Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[O:24]1[CH:3]([CH:2]([CH3:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(C)CCCC(C)CCCC(C)C
Solvent: ClCCl
Product: CC(C)CCCC(C)CCCC(C)C1CO1
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a solution of 9.6 g of 3,7,11-trimethyl-1-dodecene in 200 ml of methylene chloride was added 10.8 g of meta-chloroperbenzoic acid at room temperature, and the mixture was stirred at the same temperature for 6 hours. Thereafter, the reaction mixture was filtered and the filtrate was washed successively with aqueous sodium thiosulfate, aqueous sodium hydrogen carbonate and aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was distilled under reduced pressure to give 6.8 g (yield 59%) of 1,2-epoxy-3,7,11-trimethyldodecane. The physical constants of the compound are as follows.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.C=C(OP(O)(O)=O)C(O)=O.[NH2:24][C@H:25]([C:31]([O-:33])=[O:32])[CH2:26][CH2:27][C:28]([O-:30])=[O:29]>>[NH2:24][C@H:25]([C:31]([OH:33])=[O:32])[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: C=C(OP(=O)(O)O)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Subsequently, the citrate synthase gene, phosphoenolpyruvate carboxylase gene and glutamate dehydrogenase gene derived from Escherichia coli were introduced into the SC17sucA strain.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:25][NH2:26].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>O1CCCC1.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)([C:13]([F:15])([F:14])[F:16])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:25][NH:26][C:34](=[O:36])[CH3:35]
Reactant: NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To the solution of 1-{2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]phenyl}methanamine (0.12 g) and triethylamine (0.04 g) in tetrahydrofuran was added dropwise acetyl chloride (0.02 g), and the mixture was stirred for one hour at room temperature. The reaction solution was diluted with t-butylmethylether and then washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield N-{2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]benzyl}acetamide (0.1 g). 1H-NMR (CDCl3) δ: 1.98-2.01 (3H, m), 2.50-2.58 (1H, m), 2.82-2.87 (1H, m), 3.45-3.51 (2H, m), 3.74 (1H, d), 4.02 (1H, d), 4.41 (2H), 6.43-6.46 (1H, m), 6.58-6.59 (1H, m), 7.26-7.38 (4H, m)
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([F:43])=[C:21]([C@@:23]23[N:32]=[C:31]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[S:30][CH2:29][C@@H:28]2[CH2:27][C@H:26]([CH2:41]O)[O:25][CH2:24]3)[CH:22]=1)([O-:16])=[O:15].NC1C=CC(F)=C([C@@]23N=C(NC(=O)OC(C)(C)C)SC[C@@H]2[C@@H](OC)COC3)C=1.C(=O)(O)[O-].[Na+]>ClCCl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([F:43])=[C:21]([C@@:23]23[N:32]=[C:31]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[S:30][CH2:29][C@@H:28]2[CH2:27][C@H:26]([CH2:41][F:11])[O:25][CH2:24]3)[CH:22]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@@H](CO)C[C@H]2CS1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: CO[C@H]1COC[C@]2(c3cc(N)ccc3F)N=C(NC(=O)OC(C)(C)C)SC[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[Bis(2-methoxyethyl)amino]sulfur trifluoride (285 μl) was added dropwise to a solution of tert-butyl [(4aR,6R,8aS)-8a-(5-nitro-2-fluorophenyl)-6-hydroxymethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]carbamate obtained in Preparation Example 13 (575 mg) in dichloromethane (55 ml) at −78° C. The mixture was stirred overnight with gradual heating to room temperature. A sodium bicarbonate solution was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (240 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:79][CH2:80][C:81]#[N:82]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:82][CH2:81][C:80]#[N:79])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: N#CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added aminoacetonitrile monosulfate (14 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of aminoacetonitrile monosulfate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(cyanomethyl)acetamide. (12 mg, 0.027 mmol, 19%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=3[N+:26]([O-:28])=[O:27])[S:3][C:4]=2[C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1sc(Nc2ccc(C=O)cc2[N+](=O)[O-])nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a mixture of 0.10 g (0.39 mmole) of 2-amino-4-(4-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.18), 0.07 g (0.39 mmole) of 4-fluoro-3-nitrobenzaldehyde and 2 mL of dimethylformamide was added 0.19 g (0.59 mmole) of cesium carbonate. The mixture was heated at 120 degrees for 6 hours and then cooled. Water was then added and the suspension stirred at room temperature for one hour. The precipitate was collected by filtration, washed with water and dried under vacuum to give 0.16 g of 4-(4-chloro-phenyl)-2-(4-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.18a).
Reaction SMILES: [OH-].[Na+].Cl[C:4]1(Cl)[CH:6]([CH3:7])[C:5]1([C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)C.[CH3:23]O>>[CH3:4][C:5]([C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([O:17][CH3:23])=[O:16])=[CH:11][CH:10]=1)=[CH:6][CH3:7]
Reactant: CC1C(Cl)(Cl)C1(C)c1ccc(OC(C)(C)C(=O)O)cc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CC=C(C)c1ccc(OC(C)(C)C(=O)OC)cc1

Procedure:
Sodium hydride (15.1 g., 0.36 mole, 57% in oil dispersion) was placed in a 2-liter flask and rinsed three times with pentane to remove the oil. Anhydrous dimethylsulfoxide (240 ml.) was then added, and the flask was evacuated and flushed with nitrogen. The mixture was heated to 75°-80°C. for 45 minutes, then cooled in an ice bath. A solution of 133.2 g. of ethyltriphenylphosphonium bromide in 720 ml. of dimethylsulfoxide was then added, the mixture stirred for 15 minutes and then treated with a solution of 70.8 g. (0.30 mole) of methyl 2-(p-acetylphenoxy)-2-methylpropionate in 120 ml. of dimethylsulfoxide. The reaction mixture was stirred for three hours at room temperature and then poured into water. The organic layer was separated, washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate to give 81.8 g. of methyl 2-[p-(1,2-dimethylvinyl)phenoxy]-2-methylpropionate as an oil (mixture of geometric isomers). c. 2-[p-(2,2-Dichloro-1,3-dimethylcyclopropyl)phenoxy]-2-methylpropionic acid [I; A, A', R1 and R3 are CH3, R, R3' and Q are H, R 2 and R2' are Cl, and n is 0; para orientation] was prepared from 24.8 g. of methyl 2-[p-(1,2-dimethylvinyl)phenoxy]-2-methylpropionate, 28 g. of potassium t-butoxide and 50 ml. of chloroform in 500 ml. of pentane according to the procedure described above in Example 1, part (b). The methyl ester thus obtained was hydrolyzed in the usual manner with sodium hydroxide in 95% methanol. The acid fraction thus obtained was recrystallized from a benzene-hexane mixture to give 12.5 g. of 2-[p-(2,2-dichloro-1,3-dimethylcyclopropyl)phenoxy]-2-methylpropionic acid, m.p. 138°-145°C. (mixture of geometric isomers).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.[CH2:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)[CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=1
Reactant: COc1cccc(OC)c1
Reactant: CCc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(OC)cccc2OC)cc1
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
To a mixture of 1,3-dimethoxybenzene (6.9 g, 50 mmol) and tetrahydrofuran (70 mL), n-butyllithium (1.57 M in hexane, 35 mL) was added in ice and stirred for 1.5 hours. Subsequently, 4-ethylbenzyl bromide (10 g, 50 mmol) was added in ice and stirred for an additional 3.5 hours. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-85:15) to give 1,3-dimethoxy-2-(4-ethylbenzyl)benzene (6.37 g, 49%, mp 62.5-66.5° C.) as a light-yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:7][C:8]=1[CH:9]=O)#[N:2].O.[NH2:23][NH2:24]>CO>[C:1]([C:3]1[C:8](=[CH2:9])[NH:7][C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]=1[NH:23][NH2:24])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)c(C=O)nc1N1CCCCC1
Reactant: NN
Solvent: CO
Solvent: O
Product: C=C1NC(N2CCCCC2)=C(C(=O)OCC)C(NN)=C1C#N
Temperature: 25 °C

Procedure:
28.7 g of 5-cyano-6-formyl-2-piperidinyl-3-pyridine-carboxylic acid, ethyl ester (0.1 mol) are dissolved in 100 ml of methanol. 5.5 g of hydrazine hydrate are added and the solution is stirred at room temperature over night. The title compound is filtered off and recrystallized from methanol. Yield 20.5 g (68%); m.p. 168°-170° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]([CH3:21])[N:18]([NH2:20])[CH:19]=1.C(O)(=O)C.[CH:26](N)=[NH:27]>CC(O)CC>[Br:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]([CH3:21])[N:18]([NH:20][CH:26]=[NH:27])[CH:19]=1
Reactant: N=CN
Reactant: Cc1nc(-c2cnn(C)c2Br)cn1N
Solvent: O=C(O)C(F)(F)F
Solvent: CCC(C)O
Solvent: CC(=O)O
Product: Cc1nc(-c2cnn(C)c2Br)cn1NC=N
Temperature: 100 °C
Reaction time: 18 h

Procedure:
4-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-2-methyl-1H-imidazol-1-amine, trifluoroacetate salt (4.90 g, 113.2 mmol) was combined with formamidine acetate (98%, 4.92 g, 46.3 mmol) in 2-butanol (40 mL), and the reaction mixture was heated at 100° C. for 6 hours, then allowed to cool to room temperature and stir for 18 hours. The off-white solid was collected by filtration and washed with 2-propanol followed by diethyl ether. The solid was then triturated with aqueous ammonium hydroxide (7.5 M, 40 mL); filtration provided a white solid, which was washed with 2-propanol followed by diethyl ether to provide the product. Yield: 2.70 g, 9.54 mmol, 72%. 1H NMR (500 MHz, CD3OD), presumed to be a mixture of rotamers or tautomers: δ 2.26 and 2.31 (2 s, 3H), 3.89 and 3.89 (2 s, 3H), 7.26 and 7.40 (2 s, 1H), 7.41 and 7.96 (2 br s, 1H), 7.85 and 7.82 (2 s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:47]=[C:46]([S:48]([N:51](CC2C=CC(OC)=CC=2OC)[C:52]2[S:53][CH:54]=[N:55][N:56]=2)(=[O:50])=[O:49])[C:45]([F:68])=[CH:44][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:14][C:13]=1[C:28]1[N:32]([CH:33]2[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]2)[N:31]=[CH:30][CH:29]=1>ClCCl>[NH:35]1[CH2:34][CH:33]([N:32]2[C:28]([C:13]3[CH:14]=[C:15]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[CH:16]=[CH:17][C:12]=3[O:11][C:10]3[C:9]([Cl:8])=[CH:47][C:46]([S:48]([NH:51][C:52]4[S:53][CH:54]=[N:55][N:56]=4)(=[O:50])=[O:49])=[C:45]([F:68])[CH:44]=3)=[CH:29][CH:30]=[N:31]2)[CH2:36]1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnn2C2CNC2)cc1F
Temperature: 40 °C
Yield: 127.3 %

Procedure:
Trifluoroacetic acid (0.50 mL, 6.53 mmol) was added to a solution of tert-butyl 3-{5-[4-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,3,4-thiadiazol-2-yl)amino]sulfonyl}-5-fluorophenoxy)-4′-(trifluoromethyl)biphenyl-3-yl]-1H-pyrazol-1-yl}azetidine-1-carboxylate (Preparation 40, 419 mg, 0.465 mmol) in dichloromethane (20 mL). The mixture was then heated to 40° C. for 18 hours under an atmosphere of nitrogen. The reaction was then cooled to room temperature and concentrated in vacuo to afford a brown residue (385.4 mg). The residue was purified by preparative HPLC (Trilution method) to afford the title compound as a white solid (46.3 mg, 11% over 2 steps).
Reaction SMILES: C([O-])(=[O:8])C1C=CC=CC=1.C(C1C=[C:16]([CH:30]=C(C(C)(C)C)C=1O)[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1)=[O:18])(C)(C)C.[C:38]([C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:50]=1[OH:51])[C:45](Cl)=[O:46])([CH3:41])([CH3:40])[CH3:39]>ClCCl>[C:38]([C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:50]=1[OH:51])[C:45]([O:8][CH2:30][CH2:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1)=[O:18])=[O:46])([CH3:41])([CH3:40])[CH3:39]
Reactant: O=C([O-])c1ccccc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(C(=O)Oc2ccc(Cl)c([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)OCCC(=O)Oc2ccc(Cl)c([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Yield: 86 %

Procedure:
A solution of the benzoate (13.7 g, 55.9 mmole) from (a) and 3,5-di-t-butyl-4-hydroxybenzoyl chloride (15.0 g, 55.9 mmole) in dichloromethane (50 ml) were heated under reflux for 42 hours. The solvent was removed by rotary evaporation, and the residue crystallized from 10% toluene in hexane, to give the product (22.9 g, 86%) as a white solid. m.p. 106°-108° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15]1>C1CCCCC1.CCOC(C)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH:16]=[C:17]2[C:22]([CH:21]=[CH:20][CH:19]=[CH:18]2)=[N:14]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: BrCCCCC#Cc1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C(#Cc1ccccn1)CCCCn1cc2ccccc2n1
Yield: 9 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05 mmol, Example 124(B)) and indazole (124 mg, 1.05 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-indazole (26 mg, 94 μmol, 9%) as a brown oil and (cyclohexane/AcOEt 1:1) to yield 1-(6-(pyridin-2-yl)hex-5-ynyl)-1H-indazole (15 mg, 54 μmol, 5%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:5].[OH-].[Na+].[CH2:22]=O>CCO>[Br:19][C:16]1[CH:17]=[N:18][C:2]2[NH:1][CH2:22][N:6]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[C:4](=[O:5])[C:3]=2[CH:15]=1
Reactant: C=O
Reactant: Nc1ncc(Br)cc1C(=O)NCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2cc(Br)cnc2NCN1Cc1ccc(F)cc1
Yield: 87 %

Procedure:
To a solution of 2-amino-5-bromo-N-(4-fluorobenzyl)nicotinamide (200 mg, 0.62 mmol) and NaOH (50 mg, 1.23 mmol) in 10 mL of EtOH was added HCHO (1 mL, 37% in water) and then the mixture was heated at reflux for 30 minutes. After being concentrated in vacuo, the residue was suspended in water and extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product of 6-bromo-3-(4-fluorobenzyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (180 mg, yield: 87%) without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.28˜8.32 (m, 2H), 7.26˜7.31 (m, 2H), 7.02 (t, J=8.4 Hz, 2H), 5.01 (s, 2H), 4.68 (d, J=2.4 Hz, 2H). MS (M+H)+: 336/338.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](O)[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].[C:12](=[O:15])([O-])[O-].[K+].[K+].[CH3:18]I>CCC(C)=O>[CH3:18][O:11][C:3]1[CH:4]=[C:5]([CH3:10])[C:6]([O:15][CH3:12])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CI
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cc(C)c(OC)c(C)c1C
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
A 2 L 3-N flask was charged with 2,3,5-trimethyl-benzene-1,4-diol (Ex-1B-1) (50 g, 0.33 mol) and MEK (750 mL) to yield an amber solution. Potassium carbonate (210 g, 1.64 mol) was charged to the solution. After 30 min at RT, MeI (81.2 mL, 1.31 mol) was added to the brown suspension. The reaction mixture was heated to 65° C. for 72 h. After cooling to RT, the reaction mixture was concentrated to dryness by rotary evaporation to give a white paste. The paste was washed with EtOAc (3×300 mL). The EtOAc extracts were combined and concentrated by rotary evaporation. The resulting yellow-brown oil was chromatographed (80:20/Heptanes:EtOAc) to yield 1,4-dimethoxy-2,3,5-trimethyl-benzene (Ex-1B-2) (47.2 g, 80%). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.55 (s, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15]([OH:17])=O)([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15]([Cl:21])=[O:17])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C12CCC(c3ccccc3)(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C12CCC(c3ccccc3)(CC1)CC2
Temperature: 25 °C

Procedure:
To an ice-water cooled solution of 4-phenylbicyclo[2.2.2]octane-1-carboxylic acid (479 mg, 2.07 mmol) in DCM (20 mL) was added DMF (2-3 drops) followed by oxalyl chloride (0.20 mL, 2.14 mmol). The reaction mixture was allowed to warm to ambient temperature overnight and then solvent was evaporated under reduced pressure to leave crude 4-phenylbicyclo[2.2.2]octane-1-carbonyl chloride which was used directly in the next stage. This was redissolved in a 1:1 solution of MeCN and THF (10 mL) and added dropwise to an ice water cooled solution of 2M trimethylsilyldiazomethane (1.5 mL, 3.0 mmol) and triethylamine (0.40 mL, 2.60 mmol) in a 1:1 solution of MeCN and THF (20 mL). The resulting yellow reaction mixture was allowed to stir at 0° C. for 6 hrs and then allowed to stand at ambient temperature overnight. The solvent was removed under reduced pressure and the residue redissolved in EtOAc (100 mL) and washed with water (50 mL), NaHCO3 (50 mL) and brine (50 mL). The organic phase was dried (MgSO4), concentrated to leave a red brown gum. This was purified on a 12 g silica Crawford silica cartridge, eluting 0-10%-20% EtOAc using an Isco Companion, to give 2-diazo-1-(4-phenylbicyclo[2.2.2]oct-1-yl)ethanone (238 mg; 0.933 mmol, 45%) as a pale yellow gum which formed a cream solid on standing; 1H NMR (CDCl3) δ1.82-1.91 (m, 12H), 5.38 (s, 1H), 7.15-7.21 (m, 2H), 7.29-7.31 (m, 4H); MS m/e MH+ 255.
Reaction SMILES: Cl[C:2]1[C:3]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][S:10][C:4]=2[N:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(N(CC)CC)C.CC(O)C>O>[Cl:9][CH2:8][C:6]1[N:7]=[C:2]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:3]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][S:10][C:4]=2[N:5]=1
Reactant: ClCc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: NCc1ccccn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: ClCc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 27.4 %

Procedure:
A reaction mixture of 4-chloro-2-chloromethyl-5-phenylthieno[2,3-d]pyrimidine (0.50 g, 1.69 mmol), 2-aminomethylpyridine (0.17 ml, 1.69 mmol), triethylamine (0.26 ml, 1.86 mmol) and propan-2-ol (15 ml) was stirred at ambient temperature for 4 days. The solution was then poured into water (150 ml) and extracted with ethyl acetate (3×75 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:4) gave (2-chloromethyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)pyridin-2-ylmethylamine as a yellow solid (0.17 g), m.p. 97°-99° C.