Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH:16]1[CH3:29])=[O:14].CO.[OH-].[Na+].Cl>O>[Cl:10][C:8]1[CH:7]=[CH:6][C:5](/[CH:11]=[CH:12]/[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:17][CH:16]2[CH3:29])=[O:14])=[C:4]([CH:9]=1)[C:3]([OH:30])=[O:2]
Reactant: COC(=O)c1cc(Cl)ccc1/C=C/C(=O)N1CCN(Cc2ccc(F)cc2)CC1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)/C=C/c1ccc(Cl)cc1C(=O)O
Reaction time: 8 h
Yield: 88.9 %

Procedure:
1.56 g (3.6 mmol) 5-Chloro-2-{(E)-3-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-3-oxo-propenyl}-benzoic acid methyl ester (Example 78) was suspended in a 1:1 mixture of methanol and water (20 ml). 0.5 ml 10 N NaOH was added and the mixture was stirred overnight. After acidification using 6.5 ml 1N HCl the product precipitated. Filtration and drying yielded 1.32 g (3.2 mmol, 87%) of the desired acid.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[CH:5][CH2:4][CH2:3][OH:2])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCC=Cc1ccc(OCc2ccccc2)cc1
Yield: 69.3 %

Procedure:
In an argon atmosphere, 3-hydroxypropyltriphenylphosphonium bromide (4.02 g) was suspended in dehydrated THF (30 ml); 60% oily sodium hydride (0.4 g) was added, followed by refluxing for 3 hours. To the reaction mixture, a solution of 4-benzyloxybenzaldehyde (2.12 g) in dehydrated THF (7 ml) was added drop by drop, followed by refluxing for 67 hours. After cooling, the insoluble matter was filtered off; the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to yield the titled compound (1.76 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26]>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[C:25]([NH2:24])=[O:26])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: NC(=O)c1ccccc1B(O)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3C(N)=O)cc1OCC2

Procedure:
Following the procedures of Example 475, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 was reacted with (2-aminocarbonylphenyl)boronic acid to give 476. MS (ESI+) 415.2. 1H NMR (400 MHz, DMSO) δ 8.42 (d, J=8.3 Hz, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.54-7.39 (m, 4H), 7.34 (s, 1H), 7.22 (dd, J=8.3, 1.7 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 5.93 (hept, J=6.2 Hz, 1H), 4.55 (q, J=5.7 Hz, 4H), 1.50 (d, J=6.6 Hz, 6H)
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[O:8]=[CH:9][C@H:10]([C@@H:12]([C@@H:14]([C@H:16]([CH3:18])[OH:17])[OH:15])[OH:13])[OH:11].[CH2:19](N)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(CN)O.C[N:35](C)[CH:36]=[O:37]>>[O:8]=[CH:9][C@H:10]([C@@H:12]([C@@H:14]([C@H:16]([CH3:18])[OH:17])[OH:15])[OH:13])[OH:11].[CH2:19]([C:6](=[CH2:7])[C:36]([NH2:35])=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCN
Agent: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Solvent: NCCO
Product: C=C(CCCCCCCCCC)C(N)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution was prepared of poly(N-acryloyloxysuccinimide)(pNAS; 1.5 g, 8.87 mmol) in dimethylformamide (DMF, 60 mL). To this solution was added triethylamine (1.5 mL), followed by the dropwise addition of the L-fucose derivative 1 (667 mg, 2.21 mmol, 25 mol % with respect to pNAS). The solution was stirred at room temperature for 12 h, and subsequently heated to 40° C. for 24 h. The solution was cooled and n-decylamine (138 mg, 20 mol % with respect to pNAS) was added as a solution in DMF (1 mL). The solution was stirred at 40° C. for a further 24 h, followed by the addition of ethanolamine (2 mL, excess as a solution in 5 mL of DMF). The reaction mixture was stirred for 243 h at 40° C., cooled and precipitated into acetone (300 mL). The polymer was recovered by centrifugation, washed with acetone (10 mL) and the finely divided white solid dissolved in deionized water (10 mL) and dialysed against water for 24 h. The clear solution was lyophilized to dryness to give the desired product in 72% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30](=O)[CH2:31][S:32][C:33]#[N:34])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[CH2:15][CH2:16]C(C([O-])=O)[O:18][C:13]=2[C:12]=1[CH2:24][CH2:25][CH3:26].CO.C[O-].[Na+].[CH2:44]([O:46]CC)C.O.CCCCCC.[C:56]([O:59][CH2:60]C)(=[O:58])[CH3:57]>>[CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]1[N:34]=[C:33]([O:46][CH3:44])[S:32][CH:31]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[CH2:15][CH2:16][CH:57]([C:56]([O:59][CH3:60])=[O:58])[O:18][C:13]=2[C:12]=1[CH2:24][CH2:25][CH3:26]
Reactant: CCOC(C)=O
Reactant: CCCc1c(OCCCOc2ccc(C(=O)CSC#N)c(OC)c2CCC)ccc2c1OC(C(=O)[O-])CC2
Reactant: CCOCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(-c3csc(OC)n3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Reaction time: 0.5 h
Yield: 39 %

Procedure:
The compound of Example 22 (20 mg, 35.9 μmol) was mixed with 2 mL of methanol and about 10 mg sodium methoxide, and the reaction mixture was held at room temperature for 30 min. The reaction mixture was poured into ethyl ether/water, and the ether layer was washed with brine, dried over sodium sulfate, and concentrated. Flash chromatography on silica gel using 20:1 to 10:1 to 5:1 hexane/ethyl acetate as eluant gave the product (24 mg, 42.1 μmol, 39% yield). High resolution mass spectrum, m/e 569.2438 (calculated for C31H39NO7S, 569.2447).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][S:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[Br:18]>C1C=CC=CC=1>[Cl-:8].[NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[CH2:9][S:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[Br:18]
Reactant: Nc1ncccn1
Reactant: ClCSc1cc(Cl)ccc1Br
Solvent: c1ccccc1
Product: Nc1nccc[n+]1CSc1cc(Cl)ccc1Br
Product: [Cl-]
Yield: 86.5 %

Procedure:
To a solution of 18.8 g of 2-aminopyrimidine in 180 ml of benzene is added 54.6 g of the product from example 25, and the mixture stirred and heated under reflux for about 12 hours. The cooled mixture is filtered to give about 62.8 g of the named compound, mp about 240°-242°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=3[N+:13]([O-:21])=[N:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[N+:13]([O-:21])=[N:12][C:11](=[O:22])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)n[n+]([O-])c5ccc(Cl)cc54)CC3)nc2N1
Yield: 18.8 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (Intermediate 205, 0.517 g) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (117 mg) and sodium acetoxyborohydride (340 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane gave 60 mg of the title compound as acetic acid salt.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5]>CC(C)=O.[O-2].[Mn+4].[O-2]>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1cc(I)ccc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
To a stirred solution of 2-hydroxy-5-iodobenzyl alcohol (43.5 g, 174.0 mmol) in acetone (700 mL) was added 85% activated manganese(IV) oxide (5 micron, 50 g, 494.0 mmol) and the solution stirred at room temperature for 16 hours. The manganese oxide was removed by filtration through diatomaceous earth and the filtrate concentrated in vacuo. The product was purified by flash silica chromatography (0-20% ethyl acetate in hexanes) The 2-hydroxy-5-iodobenzaldehyde was obtained as a greenish-yellow solid (24.3 g, 58%). A small amount of the 2-hydroxy-5-iodobenzaldehyde was recrystallized from methanol/water to afford an analytical sample and the remainder of the compound was used without further purification: mp 99-101° C. 1H NMR (CDCl3 /300 MHz) 9.83 (s, 1H), 7.79 (d, 1H, J=2.2 Hz), 7.77 (dd, 1H, J=8.7 Hz, J=2.2 Hz), 6.81 (d, 1H, J=8.7 Hz). ESHRMS 246.9229 (M-H Calc'd 246.9256).
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:4]([O:6]C)=O.C[O-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1.CCOCC>O1CCCC1.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:26]2[C:1](=[O:13])[C:2]3[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:4]2=[O:6])=[O:27])=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccccc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)C1C(=O)c2ccccc2C1=O
Temperature: 20 °C

Procedure:
Dimethyl phthalate (15.0 g) in tetrahydrofuran (100 ml) was added to a stirred suspension of sodium methoxide (8.31 g) in tetrahydrofuran (60 ml) followed by 4′-chloroacetophenone (11.8 g) in tetrahydrofuran (100 ml) at 20° C. under nitrogen. The mixture was then boiled under reflux for 18 hours then cooled to 20° C. and poured into ether (250 ml) and water (250 ml). The aqueous layer was separated and the organic layer was washed with water (3×75 ml). The combined aqueous extract and washings were acidified with concentrated hydrochloric acid and the solid which precipitated was collected by filtration. The filtrate was extracted with dichloromethane, dried and evaporated. The residue was recrystallized from ethanol to give 2-(4-chlorobenzoyl)-indan-1,3-dione.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(C(C)C)C(C)C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1cnc(N2CCOCC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A mixture of 1.00 g (3.84 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide, 0.37 ml (4.22 mmol) morpholine, 2.0 ml (12 mmol) N-ethyldiisopropylamine and a catalytic amount of 4-(N,N-dimethylamino)-pyridine was heated at 100° C. over night. After cooling to room temperature the mixture was dissolved in ethyl acetate and washed with two portions of water. The combined aqueous layers were extracted with 3 portions of dichloromethane. Drying with sodium sulfate and concentration gave 1.23 g of the crude product. Flash column chromatography afforded 1.11 g (92.9%) of the title compound as an off-white solid. M.p. 156-158° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=3)[C:21](O)=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1.C(Cl)[Cl:28].C[Si]([Cl:34])(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[ClH:28].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=3)[CH2:21][Cl:34])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1
Reactant: ClCCl
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)Nc3cccnc3)cc2)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cl
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)Nc3cccnc3)cc2)ccc1CCl

Procedure:
From 4.0 g. of 6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 150 ml. of methylene chloride, 1.55 ml. of triethylamine, 1.4 ml. of trimethylsilyl chloride and 1.6 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride hydrochloride.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=O)[CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]([N:62]2[CH2:61][CH2:60][N:59]([C:42](=[O:41])[CH2:43][NH:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:49][CH:48]=3)=[O:46])[CH2:64][CH2:63]2)=[O:19])[CH:14]=[CH:15][N:16]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccnc(Cl)c2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 40.9 %

Procedure:
DIPEA (179.7 mg, 0.24 mL, 1.39 mmol) was added to a stirred solution of 6-chloro-pyridine-4-carboxylic acid (48.6 mg, 0.37 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (148.1 mg, 0.77 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 80% EtOAc in Hexane as eluent) to afford 70 mg (49.2% yield) of biphenyl-4-carboxylic acid {2-[4-(2-chloro-pyridine-4-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 99.47, 1H NMR (DMSO-d6-D2O): δ 8.5 (s, 1H), 7.96-7.86 (d, 2H), 7.8-7.64 (m, 4H), 7.6-7.34 (m, 5H), 4.2-4.06 (dd, 2H), 3.72-3.42 (m, 6H), 3.38-3.2 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.Br[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>CCCCCC.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6][CH:7]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CC(C)(C)C(=O)CBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: CC(C)(C)C(=O)COc1ccc(Cl)cn1
Yield: 46.1 %

Procedure:
A mixture of 12.96 grams (g) (0.1 mole) of 5-chloro-2-hydroxypyridine, 17.9 g (0.1 mole) of 1-bromo-3,3-dimethyl-2-butanone, and 15 g (0.054 mole) of silver carbonate in hexane was stirred and heated at reflux temperature for 48 hours. The reaction mixture was filtered, and the solvent removed by evaporation. The residue was dissolved in methylene chloride and filtered through silica gel. Evaporation of the solvent gave 10.5 g (46 percent (%) yield) of 1-(5-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone. A sample recrystallized from pentane had a melting point of 68°-69.5° C.
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:20](OCC)(=[O:24])[C:21]([O-])=[O:22].Cl>C1COCC1>[CH2:1]([N:3]1[C:21](=[O:22])[C:20]([OH:24])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4]1(=[O:5])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: CCNS(=O)(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 145 °C
Yield: 2754.6 %

Procedure:
N-Ethyl-1-phenylmethanesulfonamide (20 g) was divided into batches of 0.5 g each and taken in an 8 mL vial. To each vial was added potassium tert-butoxide (0.426 g, 3.8 mmol), ethyl oxalate (0.408 mL, 3.01 mmol) and dry THF (4 mL). Each vial was heated in a microwave reactor at 145° C. under pressure for 20 mins. Reaction mixture from all the vials were combined and treated with 1.5 N HCl (75 mL) and extracted with EtOAc. The organic layer was washed with water (3×25 mL) and brine, dried over Na2SO4 and evaporated. A small amount of the DCM was added to the solid residue and stirred well. Filtration gave nearly pure title compound (21 g, 82.6%) as off-white solid; 1H NMR (300 MHz, CDCl3) 1.47 (t, 3H, J=7.2 Hz), 3.8 (q, 2H, J=7.2 Hz), 7.3-7.5 (m, 3), 7.9-8.0 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][C:51]=1[Cl:57]>CN(C=O)C.C(O)=O>[OH:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[C:51]([Cl:57])[CH:52]=1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: NCc1ccc(O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)NCc2ccc(O)cc2Cl)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μL, 1.65 mmol) in DMF (15 mL) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-3-chloro-phenol hydrochloride (104 mg, 0.55 mmol) and ethyl-diisopropylamine (94 mL, 0.55 mmol) in DMF (1.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2-chloro-benzylamide (51 mg) as a colourless oil. LC-MS: tR=1.01 min, [M+1]+=362.13.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:19][N:18]=1>CS(C)=O>[CH3:7][C:2]([NH:1][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:19][N:18]=1)([CH2:5][OH:6])[CH2:3][OH:4]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(Cl)nc2)c1
Reactant: CC(N)(CO)CO
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(NC(C)(CO)CO)nc2)c1
Temperature: 130 °C

Procedure:
2-Amino-2-methyl-1,3-propanediol (28.7 mg, 0.273 mmol), potassium phosphate, tribasic (58 mg, 0.273 mmol), and N-[3-(2-chloropyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (50 mg, 0.137 mmol) were dissolved in DMSO (300 μL). The mixture was heated to 130° C. for 48 hours, and then allowed to cool to room temperature. The mixture was diluted with DMSO (0.7 mL), filtered, and purified by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water+0.1% formic acid) to afford 2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,3-diol. MS ESI calcd for C20H22F3N6O2 [M+H]+ 332. found 332. 1H NMR (600 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.80 (d, J=5.2 Hz, 1H), 8.52 (d, J=23.4 Hz, 2H), 7.82 (s, 1H), 7.43 (s, 1H), 7.23 (d, J=5.1 Hz, 1H), 7.08 (s, 1H), 6.36 (s, 1H), 3.60-3.50 (m, 4H), 2.30 (s, 3H), 1.25 (d, J=12.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC.C(OC(C)C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:23]2[CH2:24][CH2:25][S:20][CH2:21][CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OC1CCSCC1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCSCC1
Yield: 60.6 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (500 mg, 1.65 mmol) obtained in Example 5 and tetrahydrothiopyran-4-ol (400 mg, 3.38 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (800 mg, 3.31 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) was added. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with a hexane/diisopropyl ether mixture, whereby the title compound (404 mg, 1.00 mmol, 61%) was obtained as a white powder.
Reaction SMILES: C(OC1C=CC(C(C2C=CC(OC(=O)C=C)=CC=2)(C2C=CC(OC(=O)C=C)=CC=2)C)=CC=1)(=O)C=C.[C:36]1([C:42]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:43]=2[O:44][CH:45](O)[CH3:46])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:58]([OH:62])(=[O:61])[CH:59]=[CH2:60].CS(O)(=O)=O>C1(C)C=CC=CC=1>[C:58]([O:62][CH2:46][CH2:45][O:44][C:43]1[C:48]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:49][CH:50]=[CH:51][C:42]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:61])[CH:59]=[CH2:60]
Reactant: C=CC(=O)O
Reactant: CC(O)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: C=CC(=O)Oc1ccc(C(C)(c2ccc(OC(=O)C=C)cc2)c2ccc(OC(=O)C=C)cc2)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCOc1c(-c2ccccc2)cccc1-c1ccccc1
Reaction time: 3 h

Procedure:
To a 50 ml 1 neck round bottom equipped with a dean stark trap was added 2,6-diphenylphenoxyethanol (5 g, 1 eq), toluene (21 ml), acrylic acid (2.7 g, 2.2 eq), methane sulfonic acid (0.3 g, 0.18 eq), Prostab 5198 (0.003 g) and heated to reflux. After 3 hours the reaction was complete. The reaction was washed with 20 ml sodium carbonate and 20 ml sodium chloride brine. The toluene mixture was filtered through thin layer of silica gel and eluted with 30 ml toluene. The filtrate was treated with the “Prostab 5198” (0.003 g) and concentrated invacuo to recover a viscous oil. >97% by GC. RI=1.6062 at 25° C.