Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][CH2:43][C:44]([OH:46])=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:48][NH:49][O:50][CH3:51]>>[CH3:51][O:50][N:49]([CH3:48])[C:44](=[O:46])[CH2:43][CH2:42][C@H:11]1[CH2:10][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33]
Reactant: CNOC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: Cl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 1.65 g of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propionic acid and 271 mg of N,O-dimethylhydroxylamine hydrochloride are used to afford the title compound as a beige oil. Rf=0.18 (EtOAc-heptane 2:1); Rt=5.09.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15]>C(=S)=S>[CH2:1]([C:3]1[CH:8]=[C:7]([C:14](=[O:16])[CH3:15])[CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCc1cc(C(C)=O)ccc1O
Temperature: 25 °C
Yield: 52.9 %

Procedure:
To a stirred solution of 2-ethylphenol (1 g, 106.4 mmol) in carbon disulfide (30 ml) was added aluminum chloride (30 g, 225 mmol) portionwise at 0° C. Then, acetyl chloride (8.4 ml, 118.1 mmol) was added, and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and poured into ice. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized with hexane-toluene to give title compound (9.24 g, 53% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO>C(Cl)Cl>[Cl:21][CH:15]1[CH:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=[CH:18][C:17]([F:20])=[CH:16]1
Reactant: Fc1ccc(C2CN(Cc3ccccc3)CCO2)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: FC1=CC(Cl)C(C2CNCCO2)C=C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Dissolve 4-benzyl-2-(2-chloro-4-fluoro-phenyl)morpholine (529 mg, 1.73 mmol) in DCM (2.5 mL). Add 1-chloroethyl chloroformate (1.25 g, 8.65 mmol); heat to 80° C.; and stir overnight. Add MeOH (2.5 mL) and stir at 65° C. for 3 hours. Concentrate under reduced pressure and purify via SCX chromatography eluting with a gradient of 0-100% of (2N NH3/MeOH) in MeOH. Combine the product fractions and remove the solvents under reduced pressure to provide the title compound as a white solid (345 mg, 92%). MS (m/z): 216 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[CH:17]1([N:23]2[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:17]1([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCN(C2CCCCC2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C3CCCCC3)C2)cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (416 mg) in DMF (10 mL) was added (3R)-1-cyclohexyl-3-pyrrolidinamine dihydrochloride (849 mg) and K2CO3 (1.35 g). After stirring for 2 hours at 120° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (318 mg). 1H-NMR (300 MHz, CDCl3) δ 1.11-1.34 (6H, m), 1.32 (3H, t, J=7 Hz), 1.57-2.09 (6H, m), 2.30-2.44 (2H, m), 2.67-2.74 (1H, m), 2.78-2.84 (1H, m), 2.98-3.06 (1H, m), 4.25 (2H, q, J=7 Hz), 4.39-4.50 (1H, m), 5.32 (1H, d, J=8 Hz), 6.68 (1H, d, J=16 Hz), 7.57 (1H, d, J=16 Hz), 7.88 (1H, d, J=1 Hz), 8.06 (1H, d, J=1 Hz).
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:15][C:16]([C:18]1C=CC=C[C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40]([OH:42])=O)=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:44][C:32]1[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:15])=[O:17])=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:29][CH:28]=2)[C:39]2[C:34]([C:33]=1[CH3:43])=[CH:35][C:36]([C:40](=[O:42])[NH:9][CH2:8][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])=[CH:37][CH:38]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](CN)c1ccccc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC[C@H](C)c3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (R)-2-phenylpropan-1-amine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 517 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C1(C)C=CC=CC=1.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:21])=[O:8]
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cnc(O)c(Cl)c1

Procedure:
6.3 g (36 mmol) of 5-chloro-6-hydroxynicotinic acid are heated under reflux in 60 ml of thionyl chloride for 4 hours. After the volatile constituents have been stripped off, 50 ml of toluene are added and the mixture is evaporated again. Colorless crystals, yield 6.9 g (quantitative), melting point: >250° C.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([NH2:4])=[O:3].CN1CCOCC1.ClC(OCC)=O.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH2:34][CH2:35][NH2:36])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1.[Cl-].[NH4+]>COCCOC>[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH2:34][CH2:35][NH:36][C:1]([C:2]([NH2:4])=[O:3])=[O:6])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: NC(=O)C(=O)O
Reactant: COc1ccc(CCN)cc1OC1CCCC1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: COc1ccc(CCNC(=O)C(N)=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a suspension of oxamic acid (1.76 g, 20 mmol) in 1,2-dimethoxyethane (75 mL) under an argon atmosphere was added dropwise N-methylmorpholine (2.55 mL, 23 mmol) followed by ethyl chloroformate (2.20 mL, 23 mmol). After stirring for 1 h at room temperature, a solution of 2-(3-cyclopentyloxy-4-methoxy-phenyl)ethylamine (4.65 g, 20 mmol) in 1,2-dimethoxyethane (30 mL) was added over 5 min, and the resulting mixture was stirred for 2 h. Saturated aqueous ammonium chloride was added and the solvent was removed under reduced pressure. The solid residue was dissolved in methanol/methylene chloride, washed successively with water, 10% hydrochloric acid, aqueous sodium bicarbonate and water and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 1% i-propanol/methylene chloride to provide the oxamide (1.82 g, 30%): m.p. 175°-175.5° C.
Reaction SMILES: C[Si](C)(C)CC[O:5][NH:6][C:7]([C@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C:11](=[O:29])[NH:10]1)=[O:8].B(F)(F)F.CCOCC>C(Cl)Cl>[OH:5][NH:6][C:7]([C@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C:11](=[O:29])[NH:10]1)=[O:8]
Reactant: C[Si](C)(C)CCONC(=O)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NO)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.5 %

Procedure:
To a solution of (4R)-1-[4-(4-fluorophenoxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid (2-trimethylsilanylethoxy)amide (85 mg, 0. 19 mmol) in methylene chloride (5 mL) was added boron trifluoride etherate (0.073 mL, 0.58 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and then quenched by addition of aqueous saturated NH4Cl solution. The mixture was diluted with water and ethyl acetate and the organic phase was washed with brine, dried over MgSO4 and concentrated to a white solid. The title compound (31 mg, 47%) was isolated by recrystallization from a mixture of ethyl acetate and methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:9]([CH3:11])[OH:10])=[CH:4][CH:3]=1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH:9]([O:10][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(O)C(Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
0.70 g of (1RS, 2SR)-2-(4-bromophenyl)-3-(4-chlorophenyl)-1-methylpropanol was dissolved in 7 ml of dimethylformamide, and 0.34 g of tert-butyldimethylchlorosilane and 0.18 g of imidazole were added thereto. The mixture was stirred at room temperature overnight. The reaction solution was poured into a saturated sodium hydrogencarbonate aqueous solution and extracted by an addition of ethyl ether. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane) to obtain 0.70 g (yield: 75%) of [(2RS, 3SR)-3-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)-4-(4-chlorophenyl)butane as colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)[N:3]=1.[Br:40][C:41]1[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][C:42]=1[CH:48]([OH:53])[C:49]([F:52])([F:51])[F:50]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:53][C@H:48]([C:42]2[CH:43]=[C:44]([Br:47])[CH:45]=[CH:46][C:41]=2[Br:40])[C:49]([F:50])([F:51])[F:52])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: OC(c1cc(Br)ccc1Br)C(F)(F)F
Product: Nc1nc(O[C@H](c2cc(Br)ccc2Br)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with 1-(2,5-dibromophenyl)-2,2,2-trifluoroethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2].CI.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[N:13]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NCC(=O)N2
Solvent: CI
Product: CCOC(=O)CN1C(=O)CN=C(c2ccccc2)c2cc(OCC)c(OCC)cc21
Yield: 55 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIag), and MeI by ethyl bromoacetate, and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. M: 160–162° C. 1H-NMR (CDCl3, 200 MHz): d 1.21 (t, 3H, CH3), 1.36 (t, 3H, CH3), 1.50 (t, 3H, CH3), 3.88–4.26 (m, 7H, 3×OCH2+1H CH2) 4.49 (AB system, ? d=0.17, JAB=17.4, 2H, —NCH2), 4.80 (m, 1H CH2), 6.71 (s, 1H Ar), 6.81 (s, 1H Ar), 7.27–7.69 (m, 5H Ar).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[O:10][C:11]=1[CH3:12])(=O)=O.C([O:27][C:28](=[O:48])[C:29]([CH3:47])([O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[C:33]([O:38][CH3:39])[CH:32]=1)C>>[CH3:39][O:38][C:33]1[CH:32]=[C:31]([CH2:30][C:29]([CH3:47])([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:28]([OH:48])=[O:27])[CH:36]=[CH:35][C:34]=1[O:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[O:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)c(OC)c1)Oc1ccccc1
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2cccs2)oc1C

Procedure:
The title compound was prepared from 2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethyl tosylate and 3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester according to the parallel synthesis procedure (A). MS (EI) 494.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[Se:27][C:26]=1[C:36]([NH2:38])=[O:37].CN(C=O)C.[OH-].[Na+]>>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][C:8]=2[O:22][CH3:23])[N:5]=[CH:4][N:3]=[C:2]3[NH:24][C:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[Se:27][C:26]=2[C:36]([NH2:38])=[O:37])[CH2:17][CH2:18]1
Reactant: NC(=O)c1[se]c(-c2ccccc2)cc1N
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cc(-c4ccccc4)[se]c3C(N)=O)c2cc1OCCCN1CCOCC1

Procedure:
The reaction of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline with 3-amino-5-phenylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a yellow color solid, mp 236-240° C. IR (KBr) vmax 34369, 3158, 2935, 1635, 1579, 1387, 1321, 1238, 1216, 1145, 1113, 902, 846 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 12.50 (1H, s), 9.16 (1H, s), 8.65 (1H, s), 7.77 (2H, br s), 7.68-7.70 (2H, m), 7.44-7.52 (3H, m), 7.39 (1H, s), 7.26 (1H, s), 4.20 (2H, br s), 3.96 (3H, s), 3.58 (4H, br s), 2.50 (2H, br s), 2.40 (4H, br s), 2.00 (2H, pentet, J=6.5 Hz); LC-MS (positive ion mode): m/z 566, 568 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=[O:31]>>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:31])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: COc1cc(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)cc(OC)c1OC
Reactant: CS(C)=O
Product: COc1cc(C(=O)/C(=N\C2CCCC2)n2ncc(C#N)c2N)cc(OC)c1OC
Reaction time: 24 h
Yield: 33.4 %

Procedure:
A light brown solution of 3-(cyclopentylamino)-2-(3,4,5-trimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (330 mg, 0.865 mmol) in DMSO (100 mL) was stored for 60 days at RT. Within one day, it became a light brown solution and no precipitation was observed during these 60 days. Then, it was poured into water (1 L) and the resulting precipitate was extracted into EA (2×75 mL). The combined extracts were washed with water, brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave the crude solid which was purified using an ISCO (40 g) column chromatography eluting with 0-70% EA in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 115 mg (33.4%) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(3,4,5-trimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as alight yellow solid. 1H NMR (400 MHz, DMSO-d6): 1.50-1.80 (br m, 8H), 3.67 (p, 1H), 3.79 (s, 3H), 3.81 (s, 6H), 7.06 (s, 2H), 7.7 (s, 1H), 8.12 (br s, 2H). LC/MS calcd. for C20H23N5O4 (m/e) 397.433, obsd. 398.3 (M+H, ES+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([NH:11][C:12]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH:13]=2)[CH:4]=1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[NH2:8][C:7]1[C:6]2[C:5]([N:11]=[C:12]3[C:13]=1[C:14](=[O:18])[CH2:15][CH2:16][CH2:17]3)=[CH:4][C:3]([Cl:2])=[CH:10][CH:9]=2
Reactant: N#Cc1ccc(Cl)cc1NC1=CC(=O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1c2c(nc3cc(Cl)ccc13)CCCC2=O
Yield: 47.5 %

Procedure:
In 200 ml of tetrahydrofuran were combined 5.00 g of 4-chloro-2-(3-oxocyclohexen-1-yl)aminobenzonitrile hydrochloride, 4.88 g (2 eq) milled anhydrous K2CO3, and 0.36 g (0.1 eq) of CuBr (CH3)2S used as a catalyst. The mechanically stirred mixture was refluxed overnight. It was then evaporated to a residue and extracted with several portions of MeOH. The insoluble inorganics were dissolved in water to remove any product not extracted by the MeOH, but none were detected. The MeOH extract was evaporated and the residue was chromatographed on silica gel and then the purified product was recrystallized from EtOAc to yield 2.07 g (47%) of a solid, melting point 285°-287° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[S:15])[NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:15][CH:20]=[C:18]([CH2:17][Cl:16])[N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)C1
Reactant: O=C(CCl)CCl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)C1

Procedure:
To a solution of 3-thiocarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.06 g, 4.60 mmol) in acetone (25 mL) was added 1,3-dichloroacetone (0.76 g, 5.98 mmol), MgSO4 (0.83 g, 6.1 mmol) and MgCO3 (3.87 g, 4.6 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (20 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to afford the desired product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]1[CH2:14][C:13](=[O:15])[NH:12][C:6]1=[N:7]2.[Br:16]Br>[N+](C)([O-])=O>[Cl:1][C:2]1[C:11]([Br:16])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]1[CH2:14][C:13](=[O:15])[NH:12][C:6]1=[N:7]2
Reactant: BrBr
Reactant: O=C1CN2Cc3c(Cl)cccc3N=C2N1
Solvent: C[N+](=O)[O-]
Product: O=C1CN2Cc3c(ccc(Br)c3Cl)N=C2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a solution of 1.30 g (8 mmole) of anhydrous ferric chloride in 30 ml of nitromethane was added 1.30 g (5 mmole) of solid 6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one and 0.80 g (5 mmole) of bromine. The system was stoppered, warmed to 50° in an oil bath overnight, cooled to room temperature and the solvent removed in vacuo. The resulting solid was suspended in water (50 ml), the mixture made basic (pH 10) with sodium bicarbonate and stirred at room temperature for 20 min. The solid was filtered under suction, washed with water, then isopropyl alcohol and dried yielding 1.19 g (78% yield) of a beige colored powder. Purification was effected by formation of the hydrochloride salt from acetonitrile; mp >275°.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18]O>>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9]2(=[O:10])[O:11][CH2:18][CH2:17][CH2:16][CH2:15][O:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: OCCCCO
Product: O=[N+]([O-])c1ccc(CP2(=O)OCCCCO2)cc1

Procedure:
4-Nitrobenzylphosphonic acid and 1,4-butanediol were treated in the same manner as in Reference Example 20 to yield 2-(4-nitrobenzyl)-1,3,2-dioxaphosphepan-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless needles having a melting point of 136°-137° C.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].Cl[C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2>C1COCC1>[CH:1]([O:4][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: Cc1ccc2nccc(Cl)c2n1
Solvent: C1CCOC1
Product: Cc1ccc2nccc(OC(C)C)c2n1
Temperature: -20 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a 100 mL flask placed with KH (30%, 2.7 g, 20.15 mmol, pre-washed with nHex) was added a solution of anhydrous isopropanol (2.04 g, 33.59 mmol) in anhydrous THF (15 mL) at room temperature under argon. The reaction mixture was cooled to −20° C. 8-chloro-2-methyl-[1,5]naphthyridine (1.20 g, 6.72 mmol) in THF (20 mL) was added dropwise and the reaction mixture was stirred at −20° C. to r.t for 2 hrs. The reaction mixture was poured into 20 mL ice-water and extracted with AcOEt (100 mL×3). The combined organic layers was dried over Na2SO4 and concentrated to give the crude product which was purified by flash column (AcOEt/Hex=1/3˜3/2) to give 8-isopropoxy-2-methyl-[1,5]naphthyridine as white solid (0.34 g, 25%). HR-MS-EI (+) m/e calcd for C12H14N2O (M+) 202.1106. found 202.1107.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1.[Cl:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(COc2nc(N)nc(-c3ccc(Cl)o3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-(5-methyl-pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile and N-chlorosuccinimide in DMF. ES-MS m/e (%): 344 (M{37Cl}+H+, 35), 342 (M{35Cl}+H+, 100).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=O)[CH2:3]1.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]4)=[O:10])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CC1CCCC(C(=O)O)C1
Product: CC1CCCC(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)C1

Procedure:
Following the procedure of Example 14, making variations only as required to use 3-methylcyclohexanecarboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (27% yield). 1H NMR (300 MHz, CDCl3) δ 8.06, 7.99, 6.99, 3.89, 3.79, 3.65-3.72, 3.56, 2.55, 1.20-1.86, 0.99, 0.92, 0.75, 0.47, 0.10. MS (ES+) m/z 400 (M+1).