Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[NH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:33]3[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: OCC1CCNCC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(CO)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 4-piperidinemethanol. A yellow solid 101 was obtained (0.0299 g, 64%). 1H-NMR (CDCl3, 400 MHz) δ 1.41–1.50 (m, 2H), 1.86–1.94 (m, 1H), 1.97–2.03 (m, 2H), 3.27 (t, J=13.6 Hz, 2H), 3.57 (d, J=5.8 Hz, 2H), 3.83 (s, 3H), 4.38 (d, J=13.5 Hz, 2H), 6.93 (d, J=6.6 Hz, 1H), 6.97 (s, 1H), 7.01–7.07 (m, 3H), 7.46–7.52 (m, 3H), 7.84 (s, 1H), 8.24 (d, J=6.2 Hz, 1H); MS (APCI) m/z 475 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](OCC)(=O)[C:11](OCC)=O.CC(C)([O-])C.[K+]>CN(C=O)C.O>[CH2:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:11]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of indole product in Example 38 (150 mg, 0.572 mmol) and diethyl oxalate (92 mg, 0.63 mmol) in DMF (5 mL), potassium tert-butoxide (71 mg, 0.63 mmol) was added in one portion at room temperature under nitrogen. The reaction mixture was warmed to reflux under nitrogen for 1 h and then was cooled down to room temperature. The mixture was diluted with water (50 mL) and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/hexanes, 1:1) to afford the N-ethyl-indole, Example 38, (144 mg, 86%): 1H NMR (500 MHz, CDCl3) δ7.18-7.28 (m, 5H), 7.09 (d, J=3.2 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.42 (dd, J=3.2, <1 Hz, 1H), 4.36 (t, J=8.0, 5.4 Hz, 1H), 4.12 (q, J=7.3 Hz, 2H), 4.00 (d, J=15.1 Hz, 1H), 3.85 (d, J=15.1 Hz, 1H), 3.07 (dd, J=11.3, 5.4 Hz, 1H), 2.66 (dd, J=11.3, 8.0 Hz, 1H), 2.50 (s, 3H), 1.44 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][NH:6][C:7](=[O:14])[C:8]([C:12]#[N:13])=[C:9]([CH3:11])[CH3:10].[CH3:19]OC(OC)N(C)C.O1CCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][N:6]1[CH:19]=[CH:10][C:9]([CH3:11])=[C:8]([C:12]#[N:13])[C:7]1=[O:14]
Reactant: CC(C)=C(C#N)C(=O)NCc1ccc(Cl)c(Cl)c1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccn(Cc2ccc(Cl)c(Cl)c2)c(=O)c1C#N
Reaction time: 1 h

Procedure:
A solution of 42.8 g. (0.15 mole) of N-(3,4-dichlorobenzyl)-2-cyano-3-methylcrotonamide and 18.0 g (0.15 mole) of N,N-dimethylformamide dimethyl acetal in 250 ml. of tetrahydrofuran is stirred at ambient temperature for 22 hr. followed by 1 hr. at reflux. The solvent is removed and the tacky solid residue is heated until molten. When evolution of dimethylamine subsides the reaction mixture is allowed to cool and the dark glassy residue is recrystallized from ethanol. The solid product is slurried in ether and isolated by filtration to give 15.79 g. (36%) of product as a brown powder: m.p. 177.5°-180.5° C; ν (ethanol) 2210 (CN) and 1670 cm.-1 (C=O); δ8.19(d, 1H, H6), 7.2-7.8 (m, 3H, aromatic protons), 6.46 (d, 1H, H5), 5.16 (s, 2H, benzyl methylene), and 2.4 (s, 3H, methyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6].Cl[C:12](OC1C=CC([N+]([O-])=O)=CC=1)=[O:13].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:39][CH:40]=[N:41]2)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([N:44]3[CH2:49][CH2:48][N:47]([C:12]([NH:6][C:5]4[CH:7]=[CH:8][C:9]([F:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[O:13])[CH2:46][CH2:45]3)=[CH:39][CH:40]=[N:41]2)=[CH:36][CH:35]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(N)ccc1F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)ccc1F

Procedure:
As described for example 78, 3-methoxy-4-fluoro-aniline, p-nitrophenyl chloroformate, diisopropylethyl amine, and 7-chloro-4-piperazinylquinoline are reacted to afford the product. LC-MS: 415 (M++1). 1H NMR (CDCl3) δ 8.78 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.50 (d, 1H), 7.35 (d, 1H), 7.00 (m, 1H), 6.85 (d, 1H), 6.70 (m, 1H), 6.65 (s, 1H), 3.85 (s, 3H), 3.75 (m, 4H), 3.25 (m, 4H).
Reaction SMILES: [Br:1][CH2:2][C:3]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[C:4](=O)[CH2:5]Br.[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[NH:16])[NH2:15]>O1CCCC1>[CH4:2].[NH:17]([C:18]1[S:19][CH:5]=[C:4]([C:3]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[CH2:2][Br:1])[N:20]=1)[C:14]([NH2:16])=[NH:15]
Reactant: CCOC(CBr)(OCC)C(=O)CBr
Reactant: N=C(N)NC(N)=S
Solvent: C1CCOC1
Product: C
Product: CCOC(CBr)(OCC)c1csc(NC(=N)N)n1
Yield: 71.9 %

Procedure:
A mixture of 25.5 g (80 mmol) of 1,4-dibromo-2,2-diethoxy-3-butanone, 11.8 g (100 mmol) of N-amidinothiourea, and 150 ml of tetrahydrofuran was heated at reflux for 3 hours. The mixture was filtered to remove some insoluble solid, and the filtrate was concentrated. The residue was triturated with 200 ml of saturated sodium bicarbonate, then extracted four times with a total of 500 ml of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and evaporated leaving a solid. Recrystallization from 250 ml of acetonitrile, after decolorization with charcoal, afforded 9.7 g (36%) of 2-guanidino-4-(2-bromo-1,1-diethoxyethyl)thiazole as a white solid, mp 157°-158°; calcd. for C10H17N4O2SBr: C, 35.62; H, 5.08; N, 16.61; Br, 23.69; S, 9.51; found: C, 35.60; H, 4.97; N, 16.99; Br, 23.75; S, 9.59.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:38]([O:42][C:43](Cl)=[O:44])[CH:39]([CH3:41])[CH3:40].CCOCC>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:43](=[O:44])[O:42][CH2:38][CH:39]([CH3:41])[CH3:40])[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(C)COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)COC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
Dissolve the compound of Example 3 (120 mg, 0.23 mmol) in dichloromethane (3 mL) and add isobutylchloroformate (38 μL, 0.30 mmol) dropwise. After stirring for 10 minutes, pour the reaction into vigorously stirred ether (10 mL) and filter. Dissolve the solids in dichloromethane (10 mL) and wash with saturated aqueous sodium bicarbonate. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (4%) to give 104 mg of the title compound (73%): mass spectrum (ion spray): m/z=618.4 (M+H).
Reaction SMILES: ClC1C=C2C(CC(=O)N2)=CC=1.ClC1C=C(C=CC=1[F:21])C=O.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26](/[C:27](=[CH:33]/[C:34]3[CH:39]=[CH:38][C:37](F)=[C:36]([Cl:41])[CH:35]=3)/[C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1>C(O)(C)C>[Cl:22][C:23]1[CH:31]=[C:30]2[C:26](/[C:27](=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:41])[C:35]=3[F:21])/[C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(F)c(Cl)c1
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: O=C1Cc2ccc(Cl)cc2N1
Solvent: CC(C)O
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in example 1, 6-chlorooxindole (5.20 g, 31.2 mmol) (Crescent) and 3-chloro-4-fluoro-benzaldehyde (5.0 g, 31.2 mmol) (Aldrich) in isopropanol to give a mixture of E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 8.89 g, 92.5%) and used for the next step without further purification.
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH2:4][CH2:5][C@H:6]2[C@H:13]([OH:14])[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]1[CH2:22][O:21][C:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH2:4][CH2:5][C@H:6]2[C@H:13]([O:14][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1
Reactant: CCCCCC1(CC[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2O)OCCO1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCCCC1(CC[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC2CCCCO2)OCCO1

Procedure:
A solution cf (1S,5R,6R,7R)-6-(3,3-ethylenedioxyoctyl)-7-hydroxy-2-oxabicyclo[3.3.0]octan-3-one (6a) (4 70 g) in dichloromethane (200 ml) was cooled on ice and dihydropyran (2.41 g) and p-toluenesulfonic acid (0.23 g) were added thereto and the resultant mixture was stirred for 1,5 hours. The crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (59).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#N)=[CH:8][CH:7]=1.[CH2:14]([Mg]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C[O:26]CC1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10](=[O:26])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1ccc(C2OCCO2)cc1
Product: O=C(Cc1ccccc1)c1ccc(C2OCCO2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(1,3-dioxolan-2-yl)benzonitrile (5.0 g, 28.54 mmol) in anhydrous THF (100 mL) was added benzyl magnesium chloride (36 mL, 20% wt solution in THF, 43 mmol) slowly at 0° C. After one hour the mixture was warmed to room temperature. After four hours the mixture was cooled to 0° C. and quenched with saturated NH4Cl. The mixture was warmed to room temperature and extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (10% ethyl acetate/hexanes) gave 1-[4-(1,3-dioxolan-2-yl)phenyl]-2-phenylethanone as a pale yellow solid: 1H-NMR (500 MHz, CDCl3): δ8.02 (2H, d, J=8.30 Hz,), 7.57 (2H, d, J=8.30 Hz,), 7.38-7.24 (% H, m), 5.86 (1H, s), 4.29 (2H, s), 4.28-4.09 (4H, m).
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1[CH:19]=[C:18]2[C:9]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15]([CH:21]=O)[C:16](=[O:20])[C:17]=32)=[CH:8][CH:7]=1.Cl.[NH2:24]O.C([O-])=O.[Na+]>C(O)=O>[OH:5][C:6]1[CH:19]=[C:18]2[C:9]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15]([C:21]#[N:24])[C:16](=[O:20])[C:17]=32)=[CH:8][CH:7]=1
Reactant: NO
Reactant: O=Cc1coc2ccc3ccc(O)cc3c2c1=O
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=CO
Product: N#Cc1coc2ccc3ccc(O)cc3c2c1=O

Procedure:
A mixture of 9-hydroxy-1-oxo-1H-naphtho[2,1-b]pyran-2-carboxaldehyde acetate (1 mm), hydroxylamine hydrochloride (1.3 mm) and sodium formate (2 mm) is refluxed for 30 hrs. in formic acid (3 parts). The product crystallize on cooling, is filtered and washed with acetone. The dry crystals are light beige, m.p. 289°-92° C.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1>>[Cl:6][C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:1]([OH:3])(=[O:5])=[O:2])[C:11]=2[CH:10]=[CH:9][N:8]=1
Reactant: Clc1nccc2ccccc12
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1cccc2c(Cl)nccc12
Temperature: 80 °C

Procedure:
To an ice-cold solution of fuming sulphuric acid (20% SO3, 2 mL) was added 1-chloroisoquinoline (1.0 g, 6.1 mmol) portionwise with stirring. After stirring at room temperature for 3 hours, the reaction was heated at 80° C. for 18 h, then cooled in an ice bath, poured onto ice (70 g), washed with ether, and concentrated in vacuo. The residues were treated with isopropanol giving a white solid which was filtered and dried to give 1-chloro-5-isoquinolinesulphonic acid (1.16 g, 4.77 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)Cl.CO.O1CCOCC1>[CH3:27][O:26][C:24]1[CH:23]=[CH:22][N:21]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)[N:19]=[C:20]2[N:25]=1
Reactant: COc1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
To a mixture of crude {1-[4-(7-methoxy-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (550 mg) in DCM (3 mL) and methanol (1.9 mL) was added a solution of 4 M hydrogen chloride in dioxane (5.8 mL) and the mixture was stirred for 2 hours at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted three times with a mixture of DCM/methanol. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography [silica; gradient elution: DCM to 8:2 DCM/ethanol] to give the title compound (220 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]4[CH2:20][CH2:19]4)[CH:13]=[CH:12][C:11]=3[CH3:22])=[O:8])[S:5][CH:6]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Br)cs1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(-c2ccc(Cl)cc2)cs1

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide a with commercially available 4-chlorophenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 203). HPLC Ret time=3.66 min. LCMS [M+H]+ 411.221.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[C:5]([C:8]1[C:16]2[S:15][C:14]([NH:17][C:18](=[O:22])[NH:19][CH2:20][CH3:21])=[N:13][C:12]=2[CH:11]=[C:10]([C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH:9]=1)(=O)[CH3:6]>CN(C=O)C>[CH2:20]([NH:19][C:18]([NH:17][C:14]1[S:15][C:16]2[C:8](/[C:5](/[CH3:6])=[N:4]/[O:3][CH3:2])=[CH:9][C:10]([C:23]3[CH:28]=[N:27][C:26]([N:29]4[CH2:30][CH2:31][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34]4)=[N:25][CH:24]=3)=[CH:11][C:12]=2[N:13]=1)=[O:22])[CH3:21]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C(C)=O)c2s1
Reactant: CON
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(/C(C)=N/OC)c2s1
Temperature: 60 °C

Procedure:
O-Methyl hydroxylamine hydrochloride (64 mg, 0.784 mmol) was added to ethyl 1-[5-[7-acetyl-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (200 mg, 0.39 mmol) in DMF (5 mL). The reaction mixture was heated to 60° C. for 4 h after which time LCMS indicated clean conversion to the desired product. The reaction was diluted with EtOAc, washed with water then brine and the organic layer dried (MgSO4), filtered and the solvent removed in vacuo. The crude product obtained was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Cl.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](Cl)=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:9])=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Oc1ccc(Cl)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Yield: 76.9 %

Procedure:
4-Chloro-2-fluoro-phenol (264 mg, 1.8 mmol) was added to a solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (506 mg, 1.5 mmol) in pyridine (8 ml) and the mixture heated at reflux for 45 minutes. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic layer was washed with 0.1M HCl, water and brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was triturated with petroleum ether and the crude product collected by filtration and purified by flash chromatography eluting with methylene chloride/ether (9/1) to give 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (474 mg, 77%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]12[CH:10]([OH:11])[O:9][CH2:8][CH:7]1[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:11][CH:10]1[O:9][CH2:8][CH:7]2[C:2]1([CH3:1])[CH:3]1[CH2:12][CH:6]2[CH2:5][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC12C3CCC(C3)C1COC2O
Solvent: c1ccncc1
Product: CC(=O)OC1OCC2C3CCC(C3)C12C
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 63 g of 2-methyl-4-oxatricyclo[5.2.1.02,6]-decan-3-ol, 42 g of pyridine, and 51 g of acetic anhydride was heated at 50° C. for 5 hours. The reaction mixture was concentrated. The concentrate was purified by distillation, obtaining 74 g (yield 96%) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cc2nc(-c3ccccc3)nn2cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cn2nc(-c3ccccc3)nc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 129.3 %

Procedure:
A mixture of methyl 6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (182 mg, 681 μmol) and lithium hydroxide monohydrate (114 mg, 2.72 mmol) in tetrahydrofurane (10 ml) and water (2 ml) is stirred for 4 hours at 25° C. The mixture is diluted with ethyl acetate, acidified to pH=0 with hydrochloric acid 37% and washed with water and brine. The organic layer is dried with magnesium sulfate and the solvent is evaporated to dryness affording 6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (223 mg, 129%) as a light yellow solid. mp.: 228-233° C. MS: m/z=254.2 (M+H+).
Reaction SMILES: C1(P(=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=O)=[C:36]([CH3:43])[CH:35]=1.[Cl:44][C:45]1[CH:46]=[C:47]([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:48]=[CH:49][CH:50]=1>>[Cl:44][C:45]1[CH:46]=[C:47]([N:51]2[CH2:56][CH2:55][N:54]([C:41]3[N:40]([C:37]4[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][C:36]=4[CH3:43])[CH:27]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:22]4[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)[CH2:53][CH2:52]2)[CH:48]=[CH:49][CH:50]=1
Reactant: COC(=O)/C=C/c1ccccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Cl)ccc1N=C=O
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COC(=O)CC1c2ccccc2N=C(N2CCN(c3cccc(Cl)c3)CC2)N1c1ccc(Cl)cc1C

Procedure:
Starting with 150 mg (0.34 mmol) of the iminophosphorane from Example 3A, 60 mg (0.36 mmol) of 4-chloro-2-methylphenyl isocyanate and 67 mg (0.34 mmol) of N-(3-chlorophenyl)piperazine, the general procedure [E] and chromatographic purification (method 2) give 97 mg (46% of theory) of product.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][C:14]([O:16]CC)=[O:15])=O)=[CH:3][CH:2]=1.[N:23]1([CH2:28]/[CH:29]=[C:30](/[C:39]2[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=2)/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45])\[C:31]2[CH:36]=[CH:35][C:34](OC)=[CH:33][CH:32]=2)[CH2:27]C[CH2:25][CH2:24]1.N1(CC=C(C2C=C(C=CC=2)C=CC(OCC)=O)C2C=CC(OC)=CC=2)CCC[CH2:51]1>>[CH3:27][N:23]([CH3:28])[CH2:24]/[CH:25]=[C:7](/[C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])\[C:4]1[CH:3]=[CH:2][C:1]([CH3:22])=[CH:6][CH:5]=1.[CH3:24][N:23]([CH3:27])[CH2:28]/[CH:29]=[C:30](\[C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45])/[C:31]1[CH:36]=[CH:35][C:34]([CH3:51])=[CH:33][CH:32]=1
Reactant: COc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C(=O)O)c2)cc1
Reactant: CCOC(=O)C=Cc1cccc(C(=CCN2CCCC2)c2ccc(OC)cc2)c1
Reactant: CCOC(=O)C=Cc1cccc(C(=O)c2ccc(C)cc2)c1
Product: Cc1ccc(/C(=C/CN(C)C)c2cccc(/C=C/C(=O)O)c2)cc1
Product: Cc1ccc(/C(=C\CN(C)C)c2cccc(/C=C/C(=O)O)c2)cc1

Procedure:
By use of the methods described in Example 3,3-bromo-4'-methyl benzophenone (Ipatieff and Friedman, J. Amer. Chem. Soc., 1939, 61, 684) was converted into ethyl 3-(4-toluoyl)cinnamate, m.p. 86°-87°, and thence into a mixture of the (E)- and (Z)-isomers of ethyl 3-(3-dimethylamino-1-(4-tolyl)prop-1-enyl)cinnamate. Hydrolysis of this ester mixture and separation of the mixture of carboxylic acids by crystallization yielded (E)-3-(3-dimethylamino-1-(4-tolyl)prop-1E-enyl)cinnamic acid, m.p. 200°-205° C., and (E)-3-(3-dimethylamino-1-(4-tolyl)prop-1Z-enyl)cinnamic acid, m.p. 200°-205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
A neat solution of aniline (4.3 mL, 47 mmol) and p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol) in a round bottom flask equipped with a reflux condenser was heated to 90° C. and hexafluoroacetone trihydrate (7 mL, 50 mmol) added over 15 minutes via syringe. Following addition, the temperature was increased to 130° C. and the resulting solution stirred over 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organics were washed with saturated NaHCO3 solution then brine. The solution was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by flash chromatography (4:1 hexanes/EtOAc) to give the title product as a white crystalline solid (5.5 g, 45%). MS (ES+) m/z 260 (MH+).