Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16][CH2:15]1.CCN(CC)CC.CCOC(C)=O>CC#N>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:14]2[CH2:15][CH2:16][CH:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH2:18][CH2:19]2)[N:7]=1
Reactant: Clc1nccc(-c2ccccn2)n1
Reactant: CS(=O)(=O)NC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCN(c2nccc(-c3ccccn3)n2)CC1
Yield: 78 %

Procedure:
A solution of 2-chloro-4-(pyridin-2-yl)pyrimidine (0.576 g, 3 mmol), N-(piperidin-4-yl)methanesulfonamide (0.64 g, 3.6 mmol) and Et3N (0.77 mL, 6 mmol) in CH3CN (15 mL) was refluxed for 2 h and TLC (petroleum:EtOAc=5:1) showed the reaction was complete. The reaction mixture was concentrated and purified by chromatography, eluted with CH2Cl2:MeOH (10:1 to 5:1) to give the title compound (0.78 g, 78%) as a yellow oil.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:12])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[N:14]#[C:15][NH2:16]>>[ClH:1].[CH2:6]([C:5]1[N:12]=[C:15]([NH2:16])[NH:14][CH:4]=1)[CH2:7][CH2:8][CH2:9][C:10]#[CH:11]
Reactant: N#CN
Reactant: C#CCCCCC(N)C(=O)OC
Agent: Cl
Product: C#CCCCCc1c[nH]c(N)n1
Yield: 87 %

Procedure:
2-Amino-oct-7-ynoic acid methyl ester hydrochloride (2.90 g, 14.1 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Hex-5-ynyl-1H-imidazol-2-ylamine hydrochloride (2.45 g, 87%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.43 (s, 1H), δ 2.44 (t, 2H), 2.14 (t, 1H), δ 2.12 (m, 2H), δ 1.64 (m, 2H), δ 1.47 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.3, 127.6, 108.5, 83.4, 68.7, 27.7, 27.1, 23.8, 17.5 ppm; HRMS (ESI) calcd for C9H14N3 (M+) 164.1182. found 164.1182.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1>[Pd].[Pd](Cl)Cl>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: Fc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Pd]
Product: Fc1ccc(-c2ccc(F)cc2)cc1

Procedure:
4,4'-difluorobiphenyl has heretofore been prepared by a process utilizing a Grignard coupling reaction. In accordance with the prior process, p-halofluorobenzene is reacted with magnesium in a solvent to form halomagnesiumfluorobenzene, the Grignard reagent. The Grignard reagent is then reacted with additional p-halofluorobenzene (the coupling reagent) in the presence of a catalyst comprised of palladium chloride or palladium supported on charcoal. This prior process results in a yield of about 80% 4-4'-difluorobiphenyl when the Grignard reagent is formed from pbromofluorobenzene and the coupling reagent is p-iodofluorobenzene. In addition, about 8% of a difluoroterphenyl byproduct is formed in the reaction. Thus, the heretofore utilized process produces a relatively low yield of 4,4'-difluorobiphenyl. In addition, the process is disadvantageous in that p-iodofluorobenzene is expensive, and a high molar ratio of the palladium chloride or palladium/charcoal catalyst is required. While p-bromofluorobenzene is much less expensive than p-iodofluorobenzene, when p-bromofluorobenzene is substituted for p-iodofluorobenzene in the coupling reaction, a very low yield of 4,4'-difluorobiphenyl is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH:43]1([N:3]2[C:2](=[O:1])[CH2:7][O:6][C:5]3[N:8]=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]5)=[CH:20][CH:19]=4)[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:4]2=3)[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: BrC1CCCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(C3CCCC3)C(=O)CO4)cc2)CCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol), potassium carbonate (44 mg, 0.318 mmol) and bromocyclopentane (0.034 mL, 0.318 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give an orange suspension. The reaction mixture was stirred at 80° C. for one hour. The reaction mixture was allowed to cool to room temperature, diluted with saturated sodium bicarbonate solution (5 mL) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as an off-white solid (12 mg, 21% yield). 1H-NMR (500 MHz, CDCl3) δ 7.32 (1H, s), 7.17-7.28 (7H, m), 7.10-717 (2H, m), 4.94 (1H, br s), 4.83 (1H, quin), 4.72 (2H, s), 2.05-2.60 (6H, m), 1.83-2.03 (5H, m), 1.54-1.82 (3H, m), 1.00-1.45 (9H, br m). LCMS (Method A) RT=8.25 min, M+H+=540.19.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5](=[O:7])[NH:4][C@@H:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15]I.[H-].[Na+]>O1CCCC1>[CH3:15][N:4]1[C:5](=[O:7])[CH2:6][CH:2]([CH3:1])[C@H:3]1[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: CI
Reactant: CC1CC(=O)N[C@@H]1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CC(=O)N(C)[C@@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
1,1-dimethylethyl 3-methyl-5-oxoprolinate (0.79 g, 3.96 mmol) was dissolved in tetrahydrofuran (8 ml) and treated with methyl iodide (0.27 ml, 4.36 mmol). The mixture was then cooled to 0° C. and treated portion-wise with sodium hydride (60% in oil, 0.170 g, 4.36 mmol). The mixture ceased bubbling after 30 minutes at 0° C. and was then allowed to warm to room temperature and stirred overnight. The mixture was quenched by addition of saturated aqueous ammonium chloride solution (10 ml) and the organic layer was separated and put aside. The aqueous layer was extracted with dichloromethane (3×20 ml) and the combined extracts were dried using a hydrophobic frit. All of the organic fractions (including that put aside earlier) were combined and evaporated to give crude 1,1-dimethylethyl 1,3-dimethyl-5-oxoprolinate (0.770 g) as a yellow gum which was used without further purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[CH:12]1[CH:17]=[C:16]([C:18]2[C:32]3[C:27](=[C:28]([Br:35])[C:29]([O-:34])=[C:30]([Br:33])[CH:31]=3)[O:26][C:25]3[C:19]=2[CH:20]=[C:21]([Br:37])[C:22]([C:24]=3[Br:36])=[O:23])[C:15]([C:38]([O-:40])=[O:39])=[CH:14][CH:13]=1.[Na+:41].[Na+]>C1C=CC=CC=1>[CH:12]1[CH:17]=[C:16]([C:18]2[C:19]3[C:25](=[C:24]([Br:36])[C:22]([O-:23])=[C:21]([Br:37])[CH:20]=3)[O:26][C:27]3[C:32]=2[CH:31]=[C:30]([Br:33])[C:29]([C:28]=3[Br:35])=[O:34])[C:15]([C:38]([O-:40])=[O:39])=[CH:14][CH:13]=1.[Na+:41].[Na+:41].[CH3:32][C:27]1([CH2:28][CH3:29])[O:26][CH2:25][CH2:19][O:8]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])c1ccccc1-c1c2cc(Br)c(=O)c(Br)c-2oc2c(Br)c([O-])c(Br)cc12
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC1(C)OCCO1

Procedure:
Reaction of 40.0 g of norbornadiene and 13.2 g of paraformaldehyde in formic acid (480 ml) containing concentrated sulfuric acid (20 drops) gave 55.3 g of diformate i. Oxidation of diformate i (55.3 g) in 900 ml of acetone at ##STR8## 0° C. with 553 ml of standard Jones reagent provided 27.2 g of keto acid ii. Treatment of 21.5 g ii with 225 ml of 48% hydrobromic acid in 225 ml of glacial acetic acid at reflux gave 28.1 g of bromo acid 1 (R2 =H, R3 =O). Esterification of 1 (R2 =H, R3 =O) with ethereal diazomethane gave methyl ester of formula (1) wherein R2 =Me, and R3 =O. Ketalization of 16.1 g of keto ester 1 (R2 =Me, R3 =O) with 35.8 g of 2-methyl-2-ethyl-1,3-dioxolane in 150 ml of benzene containing 2.7 g of p-toluenesulfonic acid at 25° C. for 20 hours give 17.0 g of pure ketal ester of formula (1) wherein R2 =Me and R3 =--O(CH2)2O--. Fluorination of 4.66 g of ester 1 (R2 =Me, R3 =--O(CH2)2O--) via enolate formation [lithium disopropylamide, tetrahydrofuran, -78° C.] and slow addition of perchloryl fluoride (-40° C.) resulted in an 86% isolated yield of a pure mixture of the desired α-fluoro ester shown in formula (2) (Rf 0.41) [hexane-ethyl acetate (4:1)] and the isomeric α-fluoro ester shown in formula (3) (Rf 0.33 in a ratio of 1:1.). Chromatography on silica gel easily provided the α-fluoro ester of formula (2), which was reduced with lithium aluminum hydride in ether at 25° C. and dehydrobrominated with 1,5-diaza-bicyclo(5.4.0)undec-5-ene (10 equivalents) in refluxing toluene. An 84% yield of the pure alcohol shown in formula (4) M+ 200.0850 was obtained. As fluorination with perchloryl fluoride can be hazardous, safety precautions should be observed.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([C:7]([F:10])([F:9])[F:8])=O)=O.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].C(C1C(=O)NC(C)=CC=1C)#N.C(C1C(=O)NC(C)=C(C)C=1C)#N.C(CC(=O)C)(=O)C.CC(C(=O)C)C(=O)C>>[C:11]([C:13]1[C:14](=[O:15])[NH:16][C:2]([CH3:1])=[CH:4][C:5]=1[C:7]([F:10])([F:9])[F:8])#[N:12]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: N#CCC(N)=O
Agent: CC(=O)C(C)C(C)=O
Agent: Cc1[nH]c(=O)c(C#N)c(C)c1C
Agent: Cc1cc(C)c(C#N)c(=O)[nH]1
Solvent: CC(=O)CC(C)=O
Product: Cc1cc(C(F)(F)F)c(C#N)c(=O)[nH]1

Procedure:
3-Cyano-6-methyl-4-trifluoromethylpyrid-2-one was prepared from 1,1,1-trifluoroacetylacetone and cyanoacetamide following the procedure of Kametani and Sato (Yakugaku Kenkyu 34, 117, 1962). 3-Cyano-4,6-dimethylpyrid-2-one and 3-cyano-4,5,6-trimethylpyrid-2-one were similarly prepared from acetylacetone and cyanoacetamide, and 3-methylpentan-2,4-dione and cyanoacetamide respectively.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]2[O:31][CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[O:31][CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(COCCCc2ccc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125(h), from tert-butyl (3'RS,4'RS)-6-(3-benzyloxy-propyl)-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained (3'RS,4'RS)-6-(3-benzyloxy-propyl)-3'-(naphthalen-2-ylmethoxy)-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine in the form of a colourless oil; MS: 467 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O:12][CH2:13][CH3:14])=[O:11].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1cccc(N=C(C)c2ccccc2)c1

Procedure:
A solution of acetophenone (95 ml), m-carbethoxy aniline (75 ml), benzene (150 ml) was refluxed in the presence of molecular sieve (50 g) with continuous removal of water. The crude product was distilled under reduced pressure to give N-(α-methyl benzylidene)-m-carbethoxyaniline (XIII). XIII had a boiling point of 205° C. at 0.1 millimeter.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:12])[N:9](S(C3C=CC=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1.[Na].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:12])[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: COc1cnc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1cnc2[nH]c(C)cc2c1
Yield: 90.7 %

Procedure:
A solution of 5-methoxy-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (950 mg, 3.14 mmol) and 40% aqueous sodium hydroxyde (106 ml) in methanol (160 ml) was heated at reflux for 30 minutes. After cooling, the mixture was poured onto cooled water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1/1). The fractions containing the expected product were combined and evaporated to give 5-methoxy-2-methyl-1H-pyrrolo[2,3-b]pyridine (462 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[OH:18].[H-].[Na+].COC1C=C(OC)C=CC=1C[N:26]([C:39]1[S:43][N:42]=[CH:41][N:40]=1)[S:27]([C:30]1[CH:35]=[C:34]([F:36])[C:33](F)=[CH:32][C:31]=1[F:38])(=[O:29])=[O:28]>CN(C)C=O.ClCCl.FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][C:33]1[C:34]([F:36])=[CH:35][C:30]([S:27]([NH:26][C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:28])=[O:29])=[C:31]([F:38])[CH:32]=1
Reactant: Nc1ncnc2c1ncn2-c1cc(Cl)ccc1O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2-c1cc(Cl)ccc1Oc1cc(F)c(S(=O)(=O)Nc2ncns2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 2-(6-amino-9H-purin-9-yl)-4-chlorophenol (0.053 g, 0.2 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60% w/w dispersion in mineral oil, 0.009 g, 0.2 mmol) and the mixture was stirred for 1 h at ambient temperature. N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.107 g, 0.24 mmol) was added and the mixture was stirred at ambient temperature for 16 h and partitioned between ethyl acetate (100 mL) and saturated aqueous ammonium chloride (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred for 1 h at ambient temperature and concentrated in vacuo. The residue was purified by preparative reverse-phase HPLC to afford 4-(2-(6-amino-9H-purin-9-yl)-4-chlorophenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as an off-white solid in 17% yield (0.018 g): 1H NMR (300 MHz, DMSO-d6) δ8.48 (br s, 1H), 8.39 (s, 1H), 8.17 (br s, 1H), 7.95-7.74 (m, 4H), 7.74-7.58 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.34-7.22 (m, 1H); MS (ES+) m/z 536.6 (M+1), 538.6 (M+1).
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1)(=O)=O.[CH3:37][O-:38].[Na+]>CO.CC(O)=O>[CH3:37][O:38][C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Yield: 90.5 %

Procedure:
A solution of [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 53; 44 mg, 0.08 mmol) and NaOMe (100 mg, 0.25 mmol) in MeOH (1.5 mL) was heated at 60° C. for 1 h. The mixture was cooled, acidified with HOAc (3 drops), and directly purified using Preparative HPLC (conditions as in Example 54) to give the title compound (35 mg, 89%). MS (ESI): mass calcd. for C22H19F6N5O, 483.15; m/z found, 484.8 [M+H]+. 1H NMR (CDCl3): 9.63 (s, 1H), 8.39 (d, J=3.3 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.06-7.02 (m, 1H), 3.88 (s, 3H), 3.50-3.44 (m, 4H), 3.26-3.22 (m, 2H), 3.11-3.07 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([CH3:38])[CH:37]=1)[C:33]#[N:34])#[N:28]>>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([CH:29]([C:27]#[N:28])[C:30]2[CH:31]=[C:32]([CH:35]=[C:36]([CH3:38])[CH:37]=2)[C:33]#[N:34])[C:12]([CH:23]([CH3:25])[CH3:24])=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Reactant: Cc1cc(C#N)cc(CC#N)c1
Product: Cc1cc(C#N)cc(C(C#N)c2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1

Procedure:
5-Isopropyl barbtric acid (Lancaster) was reacted with phosphorus oxychloride to provide 2,4,6-trichloro-5-isopropylpyrimidine. The 2,4,6-trichloro-5-isopropylpyrimidine was then reacted with benzyl alkoxide to form 2,4-bis(benzyloxy)-6-chloro-5-isopropylpyrimidine. The 2,4-bis(benzyloxy)-6-chloro-5-isopropylpyrimidine was then reacted with 3-(cyanomethyl)-5-methylbenzonitrile to form 3-((2,6-bis(benzyloxy)-5-isopropylpyrimidin-4-yl)(cyano)methyl)-5-methylbenzonitrile. The 3-((2,6-bis(benzyloxy)-5-isopropylpyrimidin-4-yl)(cyano)methyl)-5-methylbenzonitrile was treated with NaH and O2 to form ketone 3-(2,6-bis(benzyloxy)-5-isopropylpyrimidine-4-carbonyl)-5-methylbenzonitrile, which was then catalytically hydrogenated to form Compound 1.
Reaction SMILES: [Cl-].[Li+].[Cu]C#N.[Br-].[I:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Zn+].Cl[Si](C)(C)C.[CH:21]([C:23]([CH2:25][CH3:26])=[O:24])=[CH2:22]>O1CCCC1.CCOCC.O>[I:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][CH2:22][CH2:21][C:23](=[O:24])[CH2:25][CH3:26]
Reactant: [Zn+]Cc1ccccc1I
Reactant: C=CC(=O)CC
Agent: N#C[Cu]
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCC(=O)CCCc1ccccc1I
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 102.5 %

Procedure:
Lithium chloride (6.6 g, 150 mmole) (dried overnight at 115° C. under vacuum) and copper(I) cyanide (6.72 g, 75 mmole) were stirred with tetrahydrofuran (75 ml) under nitrogen for 10 minutes then cooled to −78° C. A solution of 2-iodobenzyl zinc bromide (150 ml, 0.5M in THF, 75 mmol) was added and the mixture was warmed to −15° C., held at this temperature for 20 min then re-cooled to −78° C. Chlorotrimethylsilane (19.1 ml, 150 mmol) was added followed by a solution of ethyl vinyl ketone (7.4 ml, 74.3 mmol) in tetrahydrofuran (15 ml). The mixture was stirred at −78° C. for 3 hours then warmed to room temperature and stirred for 1 hour before being poured into a mixture of water (400 ml) and ether (400 ml). The aqueous layer was extracted with ether (2×400 ml) and the combined ethereal solutions were washed with brine (2×200 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo to give the title compound as a pale yellow liquid (23 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][C:13](C)([C:19](OCC)=O)[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][CH:13]([CH3:19])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C)(Cc1ccc(N2CCN(C)CC2)cc1)C(=O)OCC
Agent: Cl
Product: CC(Cc1ccc(N2CCN(C)CC2)cc1)C(=O)O
Yield: 62.2 %

Procedure:
A solution of diethyl 2-(4-(4-methylpiperazin-1-yl)benzyl)-2-methylmalonate (1.50 g, 4.29 mmol) in conc. HCl (10 ml) was stirred at 130-140° C. in a sealed tube for 18 h. The reaction mixture was concentrated and co-distilled with toluene to afford 700 mg (63.6%) of 2-(4-(4-methylpiperazin-1-yl)benzyl)propanoic acid as dark brown solid.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12][CH3:13])[C:5](=[O:11])[CH2:6][C:7](OC)=O.C(Br)/[CH:15]=[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])\[CH3:17].CC(=CCC/C(=C/CO)/C)C.[OH-].[Na+]>C(O)C.O>[CH3:2][O:3][CH:4]([O:12][CH3:13])[C:5](=[O:11])[CH2:6][CH2:7]/[CH:15]=[C:16](\[CH3:17])/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COC(=O)CC(=O)C(OC)OC
Agent: CC(C)=CCC/C(C)=C/CO
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COC(OC)C(=O)CC/C=C(\C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 350 ml of anhydrous ethanol was dissolved 17.4 g of sodium metal, and to this was added dropwise 160 g of methyl 4,4-dimethoxyacetoacetate with stirring at room temperature. One hour later, geranyl bromide prepared from 130 g of geraniol was added dropwise to the above-obtained mixture under ice-cooling. The mixture was then allowed to stand overnight at room temperature and refluxed for one hour. To this reaction mixture was added 42 g of sodium hydroxide in a mixture of 1.4 1. of ethanol and 1.18 1. of water, and the mixture was heated under reflux for 6 hours and extracted with n-hexane. The n-hexane extract was distilled under reduced pressure to give 134 g of the desired product, b.p. 92°-95° C./0.05 mmHg.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:19])[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1>C(O)C>[CH2:6]([O:5][C:1]([CH2:2][CH2:3][N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:19])[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1)=[O:4])[CH3:7]
Reactant: CCC(=O)N(C)C1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCC(N(C)C(=O)CC)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
14 g of ethyl acrylate in 45 ml of ethanol are added dropwise to 23.8 of the amine obtained in Stage C of Example 1 dissolved in 45 ml of ethanol. The mixture is stirred at room temperature for 3 hours, evaporated, and the residual oil is distilled in a Kugelrohr (bulb tube) at 120° C. and 0.09 mm Hg.