the solution. To a portion (11.5 grams) of the solution was added a 60% total solids TiO2 dispersion in isopropanol (40.3 grams) and a dispersing aid, Nuosperse 657 (3.5 grams). A 2 mil dry coating was prepared on a three by six inch steel Q panel and conditioned for 15 minutes at 200° C. The coated panel was then placed in a muffle furnace at 510° C. and its condition checked after 1, 2, 3, and 4 hours. At all times, the coating remained white, uncracked and adhered to the substrate. In comparison with the results contained in Control B and Examples 1-9, this demonstrates the usefulness of the highly filled co-condensate in this elevated temperature application.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16](=[CH:22][C@@H:23]3[CH2:43][CH2:42][C:25]4(O[C@@H](C5C=CC=CC=5)[C@H](C5C=CC=CC=5)[O:26]4)[CH2:24]3)[C:17]([O:19]CC)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[OH-].[K+].Cl.C(Cl)(Cl)Cl>CO.O1CCOCC1>[CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:22]\[C@@H:23]3[CH2:43][CH2:42][C:25](=[O:26])[CH2:24]3)/[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=C[C@@H]1CCC2(C1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C1CC[C@@H](/C=C(/C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Ethyl 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2S,3S,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]acrylate (1.77 g, (E), (Z) mixture) was dissolved in a mixed solvent of methanol (21.2 mL) and dioxane (21.2 mL), and to this solution was slowly added 8 M aqueous potassium hydroxide solution (21.2 mL), which had been separately prepared. It was stirred at room temperature for 10 minutes, and then stirred in an oil bath at 70° C. for 2 hours under heating. It was left to be cooled to room temperature, and hydrochloric acid was carefully added thereto under ice-cooling. The mixture was stirred for 2 hours under heating in an oil bath at 90° C., and cooled to room temperature again. Chloroform was added thereto and the organic layer was separated. The aqueous layer was extracted with chloroform, combined with the organic layer, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]acrylic acid (952 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].C(Cl)(Cl)Cl.[CH3:19][CH2:20]OCC>C(O)(=O)C>[CH3:19][C:20]1[NH:1][C:2]2[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]=2[N:8]=1
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CCOCC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2CC(C)C

Procedure:
10 g of 5,6-diamino-1-(2-methylpropyl)-2,4-(1H,3H)-pyrimidine dione was refluxed in 50 ml of acetic acid for 1 hour. 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 10.8 g. The amide was refluxed in 30 ml of 2N NaOH for 1 hour and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 50 ml of acetic acid. Yield 3.3 g. NMR (see Table I).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[CH:17]1(B(O)O)[CH2:19][CH2:18]1>C1COCC1.[Pd](Cl)Cl.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>[NH2:11][C:10]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][C:7]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c(C2CC2)nc1C(=O)O

Procedure:
A microwave vial was charged with amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (0.5 g, 1.754 mmol), cyclopropylboronic acid (0.753 g, 8.77 mmol), and 1,1′Bis(diphenylphosphosphino) ferrocene palladium dichloride (0.143 g, 0.175 mmol). The mixture was taken up as a solution in THF (6 ml) and flushed with N2, sealed and heated using microwave radiation at 150° C. for 20 minutes. The reaction mixture was filtered through Celite® (filter material) and washed through with EtOAc (20 ml). The filtrate was partitioned between EtOAc (30 ml) and water (50 ml). The phases were separated and the organic portion was washed with brine (30 ml), dried over MgSO4, filtered and concentrated under vacuum.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C(=O)([O-])[O-:11].[Ca+2:14]>O>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:1]([O:9][OH:11])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Ca+2:14].[Ca+2:14].[OH:11][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:11][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:11][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)C(=O)O
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
An aqueous solution of malic acid was prepared by mixing 134.09 g of malic acid with 50 mL of water. An aqueous solution of calcium carbonate was also prepared in a separate container by thoroughly mixing 200.18 g of calcium carbonate in 50 mL of water. The calcium carbonate solution was then slowly added to the malic acid solution. The resulting solution was spray dried to produce a powdered dicalciumhydroxy malate.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2]([Cl:4])=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=O)([O-:9])=[O:8]>C(Cl)Cl.CN(C=O)C>[Cl:4][C:2]1[CH:19]=[C:18]([CH:17]=[CH:16][C:1]=1[Cl:6])[CH2:10][NH:7][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Oxalyl chloride (4.8 ml) was added to a solution of 3-nitro-4-methylbenzoic acid (9.06 g) in methylene chloride (100 ml) and DMF (a few drops) and the reaction stirred at ambient temperature for 16 hours. The reaction mixture was evaporated and the residue was dissolved in methylene chloride (100 ml). 3,4-Dichlorobenzylamine (7.04 g), 4-dimethylaminopyridine (0.31 g) and triethylamine (13.9 ml) were added and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography using a 250:8:1 mixture of methylene chloride, methanol and a saturated aqueous ammonium chloride solution as eluent to give N-(3,4-dichlorobenzyl)4-methyl-3-nitrobenzamide as a solid (9.95 g); NMR Spectrum: (DMSOd6) 2.57 (s, 3H), 4.47 (d, 2H), 7.31 (m, 1H), 7.56 (m, 2H), 7.61 (d, 1H), 8.1 (m, 1H), 8.47 (d, 1H), 9.3 (t, 1H).