Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][NH:7][CH2:6]2)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:19]1[N:28]=[C:27]2[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]2[CH:29]2[CH2:31][CH2:30]2)=[CH:21][C:20]=1[F:36]>C(#N)C>[C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][N:7]([C:19]1[N:28]=[C:27]3[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]3[CH:29]3[CH2:31][CH2:30]3)=[CH:21][C:20]=1[F:36])[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC12CNCC1C2
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)NC12CC1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 51 %

Procedure:
A mixture of 1-acetylamino-3-azabicyclo[3.1.0]-hexane (150 mg, 0.70 mmol) and triethylamine (0.48 ml, 3.5 mmol) in acetonitrile (7 ml) was treated with 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (192.1 mg, 0.68 mmol) and heated to 80° for 18 hours. Filtration of the reaction mixture provided the title product as a white solid, mp 275° with decomposition (135.8 mg, 0.35 mmol, 51% yield). 1H NMR (CDCl3) 8.55 (s, 1H), 8.49 (s, 1H), 7.96 (d, J=13 Hz, 1H), 4.22 (m, 1H), 3.98 (bs, 2H), 3.81 (m, 1H), 3.68 (m, 1H), 1.82 (bs, 4H), 1.12 (m, 5H), 0.78 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:5][CH:4]=1.[BrH:15]>>[BrH:15].[CH3:14][C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:13]=[CH:12][N:11]=1
Reactant: COc1ccc(-n2ccnc2C)cc1
Agent: Br
Product: Cc1nccn1-c1ccc(O)cc1
Yield: 69 %

Procedure:
A mixture of 4 parts of 1-(4-methoxyphenyl)-2-methyl-1H-imidazole and 37.5 parts of hydrobromic acid solution 48% is stirred and refluxed overnight. After cooling, the reaction mixture is evaporated. The residue is triturated in a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 3.8 parts (69%) of 4-(2-methyl-1H-imidazol-1-yl)phenol monohydrobromide; mp. 181°-205° C.
Reaction SMILES: [Cl:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[ClH:1].[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([Cl:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: CN1CCC(O)c2cc(Cl)sc2C1
Product: CN1CCC(Oc2cccc(Br)c2Cl)c2cc(Cl)sc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2-chloro-7-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 24) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([O:12]/[C:13](/[C:23](OC)=[O:24])=[C:14](/OC(=O)C)\[C:15]([O:17][CH3:18])=[O:16])(=O)C>C(O)(=O)C.CO>[CH3:18][O:17][C:15]([C:14]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]2[C:23](=[O:24])[C:13]=1[OH:12])=[O:16]
Reactant: Nc1ccc(Br)cn1
Reactant: COC(=O)/C(OC(C)=O)=C(\OC(C)=O)C(=O)OC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1nc2ccc(Br)cn2c(=O)c1O
Temperature: 25 °C
Yield: 2.1 %

Procedure:
2-Amino-5-bromo-pyridine (664 mg, 3.85 mmol), dimethyl diacetoxyfumarate (1.00 g, 3.84 mmol) and glacial acetic acid (10 drops) in dry methanol (10 mL) were combined and heated to reflux. After 48 h the reaction was cooled to room temperature and concentrated in vacuo. Ethyl acetate (2 mL) was added to the residue which was sonicated for 2 min and the resulting precipitate collected by filtration and washed with cold ethyl acetate (1 mL) and dried on the pump to afford 7-bromo-3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester as a yellow solid (24 mg, 2%): 1H NMR (300 MHz, CDCl3) δ 4.19 (3H, s, OCH3), 7.53 (2H, d, J=1.4 Hz, H8 and H9), 9.00 (1H, d, J=1.4 Hz, H6), 10.53 (1H, br s, OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH2:19]([NH:26][CH2:27][CH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:19]([N:26]([CH2:27][CH2:28][C:29]1[N:30]=[CH:31][CH:32]=[CH:33][N:34]=1)[CH2:10][CH2:9][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CNCCc2ncccn2)cc1
Reactant: O=CCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(C(CCN(CCc2ncccn2)Cc2ccccc2)c2ccc(F)cc2)cc1

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propanal (0.908 g, 3.69 mmol) in DCE (12 mL) at room temperature was added N-benzyl-2-(pyrimidin-2-yl)ethanamine (0.704 g, 3.30 mmol), acetic acid (0.208 g, 3.46 mmol) (0.20 mL). and NaBH(OAc)3 (0.834 g, 3.94 mmol) The reaction mixture was stirred at room temperature for 3 h, quenched with 5 M NaOH (1×), diluted with EtOAc, washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 40% to 70% EtOAc in hexanes) gave N-benzyl-3,3-bis(4-fluorophenyl)-N-(2-(pyrimidin-2-yl)ethyl)propan-1-amine.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:32])[C@@H:17]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])C1C=CC=CC=1.C(OC(N[C@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)=O)(C)(C)C>>[C:28]([O:27][C:25]([NH:24][C@@H:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:32])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1

Procedure:
Compound 22 was synthesized from compound 21, following the procedure as described for compound 3a, as a foam. MS (ESI, EI−) m/z=347 (MH−).
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.[Li]CCCC.[C:16]([O:21][CH3:22])(=[O:20])[CH:17]([CH3:19])[CH3:18].IC[CH2:25][CH2:26][CH2:27][O:28][CH3:29]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:18][C:17]([CH3:1])([CH2:19][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:16]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(C)C
Reactant: COCCCCI
Reactant: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCCCCC(C)(C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To N-isopropylcyclohexylamine (5.96 ml) in THF (30 ml) was added dropwise n-BuLi (1,6-M, 22.7 ml) at -78° C., and the mixture was stirred for 30 min, to which a THF (5 ml) solution of methyl isobutyrate (3.43 g) was added, and stirred at -78° C. for 45 min. Then, a HMPA (6.3 ml) solution of 1-iodo-4-methoxy-butane (9.05 g) was added to the mixture, and stirred at room temperature for 1 h to give methyl 2,2-dimethyl-6-methoxycaproate (4.81 g, 85%) after usual work-up.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([CH3:38])[CH:37]=1)[C:5]([N:7]([CH3:34])[C@@H:8]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6].Cl.COC(=O)[C@H](C[C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)NC=1)N>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([CH3:38])[CH:37]=1)[C:5]([N:7]([CH3:34])[C@@H:8]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:46][C:54]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[CH:12][CH:11]=1)=[O:6]
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(O)cc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Product: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-O-benzyl-(D)-tyrosine (prepared by O-benzylation of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine (example 64)) with (L)-tryptophan methyl ester hydrochloride according to example 1 followed by hydrolysis of the methyl ester moiety according to example 12 gives N-(3,5-dimethylbenzoyl)-N-methyl-O-benzyl-(D)-tyrosyl-(L)-tryptophan; FAB-MS m/e 602 (M-H)-.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH3:12])[CH2:10][OH:11].C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH3:12])[CH:10]=[O:11]
Reactant: CC(CO)c1c(Cl)cccc1Cl
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C=O)c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(2,6-dichlorophenyl)propan-1-ol (278 mg, 1.4 mmol) in DMSO (6 ml) was added triethylamine (1.1 ml, 8.1 mmol) followed by pyridine-sulphur trioxide (322 mg, 2.0 mmol). After 1 h more pyridine-sulphur trioxide (161 mg, 1.0 mmol) was added and the mixture stirred for a further 1 h. The mixture was partitioned between EtOAc (3×20 ml) and water (20 ml). The combined organic layers were washed with brine (20 ml) then separated and dried (Na2SO4). The solvent was evaporated and the residue azeotroped with toluene (2×20 ml). The aldehyde was used directly without further purification. 1H NMR (250 MHz, CDCl3) δ 1.51 (3H, d, J=7.0 Hz), 4.17 (1H, q, J=7.0 Hz), 7.20 (1H, t, J=8.0 Hz), 7.33 (2H, d, J=8.5 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:30]=[CH:29][C:18]3[CH2:19][CH2:20][N:21]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:22][CH2:23][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:24]1([N:21]2[CH2:22][CH2:23][C:17]3[CH:16]=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:30]=[CH:29][C:18]=3[CH2:19][CH2:20]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c(cc1OC1CCNCC1)CCN(C1CCCC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylic acid-tert-butyl ester (E5a) (593 mg, 1.43 mmol) was dissolved in dichloromethane (5 ml) and treated with trifluoroacetic acid (3 ml). The solution was stirred at room temperature for 1 hour, concentrated in vacuo and applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title product (E5). MS (ES+) m/e 315 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[N:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1>>[F:8][C:6]1[CH:7]=[C:2]([C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:3]=[N:4][CH:5]=1
Reactant: Fc1cncc(Br)c1
Reactant: OB(O)c1ccncc1
Product: Fc1cncc(-c2ccncc2)c1

Procedure:
Prepared from 3-bromo-5-fluoropyridine (439.0 mg, 2.50 mmol) and pyridin-4-ylboronic acid (509.9 mg, 3.73 mmol) according to Method K, except the product was purified by silica gel chromatography (ethyl acetate, Rf=0.21) instead of preparative HPLC; 1H NMR (300 MHz, chloroform-D) δ ppm 7.50-7.51 (m, 2H), 7.65 (dt, J=9.1, 2.4 Hz, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.73-8.76 (m, 3H). MS (DCI/NH3) m/z=175 (M+H)+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:15](=[O:18])([O-])[O-].[K+].[K+].[N+]([C:24]1[CH:25]=[C:26]([C:32]#[N:33])[C:27](=[CH:30][CH:31]=1)[C:28]#[N:29])([O-])=O.Cl>C1C=CC=CC=1.CN(C)C=O>[C:32]([C:26]1[CH:25]=[C:24]([CH:31]=[CH:30][C:27]=1[C:28]#[N:29])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:18][C:15]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([C:32]#[N:33])[CH:25]=1)#[N:33]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: O=C([O-])[O-]
Reactant: OCCCCCCCCCCCCO
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#Cc1ccc(OCCCCCCCCCCCCOc2ccc(C#N)c(C#N)c2)cc1C#N
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A mixture of 1,12-dodecanediol (2.2 g, 0.011 mol), anhydrous potassium carbonate (4.1 g, 0.031 mol), 35 ml of dimethylformamide and 5 ml of benzene was heated at reflux under a nitrogen atmosphere for 12 hours. A small quantity of water was collected in a Dean-Stark trap. The benzene was removed by distillation. To the cooled reaction medium was added 4.0 g (0.023 mol) of 4-nitrophthalonitrile, which resulted in an immediate color change to a deep blue. After 10 minutes at room temperature, the reaction medium had turned to a yellowish-orange and remained this color throughout the entire reaction. The mixture was stirred and heated at 100° C. for 16 hours under a nitrogen atmosphere. The cooled reaction mixture was poured into 200 ml of cold dilute hydrochloric acid and extracted with three 75 ml portions of chloroform. The combined extract was washed with water, dried over anhydrous sodium sulfate, charcoaled and concentrated at reduced pressure. Recrystallization of the crude produced from ethanol-water yielded 3.1 g (70%) of 1,12-bis(3,4-dicyanophenoxy) dodecane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:15]2[C@H:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C@@H:14]2O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:32])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]2[C@@H:15]([C@@H:14]([Cl:32])[CH2:13][CH2:12][C:11]2([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reactant: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2Cl

Procedure:
A solution of 1 g of (3aR, 4S, 7aR)-2-tert-butyloxycarbonyl-7,7-diphenyl-4-perhydroisoindolol in 10 cm3 of thionyl chloride is stirred for 3 hours at 80° C. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa). 1.03 g of (3aR, 7S, 7aR)-2-tert-butyloxycarbonyl-7-chloro-4,4-diphenylperhydroisoindole are obtained in the form of a solid which is used in the crude state in the following test.
Reaction SMILES: [C:1]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([C@H:28]1[CH2:33]N[CH2:31][CH2:30][NH:29]1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([N:19]3[CH2:31][CH2:30][NH:29][C@@H:28]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:33]3)[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Reactant: CC(C)(C)c1cc2c(s1)Nc1ccccc1N=C2N
Product: CC(C)(C)c1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Yield: 36.7 %

Procedure:
By using a method similar to the method of Example 460, using 2-tert-butyl4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (0.934 g, 3.44 mmol) and (S)-2-phenethyl-piperazine (0.655 g, 3.44 mmol) gives 0.561 g of the title compound as a yellow solid: mp 93–96° C.; mass spectrum (ion spray): m/z=445 (M+1); Analysis for C27H32N4S(0.5 H2O): calcd: C, 71.49; H, 7.33; N, 12.35; found: C, 71.27; H, 6.88; N, 12.29.
Reaction SMILES: CP(C1C=CC(N)=C(S(C(C)C)(=O)=O)C=1)(C)=O.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([P:41]([CH3:44])([CH3:43])=[O:42])=[CH:37][C:36]=2[S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])[C:31]([Cl:51])=[CH:30][N:29]=1.[N:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N:58]1[CH2:63][CH2:62][N:61]([C:64]2[S:68][C:67]([NH2:69])=[N:66][N:65]=2)[CH2:60][CH2:59]1>>[Cl:51][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([P:41]([CH3:44])([CH3:43])=[O:42])=[CH:37][C:36]=2[S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])=[N:33][C:28]([NH:69][C:67]2[S:68][C:64]([N:61]3[CH2:60][CH2:59][N:58]([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][N:52]=4)[CH2:63][CH2:62]3)=[N:65][N:66]=2)=[N:29][CH:30]=1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1nnc(N2CCN(c3ccccn3)CC2)s1
Agent: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)s2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine. 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine is then reacted with 5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-thiadiazol-2-amine according to the procedure described in Example 32.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CC(C)([O-:25])C.[K+].[N+]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)([O-])=O>CN(C)C=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:25][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1Oc1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C

Procedure:
Methyl 4-(4-phenoxyphenoxy)benzoate is synthesized as follows. A mixture of 15.00 g (80.6 mmoles) of -phenoxyphenol, 130 ml of N,N-dimethylformamide and 75 ml of toluene is agitated under nitrogen atmosphere. Potassium t-butoxide (9.32 g, 80.6 mmoles) is added with vigorous stirring and the mixture is heated to reflux. An azeotrope of t-butanol and toluene (85 ml) is collected at temperatures of 120° C. to 135° C. and is discarded. The mixture is cooled to ambient temperature, and a solution of 14.59 g (80.6 mmoles) of methyl 4-nitrobenzoate in 30 ml of N,N-dimethylformamide is added over a period of 15 minutes with cooling in a water bath. The mixture is heated at 100° C. for 14 hours, cooled to 20° C., and quenched with 1500 ml of ice water. The precipitate is filtered, dried in air and dissolved in 500 ml of acetone. The solution is filtered to remove insolubles, and the filtrate is concentrated by evaporation and cooled to precipitate methyl 4-(4-phenoxyphenoxy)benzoate. The recovered product weighs 1 23 g (82 percent yield) and has a melting point of 14° C. as determined by DSC.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)c1ccc(C=O)cc1
Solvent: CO
Product: CC(C)c1ccc(C=NNc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 92.1 %

Procedure:
In 20 ml of methanol was dissolved 3.06 g of 4-nitrophenylhydrazine. With 2.96 g of 4-isopropylbenzaldehyde added, the solution was refluxed at 100° C. for one hour. With the progress of reaction, crystals gradually precipitated. The crystals were collected by suction filtration, washed with methanol, and dried at 80° C. for 2 hours, obtaining 5.21 g (yield 92%) of pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]#[N:23])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-:28].[Na+].O.Cl>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]([NH2:23])=[O:28])(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: N#Cc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Temperature: 78 °C
Yield: 52 %

Procedure:
2-({4-[(E)-2-(2,4-Difluorophenyl)vinyl]phenyl}sulfonyl)benzonitrile (Example 47, 100 mg, 0.26 mmol) was dissolved in ethanol (0.26 mL) and 4N sodium hydroxide (0.11 mL, 0.26 mmol) was added. The reaction was heated to 78° C. for 12 hours. After cooling, water and ethyl acetate were added. The aqueous layer was acidified with HCl and extracted with ethyl acetate (×2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate, to yield the title compound as a white solid (54 mg, 52%). δH (400 MHz, d6 DMSO): 8.09 (1H, dd, J=0.9, 7.8 Hz), 7.99 (2H, d, J=8.5 Hz), 7.95 (1H, s), 7.86 (1H, q, J=8.2 Hz), 7.80 (2H, d, J=8.5 Hz), 7.74-7.62 (2H, m), 7.58 (1H, s), 7.47-7.27 (4H, m), 7.15 (1H, td, J=1.7, 8.5 Hz); m/z (ES+) 400 [MH+], 383 [(MH+)−17].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[NH2:17][C@@H:18]([CH3:21])[CH2:19][OH:20]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@H](N)CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H](CO)Nc1cc(Cl)nc(Cl)n1
Reaction time: 12 h

Procedure:
To a solution of 2,4,6-trichloropyrimidine (4.70 g, 25.6 mmol) and triethylamine (7.78 g, 77.0 mmol) in acetonitrile (150 mL) was added a solution of (S)-2-aminopropan-1-ol (2.31 g, 30.7 mmol) in acetonitrile (150 mL) at 0° C. The reaction mixture was allowed to room temperature and stirred for 12 h, then filtered and concentrated. Purification via column chromatography (elutriant: petroleum ether/ethyl acetate=4/1) afforded the title product.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O:9]C)=[O:8])[CH2:4][O:3]1.[OH-].[K+:13]>CO.CCOCC>[K+:13].[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O-:9])=[O:8])[CH2:4][O:3]1
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC1(C)OC[C@H](C(=O)[O-])O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a solution of methyl(R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (0.16 mL, 1.0 mmol) in MeOH (2 mL), 2 N KOH (0.5 mL, 1 mmol) was added. The resulting solution was stirred at RT for 20 min and concentrated in vacuo. The residue obtained was suspended in ether (10 mL) and sonicated for 5 min. The ether was then removed and the resulting residue was dried in vacuo for 4 h to obtain (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid potassium salt (173 mg, 94%) which was directly used in the next step without purification.