Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].C([Li])CCC.[CH:19]([O:21][CH2:22]Cl)=[O:20]>O1CCCC1>[CH3:22][O:21][C:19]([C:5]1[S:1][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])=[CH:3][CH:4]=1)=[O:20]
Reactant: O=COCCl
Reactant: COc1ccccc1-c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2OC)s1
Temperature: 25 °C
Yield: 60 %

Procedure:
2-Thienyl-1-methoxybenzene (10 g, 53 mmol) is cooled to −78° C. in dry tetrahydrofuran (265 ml) under nitrogen while stirring. n-Butyl lithium in hexanes (1.6M, 37 ml, 59 mmol, 1.1 eq.) is added slowly and the resulting mixture is stirred cold for an hour. Chloromethyl formate (4.1 ml, 53 mmol, 1.0 eq.) is added and the reaction is stirred cold for another hour. The mixture is allowed to warm to room temperature before quenching with saturated bicarbonate solution and ethyl acetate. The layers are separated and the organic phase is washed with brine, dried over sodium sulfate and concentrated. The residue is purified via flash chromatography in 5% ethyl acetate/hexanes to afford 7.9 g of 2-(5-methoxycarbonylthien-2-yl)-1-methoxybenzene (61%).
Reaction SMILES: CC([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=C.OO.[OH:19]S(O)(=O)=O>CC(C)=O>[OH:19][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: C=C(C)c1ccc(OC(C)C(=O)OC)cc1
Agent: OO
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(O)cc1
Yield: 57 %

Procedure:
A solution of 10 g methyl 2-(4-(1-methylethenyl)phenoxy)propanoate, 1.2 equivalents 30% aqueous H2O2 in 30 ml acetone, and 0.1 equivalent 98% H2SO4 was refluxed for about 2 hours. Workup gave a 57% yield of methyl 2-(4-hydroxyphenoxy)propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[NH:22][C:21]1=[O:28]>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH2:18][CH2:19][N:20]3[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[NH:22][C:21]3=[O:28])[CH2:12][CH2:13]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Cl)ccc1N1CCNCC1
Reactant: Cc1cn(CCCCl)c(=O)[nH]c1=O
Product: COc1cc(Cl)ccc1N1CCN(CCCn2cc(C)c(=O)[nH]c2=O)CC1
Product: Cl

Procedure:
substituting 1-(4-chloro-2-methoxyphenyl)piperazine and 1-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione gave 1-{3-[4-(4-chloro-2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 154°-155° C.; Anal.: Calcd. for C19H25ClN4O3.(HCl)2 : C, 44.05; H, 6.37; N, 10.81%; Found: C, 44.26; H, 6.08; N, 10.46%;
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)=[N+:2]=[N-:3].[CH3:14][Si:15]([CH3:20])([CH3:19])[C:16]#[C:17]C>>[O:11]1[C:7]2([CH2:6][CH2:5][CH:4]([N:1]3[CH:17]=[C:16]([Si:15]([CH3:20])([CH3:19])[CH3:14])[N:3]=[N:2]3)[CH2:13][CH2:12]2)[O:8][CH2:9][CH2:10]1
Reactant: CC#C[Si](C)(C)C
Reactant: [N-]=[N+]=NC1CCC2(CC1)OCCO2
Product: C[Si](C)(C)c1cn(C2CCC3(CC2)OCCO3)nn1
Reaction time: 2 h
Yield: 104.7 %

Procedure:
A mixture of 8-Azido-1,4-dioxa-spiro[4.5]decane (1.00 g, 5.43 mmol) and 1-(trimethylsilyl)propyne (3.76 mL, 27.1 mmol) was submitted to microwave at 120° C. for 2 h. The mixture was concentrated under vacuum to remove the excess of 1-(trimethylsilyl)propyne and crude 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-trimethylsilanyl-1H-[1,2,3]triazole (1.6 g, 105%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:15])([CH3:14])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][OH:25])[CH:20]=[C:21]([F:23])[CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:24][O:25][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:15])([CH3:14])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CCN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)cc(F)c1
Product: CCN1c2cc(OCc3cc(F)cc(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,5-difluorophenyl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[Br:13].Cl[Sn]Cl.O.[OH-].[Na+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[Br:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(N)c1Br
Temperature: 25 °C
Yield: 100.1 %

Procedure:
2-Bromo-3-nitro-benzoic acid methyl ester (12.9 g, 49.5 mmol) (prepared from 2-amino-3-nitro-benzoic acid as described by Webber E. S., et al., see patent application number WO 01/16136 A2) and SnCl2 (42 g, 223 mmol) were refluxed in methanol (225 mL, 0.2 M) and H2O (5.3 g, 243 mmol) for 2 hours. After cooling at ambient temperature, diatomaceous earth (20 g) and dichloromethane (1 L) were added followed with 3N aqueous sodium hydroxide (150 mL) with vigorous stirring. The mixture was filtered and the organic phase was washed with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate, filtered and all volatiles were removed under reduced pressure to afford Intermediate 5(a) (11.4 g) in 98% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:13](=[O:15])[C:12]3[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][S:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(SCc2cccc([N+](=O)[O-])c2C(=O)O)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2c(c1)SCc1cccc([N+](=O)[O-])c1C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
In methylene chloride (30 ml) was suspended 2-(3-methoxyphenylthiomethyl)-6-nitrobenzoic acid obtained in Reference Example 17 (0.92 g, 2.88 mmol), and trifluoroacetic anhydride (0.81 ml, 5.76 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was ice-cooled, and boron trifluoride etherate (0.13 ml, 1.06 mmol) was added thereto, followed by reaction for one hour. After the reaction was completed, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give 3-methoxy-10-nitro-6,11-dihydrodibenzo[b,e]thiepin-11-one (0.40 g, 46%).
Reaction SMILES: [C:1]1([NH:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][OH:11]>CCO>[OH:11][N:10]=[C:8]([NH2:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CNc1ccccc1
Reactant: NO
Solvent: CCO
Product: NC(=NO)Nc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-phenylcyanamide was dissolved in EtOH (7 mL) and treated with H2NOH (1.5 eq of a 50% aq solution). The mixture was stirred at room temperature for 12 hours then reduced to dryness to afford 2-hydroxy-1-phenylguanidine (5) as a clear yellow oil, which was used without purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:41])([F:40])[CH2:12][CH2:13][CH:14]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[N:23]2)=[CH:20][CH:21]=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.O>[F:41][C:11]([F:10])([F:40])[CH2:12][CH2:13][CH:14]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:36])=[CH:38][CH:39]=1)[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 3-aminopropionate hydrochloride (23 mg, 0.19 mmol), (+/−)-4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoic acid (44 mg, 0.096 mmol), hydroxybenzotriazole hydrate (15 mg, 0.096 mmol), and triethylamine (55 ul, 0.39 mmol) in dichloromethane (0.96 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.11 mmol). The mixture was stirred for 2 hours at ambient temperature. The reaction was diluted with water and the organic layer was separated. The aq. layer was extracted with dichloromethane (2×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was used without further purification.
Reaction SMILES: C(OP([C:9]([O:25][CH3:26])([O:23][CH3:24])[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.[CH3:32][C:33]1[S:37][C:36]([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH:48]=O)[CH:46]=3)[C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=2)=[CH:35][CH:34]=1.CC1SC(C2C3C(=CC=C(C=O)C=3)C(CC)(CC)CC=2)=CC=1>C1COCC1.CCOCC>[CH3:26][O:25][CH:9]([O:23][CH3:24])[CH2:10]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)=[CH:48]\[C:45]1[CH:46]=[C:47]2[C:42]([C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=[C:38]2[C:36]2[S:37][C:33]([CH3:32])=[CH:34][CH:35]=2)=[CH:43][CH:44]=1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)s1
Agent: CCC1(CC)CC=C(c2ccc(C)s2)c2cc(C=O)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(/C(=C/c2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)CC(OC)OC)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a cold (−78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4 g, 3.6 mmol), in THF (20 mL) was added n-BuLi (1.6 M solution in hexane, 2.5 ml, 4 mmol). The mixture was stirred for 20 minutes at −78° C. and 10 min. at −10° C. The reaction mixture was recooled to −78° C. and 1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound G, 650 mg, 2.3 mmol) in THF (4 mL) was added to it. The mixture was stirred for 2 hours at −10° C. and diluted with ether (100 mL), washed with brine (10 mL) dried with MgSO4 and the solvent was removed by distillation to to afford a cis and trans (E and Z) isomeric mixture. Purification by chromatography on silica gel of the crude material afforded the title compound as an oil (˜90% purity).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)c2cc3ccccc3[nH]2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure D using Indole-2-carboxylic acid (Aldrich) and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 3-B), the title compound was prepared.
Reaction SMILES: [Na].COS([O-])(=O)=O.CN(C)[C:10]1[CH2:14][CH2:13][CH2:12][N+:11]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:23]([O:25][C:26](=[O:38])[CH2:27][C:28]1[CH:37]=[CH:36][C:33]([O:34][CH3:35])=[C:30]([O:31][CH3:32])[CH:29]=1)[CH3:24].O>C(O)C.C(OCC)C>[CH2:15]([N:11]1[CH2:12][CH2:13][CH2:14][C:10]1=[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:38])[C:28]1[CH:37]=[CH:36][C:33]([O:34][CH3:35])=[C:30]([O:31][CH3:32])[CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C1=[N+](Cc2ccccc2)CCC1
Reactant: CCOC(=O)Cc1ccc(OC)c(OC)c1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=C1CCCN1Cc1ccccc1)c1ccc(OC)c(OC)c1

Procedure:
Add (dropwise at 90°, with stirring, in a stream of nitrogen) a solution of 2.6 g of sodium in 50 ml of ethanol to 34.5 g of 2-dimethylamino-1-benzyl-1-pyrroliniummethylsulfate and 19.7 g of homoveratric acid ethyl ester. Keep the resulting reaction mixture at this temperature for a further 30 minutes and then distribute it between water and diethyl ether. Dry the ether solution over sodium sulfate and then concentrate it to obtain a yield [32.2 g (96% of theory)] of title compound.
Reaction SMILES: [CH:1]1([N:7]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([O:31][CH3:32])(=O)[CH:28]=[CH2:29].C(O)(=[O:35])C>>[CH:21]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:29](=[O:35])[CH2:28][CH2:27][O:31][CH3:32])=[CH:12][CH:13]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C=CC(=O)OC
Reactant: c1cc(N(C2CCCCC2)C2CCCCC2)ccc1NC1CCCCC1
Reactant: CC(=O)O
Product: COCCC(=O)N(c1ccc(N(C2CCCCC2)C2CCCCC2)cc1)C1CCCCC1
Temperature: 82 °C

Procedure:
A 100 ml 3-neck flask was fitted with an overhead stirrer, a thermocouple and a nitrogen inlet. The flask was charged with N,N,N′-tricyclohexyl-para-phenylenediamine (27.1 g), methyl acrylate (150 ml) and glacial acetic acid (10 ml). The reaction was stirred at 82° C. until complete. The reaction mass was taken up in xylenes, extracted with aqueous sodium hydroxide and washed three times with water. Solvent was removed by rotary evaporation. The reaction mass was taken up in hexanes. Some polymer precipitated and was removed. Solvent was removed by rotary evaporation. The product was taken up in xylenes and filtered. Solvent was removed by rotary evaporation. Remaining volatiles were removed by vacuum distillation (29″, 196° C.) to yield a viscous, dark yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=O)[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CC1C=C(C=C(C)C=1)C(O)=O.[Br:24]Br.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:24][CH2:11][C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: BrBr
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1cc(C)cc(C(=O)O)c1
Product: Cc1cc(CBr)cc(C(=O)O)c1

Procedure:
In general, 5-alkyl-3-formyl-benzoic acids may be prepared from 5-bromo-3-formyl-benzoic acid which in turn is prepared from 3-formyl-benzoid acid according to literature procedures (e.g. D. Zhao, J. S. Moore, J. Org. Chem. (2002), 67, 3548-3554). Thus, a 5-bromo-3-formyl-benzoic acid ester is reacted with the appropriate alkenyl boron derivative (e.g. 2,4,6-trivinyl-cyclotriboroxane) under Suzuki conditions (Lit.: e.g. F. Kerins, D. F. O'Shea, J. Org. Chem. (2002), 67, 4968-4971) followed by catalytic hydrogenation and subsequent ester cleavage to give the desired 5-alkyl-3-formyl-benzoic acid. Alternatively, the alkyl group may also be introduced using the appropriate alkyl-Zn reagents under Negishi conditions (e.g. H. Matsushita, E. Negishi, J. Org. Chem. (1982), 47, 4161-4165). The 3-formyl-group may require protection e.g. as an acetal during these transformations. More specifically, 5-methyl-3-formyl-benzoic acid may be prepared by brominating 3,5-dimethylbenzoic acid using Br2 in the presence of 2,2′-azo-bis-isobutyronitrile (Lit. e.g. Y. Sawada, et al. J. Pesticide Sci. (2002), 27, 365-373) to give 3-bromomethyl-5-methyl-benzoic acid which is then oxidised with MnO2 (Lit. e.g. S. Goswami, et al. Chem. Letters 34 (2005), 194-195) to give the desired 5-methyl-3-formyl-benzoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=1.[CH3:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:18]([NH:17][CH3:16])=[O:19])=[CH:26][CH:25]=2)[N:7]=1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of (S)-4-(4,6-dichloro-1,3,5-triazin-2-yl)-3-methylmorpholine (step (i) example 1) (4 g, 16.1 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (4.67 g, 16.1 mmol), bis(triphenylphosphene)palladium(II) dichloride (0.66 g, 0.8 mmol) and 2M Na2CO3 (8 ml, 19.6 mmol) in DME (32 ml) was heated in the microwave at 90° C. for 90 minutes. The mixture was diluted with DCM (200 mL), washed with water (200 mL), the organic layer passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a black oil. The oil was purified by flash chromatography using Pet ether, EtOAc 0-100% gradient to yield an off-white solid of (S)-1-(4-(4-chloro-6-(3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea. (932 mg, 15%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)=[N:10][CH:9]=2)[CH:7]=1.[H-].[Na+].Br[CH2:32][CH2:33][OH:34]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:17]=[N:16][N:15]([CH2:32][CH2:33][OH:34])[CH:14]=3)=[N:10][CH:9]=2)[CH:5]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][N:20]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(-c3cn[nH]c3)s2)c1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(-c3cnn(CCO)c3)s2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6 %

Procedure:
To a sealed tube was added N-{3-methyl-5-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine (38.0 mg, 0.095 mmol), DMF (950 μL, 0.1 M) and NaH (15.0 mg, 0.380 mmol, 60% wt). The reaction was allowed to age for 20 minutes. Next was added 2-bromo ethanol (11.8 mg, 0.095 mmol) and the reaction was allowed to stir at rt for 4 hours. The completed reaction was quenched with H2O (100 μL) and was concentrated in vacuo. Purification by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v formic acid modifier) to afford the title product (2.8 mg, 0.0057 mmol, 6.0%). MS ESI: [M+H]+ m/z 447.1. 1H NMR (600 MHz, DMSO) δ 10.24 (s, 1H), 8.82 (d, J=4.9, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.44 (s, 1H), 7.26 (d, J=4.9, 1H), 7.16 (s, 1H), 4.18 (t, J=5.5, 2H), 3.74 (s, 2H), 2.30 (s, 3H). rhSTK activity=+++
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.O.[NH2:14][NH2:15]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:14][NH2:15])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(Br)cc1

Procedure:
Ethyl-4-bromobenzoate is treated with hydrazine monohydrate in methanol under reflux conditions to obtain product X, 4-bromobenzoic hydrazide. Reaction of compound X with bromobenzoic acid in pyridine at 120° C. gives product XI, bis-(4-bromophenyl) hydrazine. Compound XI is then treated with sulfonyl chloride to afford 2,5-bis-(4-bromophenyl)-1,3,4-oxadiazole (Compound XII), which is further reacted 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane under conditions similar to step-3 in Example 1. The resulting product thus obtained is subjected to Suzuki coupling conditions similar to step-5 in Example 1 to obtain the desired product XIII. Other alligator clips which can be introduced are CN, SCN, NH2, pyridine.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]=2[CH2:24][CH3:25])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:28])=O.C(=O)([O-])O.[Na+].O>C1(C)C=CC=CC=1>[Cl:28][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[O:11][C:10]=1[CH2:24][CH3:25]
Reactant: O=S(Cl)Cl
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl {2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (705 mg) in toluene (10 mL) was added thionyl chloride (290 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled, neutralized with saturated aqueous sodium hydrogen carbonate, and poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (742 mg, 100%) as a yellow solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([C:14]([F:17])([F:16])[F:15])[C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:18])(=O)C.[OH-].[Na+]>CO.O>[Br:13][C:9]1[C:8]([C:14]([F:16])([F:15])[F:17])=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH:5]([CH3:18])[CH2:6]2
Reactant: CC(=O)N1c2ccc(Br)c(C(F)(F)F)c2CC1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1Cc2c(ccc(Br)c2C(F)(F)F)N1
Yield: 79.5 %

Procedure:
A mixture of 1-acetyl-5-bromo-2-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-indole (0.130 g, 0.404 mmol; step B above) and NaOH (0.086 g; 2.15 mmol) in MeOH/H2O (4:1; 13 mL) was heated at reflux 3 h. The solvent was removed, the residue was partitioned between Et2O/H2O, and the layers were separated. The aqueous layer was extracted with Et2O (×2). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo, affording 0.090 g of the title compound as a pale yellow oil which was used without further purification: MS (APCl) m/z 282 (M+H, 81Br).