Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:31]1[C:35]([CH2:36][C:37](O)=[O:38])=[N:34][N:33]=[N:32]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:37](=[O:38])[CH2:36][C:35]1[NH:34][N:33]=[N:32][N:31]=1)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(O)Cc1nnn[nH]1
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cc1nnn[nH]1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 119.8 %

Procedure:
A solution of 0.416 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide and 0.282 g of 2-(1H-tetrazol-5-yl)acetic acid in 4 ml of dimethylformamide was treated at room temperature under nitrogen with 0.461 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride. The mixture was stirred for 0.5 hours at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to give 0.630 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1H-tetrazol-5-yl)acetyl]valerohydrazide in the form of an off-white foam.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][O:21][CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)=[O:24])(=[O:13])=[O:12])=[C:6]([CH3:38])[CH:5]=1>C(OCC)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][O:21][CH2:22][C:23]([N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)=[O:24])(=[O:12])=[O:13])=[C:6]([CH3:38])[CH:5]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (1.15 ml, 2.30 mmol, 2 M solution in diethyl ether) was added at room temperature to a solution of tert-butyl 4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazine-1-carboxylate (Example 101) (310 mg, 0.574 mmol) in diethyl ether (2-5 ml). The reaction mixture was stirred for 2 h at room temperature and then refluxed for 10 min. The resulting solid was filtered off and dried. Yield: 210 mg (77%), white solid
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10]C(=O)C(F)(F)F)[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)C(F)(F)F)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
(R)—N-(1-(4-bromophenyl)ethyl)-2,2,2-trifluoroacetamide (20 g, 68 mmol) was dissolved in methanol (200 mL) and cooled in an ice-water bath. Then aqueous NaOH (2 M, 100 mL) was added to the above mixture. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated and then partitioned between CH2Cl2 and water. The aqueous layer was extracted with addition CH2Cl2 and the combined organic phases were dried over Na2SO4, filtered and concentrated to give (R)-1-(4-bromophenyl)ethan amine (9.8 g, 73%). 1H NMR (DMSO): 1.19 (m, 3H), 3.92 (m, 1H), 7.28 (m, 2H), 7.42 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.CC(C1C=CC=C(C(F)(F)F)C=1)=O>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:11]=2)[N:3]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CO
Agent: O=[Mn]=O
Agent: CC(=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.00 g (11.2 mmol) of [2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (synthesized as described in example 1K]-M], but starting with 3-(trifluoromethyl) acetophenone instead of 4-(trifluoromethyl) acetophenone), was dissolved in 56 ml of CH2Cl2 and treated with 14.6 g (15 eq.) of MnO2. After vigorous stirring for 2 h at ambient temperature, the reaction mixture was filtered over Celite and carefully rinsed with CH2Cl2. Evaporation of the solvent left 2.659 g of the title compound as white crystals of mp. 61–63° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:20]([C:19]1[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=1)=[O:21]
Reactant: COc1cccc(OC)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(OC)c1
Temperature: 0 °C

Procedure:
1,3-Dimethoxybenzene (5.00 g, 36.2 mmol) and AlCl3 (5.79 g, 1.2 eq.) were dissolved in 360 ml of CH2Cl2 and cooled down to 0° C. 4-Fluoro-benzoyl chloride (4.34 mL, 1.0 eq.) was slowly added via dropping funnel and the mixture allowed to react for another h at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over sodium sulfate, and evaporation of the solvents, followed by short flash chromatography (SiO2, hexane/AcOEt 8/2), yielded 7.75 g of the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][O-:18].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:18][CH3:17])=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: COc1cc2nc(N)c(Cl)nc2cc1OC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nc(N)c(OC)nc2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To 2-amino-3-chloro-6,7-dimethoxyquinoxaline (3.27 g, 13.6 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (4.41 g, 20.4 mmol) in methanol was added at room temperature and stirred further at room temperature for 2 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 2.73 g of the titled compound (yield, 85%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 67.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[S:8][C:9]3[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[N:5]=[CH:4][N:3]=1.[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.BrC1C=C(C=CC=1)N>C(O)(C)C>[Br:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:7]3[S:8][C:9]4[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[N:5]=[CH:4][N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1cccc2c1sc1c(Cl)ncnc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc2c1sc1c(Nc3cccc(Br)c3)ncnc12
Temperature: 85 °C
Reaction time: 7.5 h
Yield: 58.3 %

Procedure:
A mixture of 4-chloro-6-nitrobenzothienopyrimidine (166 mg, 0.62 mmol), m-bromoaniline (0.08 mL, 0.73 mmol) and m-bromoaniline hydrochloride (144 mg, 0.69 mmol) in isopropanol (4.5 mL) was heated at 85° C. stirring under N2 for 7.5 hours. The dark brown solid was collected by Buchner filtration and washed with isopropanol and air dried to give 4-([3-bromophenyl]amino)-6-nitrobenzothieno[3,2-d]pyrimidine (145 mg, 67%), mp 247.0-248.1° C.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH:35]([C:37]([O:39]CC)=[O:38])[CH3:36])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:51])([F:50])[F:52])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH:35]([C:37]([OH:39])=[O:38])[CH3:36])[CH2:31][CH2:30]4)[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1
Reactant: CCOC(=O)C(C)N1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)N1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of 2.4 mg (0.10 mmol) LiOH in 0.8 mL water was added to 50 mg (0.06 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(1-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL THF and the reaction mixture was shaken for 2 h at RT and for 4 h at 50° C. It was then purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:31])[CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=3)[CH2:18]2)=[O:11])=[C:4]([N+:32]([O-])=O)[CH:3]=1.O.NN>CO.[Ni]>[NH2:32][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:31])[CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[CH2:18]1)=[O:11]
Reactant: COc1cc2c(cc1OC)CC(N(C)CCCNC(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])CC2
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)CC(N(C)CCCNC(=O)Cc1cc(Cl)c(Cl)cc1N)CC2

Procedure:
Here, 1-[2-(4,5-dichloro-2-nitro-phenyl)-1-oxo-ethylamino]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (15.8 g, 0.031 mol) is dissolved in methanol (300 ml) and mixed with 98% hydrazine hydrate (4.65 ml). Raney nickel (2 g) is added in batches with stirring. Then the mixture is stirred for 2 hours at ambient temperature, the catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo. The viscous residue is purified by column chromatography over alumina N (400 g) [activity II, eluant: methylene chloride and increasing amounts of ethanol (up to 1%]. Yield: 13.9 g. IR spectrum (methylene chloride): 1660 cm-1 (C=O), 1515 cm-1 (Amide-II).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21](F)=C[CH:19]=2)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=1)=[O:11].[N:26]1C=CC=C(B(O)O)C=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:19]=[N:26][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=1)=[O:11]
Reactant: Cc1ccc(-c2ccc(F)cc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: OB(O)c1cccnc1
Product: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-(4-fluorophenyl)-6-methylpyridin-2-yl)methanone in Example A73 using pyridin-3-ylboronic acid. ESI-MS (m/z): 325 [M+1]+.
Reaction SMILES: Br[C:2]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4][CH2:3]1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[NH:30]([CH2:3][C:2]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:13])[Cl:14])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: CC1(Br)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Yield: 48 %

Procedure:
2,2,2-Trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)-cepham-4-carboxylate (1.10 g) was dissolved in methylene chloride (15 ml) and to this solution was added aniline (0.28 g). And to the solution was added silver fluoroborate (0.45 g) under stirring under ice-cooling and the mixture was stirred for 4 hours at the same temperature. After the reaction was completed, the reaction mixture was filtered. The filtrate was washed with a dilute aqueour solution of phosphoric acid and then with water, dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml and the second to eighth fractions were collected and then the solvent was distilled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g), mp 148° to 149°C. Infrared Absorption Spectrum (CHCl3) 3400, 1780, 1765, 1680 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.CO.Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[CH2:30][CH2:31][NH:32][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCN(C(=O)OC(C)(C)C)C2C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCNC2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 124.8 %

Procedure:
To a solution of tert-butyl 6-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.16 g) in the mixture solvent of CH2Cl2 and MeOH was added a solution of HCl in EtOAc (30 mL). The reaction mixture was stirred at room temperature for 4 h, and filtered to give the title compound as a solid (1.20 g, 100%), HPLC: 99.69%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.45 (m, 2H), 1.78 (m, 3H), 1.80 (m, 2H), 2.10 (m, 1H), 2.42 (m, 5H), 2.82 (m, 3H), 4.03 (s, 3H), 4.10 (m, 2H), 6.76 (s, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.24 (s, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.41 (s, 1H), 8.54 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]2[O:13][CH2:12][O:11][C:10]=12)[CH:6]=[O:7].[C:14]([Mg]Cl)#[CH:15]>C1COCC1>[OH:7][CH:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[C:14]#[CH:15]
Reactant: COc1cc(C=O)cc2c1OCO2
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1cc(OC)c2c(c1)OCO2

Procedure:
3-Hydroxy-3-(4-methoxy-1,3-benzodioxol-6-yl)-1-propyne was prepared according to Method A above from 3-methoxy-4,5-methylenedioxybenzaldehyde (0.721 g, 4 mmol) (Lancaster) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 629 mg, 76%).
Reaction SMILES: [I:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.OC[C@H]1CCN(C(OC(C)(C)C)=O)C1>>[I:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CI)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CI)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 100 starting with tert-butyl (S)-3-hydroxymethylpyrrolidine-1-carboxylate.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][NH:16][C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:21]=1)(=[O:3])[CH3:2].Cl[C:27]1[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([C:37](=[O:39])[CH3:38])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C.O>CC(O)C.C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[C:7]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:27]4[N:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[C:30]([C:37](=[O:39])[CH3:38])=[CH:29][N:28]=4)[C@H:17]([CH:18]([CH3:19])[CH3:20])[C:12]3=[N:11][C:10]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CC(=O)OCc1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of (R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methyl acetate (160 mg, 0.456 mmol) in iPrOH (4 mL) and DCM (2 mL) was added 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (306 mg, 1.37 mmol) and DIEA (353 mg, 2.74 mmol). The mixture was stirred at 60° C. overnight. Water (5 mL) was added to the mixture and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (2×10 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to afford (R)-(2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methyl acetate (150 mg, 44.4% yield) as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3]NC(NC1C2C(=C(F)C=CC=2)CC1)=O.[CH:18]1([C:27]([NH2:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>>[CH:18]1([CH:27]2[NH:29][CH2:3][CH2:2][O:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: NC(=O)C1CCc2ccccc21
Reactant: O=C(NCCCl)NC1CCc2c(F)cccc21
Product: c1ccc2c(c1)CCC2C1NCCO1

Procedure:
As depicted in Scheme 2, the reaction of an appropriately substituted indanyl amine, for example 4-fluoroindanylamine (known compound, U.S. Pat. No. 5,486,541) with 2-chloroethyl isocyanate (SM4) under basic conditions, in an appropriate solvent yielded the corresponding indanyl carboxamide intermediate (a), for example, [(2-chloroethyl)amino]-N-(4-fluoroindanyl)carboxamide. Intermediate (a) was heated under basic conditions in an appropriate solvent to yield the appropriate indanyl 1,3-oxazolidine, a compound of formula I and an intermediate (b), for example, 2-[aza(4-fluoroindanyl)methylene]-1,3-oxazolidine, described in detail in Example 2, Step B, as set forth below. Compound (b) was reacted with an isothiocyanate, for example, methyl isothiocyanate, under basic conditions yielding the corresponding amino methane-1-thione, for example, 2-[aza(4-fluoroindanyl)methylene](1,3-oxazolidin-3-yl)(methylamino)methane-1-thione, a compound of formula I, described in detail in Example 2, Step C, as set forth below.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35](Br)[CH:36]=[CH2:37]>>[CH2:37]([O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 9.53 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenyloxy)-propoxy]phenyl}piperidine-1 carboxylate and 3.42 ml of allylbromide are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.31 (1:2 EtOAc-heptane); Rt=6.03.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH:18]=[CH2:19])=[O:4]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC)CCC1
Temperature: 50 °C
Yield: 59 %

Procedure:
Palladium (II) acetate (0.095 g) was added to a solution of the product from step 27a (1.62 g, 5.9 mmol), tributyl(vinyl)tin (1.72 mL, 5.9 mmol), and triphenylphosphine (0.215 g, 0.82 mmol) in THF (20 mL) under a nitrogen atmosphere. The reaction was heated to 50° C. for 3 h, cooled to room temperature and concentrated. The residue was purified by FCC on silica gel eluting ethyl ether:hexanes (2:98) to give 2-vinyl-cyclopent-1-enecarboxylic acid methyl ester (0.53 g, 59%) as an oil.