Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.N1CCCC1.N1CCCC1.[Li].[CH3:17][CH:18]([CH2:45][CH3:46])[C:19]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:43])[C:30]=2[CH2:32][CH2:33][CH:34]2[CH2:39][CH:38]([OH:40])[CH2:37][CH:36]([O:41][CH3:42])[O:35]2)[CH:25]=[C:24]([CH3:44])[CH:23]=1)=[O:20].IC>O1CCCC1.O>[CH3:17][C:18]([CH3:1])([CH2:45][CH3:46])[C:19]([O:21][CH:22]1[CH:31]2[C:26]([CH:27]=[CH:28][CH:29]([CH3:43])[CH:30]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH:38]([OH:40])[CH2:37][CH:36]([O:41][CH3:42])[O:35]2)=[CH:25][CH:24]([CH3:44])[CH2:23]1)=[O:20]
Reactant: [Li]CCCC
Reactant: CCC(C)C(=O)Oc1cc(C)cc2ccc(C)c(CCC3CC(O)CC(OC)O3)c12
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCNC1
Product: CCC(C)(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CC(OC)O3)C21
Yield: 96.3 %

Procedure:
n-Butyl lithium (2.5M solution in hexane, 53.1 ml, 132.7 mmol) was added slowly to a stirred and cooled (−30° C.) solution of pyrrolidine (11.0 ml, 132.7 mmol) in dry tetrahydrofuran (100 ml). The solution was stirred at −25° C. for 1 hour. The above freshly prepared solution of lithium pyrrolidine was transferred slowly by cannula to a stirred and cooled (−35° C.) solution of the acetals III (18.7 g, 44.2 mmol) in dry tetrahydrofuran (200 ml). The mixture was stirred for 1 hour at −35° C. Iodomethane (6.9 ml, 110.6 mmol) was added slowly and the mixture was stirred for another 1 hour. Water (20 ml) was added to quench the reaction. After the cold bath was removed, saturated aqueous ammonium chloride solution (300 ml) was added and the mixture was stirred for 30 min. The mixture was extracted with toluene (3×250 ml). The combined organic extracts were washed with water (2×250 ml) and dried (Na2SO4). Evaporation of solvent gave crude acetal dimethylbutanoates IV (18.5 g, yield 96%) as a light brown syrup (HPLC purity >93%). This was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[S-:14][C:15]#[N:16].[Na+]>C1(C)C=CC=CC=1.OS(O)(=O)=O>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[S:14])[NH2:16]
Reactant: N#C[S-]
Reactant: COC(=O)[C@@H](C)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)c1ccc(NC(N)=S)cc1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
In a 500 ml round-bottomed flask equipped with condenser and magnetic stirrer, at room temperature methyl (2S)-2-(4-aminophenyl)propanoate (17.5 g, 98 mmol) was dissolved in toluene (300 ml) and conc. H2SO4 (2.6 mmol, 50 mmol) was slowly added to the solution Sodium thiocyanate (10.29 g, 128 mmol) was added and the reaction mixture refluxed 24 h. After cooling at room temperature, the solution was washed with a saturated solution of NH4Cl (2×100 ml), dried over anhydrous Na2SO4 and evaporated under vacuum to give a crude which, after purification by flash chromatography (n-hexane/EtOAc 1/1), afforded pure (S)-methyl 2-[4-(carbamothioylamino)phenyl]propanoate (10.7 g, 48.4 mmol) as white solid (49%). 1H-NMR (CDCl3): δ 8.25 (bs, 1H, CSNH), 7.40 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.20 (bs, 2H, CSNH2), 3.75 (m, 1H), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>>[C:1]([NH:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1nc2ccccc2[nH]1
Product: O=C(NC(=S)NCCSCc1nc2ccccc2[nH]1)c1ccccc1

Procedure:
Benzoyl isothiocyanate is reacted with 2-[(2-aminoethyl)thiomethyl]benzimidazole by the procedure of Example 18 to give N-benzoyl-N'-[2-(2-benzimidazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(2-benzimidazolylmethylthio)ethyl]thiourea.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[Cl:28]COC(COCC1C=CC=CC=1)COCCCCCCC.C(OCC(O)COCC1C=CC=CC=1)CCCCCC.C=O.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:28][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCCCCCCOCC(COCc1ccccc1)OCCl
Agent: C=O
Agent: CCCCCCCOCC(O)COCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1ncc2[nH]cnc2n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-6-chloropurine (Aldrich Chemical Co.) 11.2 g, 0.066 mol) hexamethyldisilazane (160 ml), and ammonium sulfate (1.09 g) is refluxed for 2.5 hours and then cooled, concentrated and pumped to dryness. The residue is dissolved in dry toluene (210 ml) and is treated with Hg(CN)2. The mixture is heated to 80° C. and a solution of 2-(chloromethoxy)-1-(heptyloxy)-3-(phenylmethoxy)propane (prepared from 1-(heptyloxy)-3-(phenylmethoxy)-2-propanol (19 g, 0.068 mol), paraformaldehyde (4 g) and dry HCl (g) in CH2Cl2 (160 ml) as described in the first part of Example 7, in toluene (210 ml) is added to the solution and heated to 80°-85° C. for 2.5 hours. The mixture is cooled, concentrated, and diluted with CH2Cl2 (1.0 L) and is allowed to stand overnight. The CH2Cl2 solution is filtered, washed with 30% KI, 10% potassium carbonate solution and water. The organic layer is dried and concentrated. The residue is chromatographed over silica gel column using a high pressure liquid chromatographic instrument (Waters Prep 500). The column is eluted with ethyl acetate and hexane (1:1) to give the condensation product (i.e., chloropurine drivative) (6.45 g) which is hydrolysed as follows.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32]C(C(O)=O)=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 4 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol) was added dropwise to a solution of 3-(tert-butyloxycarbonyl)-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid (1.0 g, 3.7 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J. Org. Chem., 1987, Vol.52, 1521-1530) and triethylamine (1.5 ml, 10 mmol) in 10 ml of anhydrous CH2Cl2. After 4 hrs, CH2Cl2 was removed by evaporation at reduced pressure. Flash chromatography (4×20 cm, hexane-ethyl acetate, 1:2) afforded 1b as a yellow crystalline solid (1.25 g, 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.39 (d, 1H, J=1.4 Hz, NH), 8.02 (m, 1H, C6F4H), 7.9 (br s, 1H, C4-H), 7.45 (d, 1H, J=1.4 Hz, C8-H), 7.33 (d, 1H, J=9 Hz, C5-H), 4.02 (t, 2H, J=9 Hz, NCH2CH2), 3.26 (t, 2H, J=9 Hz, NCH2CH2), 1.51 (s, 9H, C(CH3)3). Anal. Calcd. for C22H18N2O4F4 : C, 58.67; H, 4.03; N, 6.22. Found: C, 58.45; H, 4.09; N, 6.13.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(C)(C)C(=O)COc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 87.4 %

Procedure:
461.5 9 (2.84 mols) of 1-chloro-3,3,4-trimethylpentan-2-one are added with stirring over the course of 1 hour to a mixture of 364.9 g (2.84 mols of 4-chlorophenol and 392 g (2.84 mols of potassium carbonate heated to 100° C. in 2,700 ml of N,N-dimethylformamide. After heating at 100° C. for ten hours, the mixture is cooled to 20° C., precipitated potassium chloride is removed by filtration, and the filtrate is evaporated under reduced pressure. The residue is taken up in 1,500 ml of dichloromethane and washed twice with 750 ml of 5% strength aqueous sodium hydroxide solution and 750 ml of water each time. After drying the organic phase over anhydrous sodium sulphate, the solvent is removed by distillation under reduced pressure and the oily residue is distilled in vacuo. 632 g (87.4% of theory) of 1-(4-chlorophenoxy)-3,3,4-trimethylpentan-2-one of boiling point 147°-148° C./0.15 torr are thus obtained.
Reaction SMILES: C(N)(C)(C)C.[Br:6]Br.[OH:8][C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>ClCCl>[Br:6][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:19])[C:9]=1[OH:8]
Reactant: BrBr
Reactant: COC(=O)c1cccc(O)c1C
Solvent: ClCCl
Solvent: CC(C)(C)N
Product: COC(=O)c1ccc(Br)c(O)c1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To a solution of tert-butylamine (1.6 mL, 15 mmol) in dichloromethane (100 mL) at −78° C. was added drop-wise over 30 minutes a solution of bromine (773 μl, 15 mmol in 15 mL of dichloromethane). The solution was stirred at −78° C. for 30 minutes. While maintaining the temperature at −78° C., a solution of methyl 3-hydroxy-2-methylbenzoate (2.5 g, 15 mmol in 15 mL of dichloromethane) was added to the reaction mixture drop-wise over 30 minutes. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The mixture was washed with 20% aqueous citric acid then brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was purified by silica gel column chromatography. Eluting with 10% diethyl ether in hexane, purified fractions were pooled and concentrated to afford 612 mg, 2.5 mmol (17%) of methyl 4-bromo-3-hydroxy-2-methylbenzoate as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.37-7.29 (m, 2H), 5.71 (s, 1H), 3.81 (s, 3H), 2.53 (s, 3H). MS (EI) for C9H9BrO3: 245 (MH+).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[S:12][C:13]2[CH2:19][C@@H:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:17][CH2:16][C:14]=2[N:15]=1)C1C=CC=CC=1.CCOCC.[BrH:32].CC(O)=O>>[BrH:32].[BrH:32].[N:20]1([C@H:18]2[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([NH2:10])[S:12][C:13]=3[CH2:19]2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: O=C(Nc1nc2c(s1)C[C@@H](N1CCOCC1)CC2)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1nc2c(s1)C[C@@H](N1CCOCC1)CC2
Reaction time: 48 h

Procedure:
Dissolved ((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester (7.46 g, 20.00 mmol) in 25 mL of 33% HBr/AcOH. Stirred mixture for 48 h. LC-MS indicated complete deprotection. Added 200 mL of Et2O resulting in a pale orange ppt. Filtered to give 7.46 mg of (S)-6-Morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-ylaminedihydrobromide a light brown solid.
Reaction SMILES: OC(C(F)(F)F)=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][C:19]3([CH3:25])[CH3:24])=[C:15]([C:26]([NH2:28])=[O:27])[CH:14]=[N:13][N:12]2[CH:29]=1.Cl[C:31]1[N:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:31]4[N:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=4)[CH2:20][C:19]3([CH3:25])[CH3:24])=[C:15]([C:26]([NH2:28])=[O:27])[CH:14]=[N:13][N:12]2[CH:29]=1
Reactant: CC1(C)CNCCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#Cc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(c2ccc(C#N)nn2)CCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 90 °C
Yield: 52.2 %

Procedure:
A stirred suspension of 6-bromo-4-(3,3-dimethylpiperidin-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt (139.5 mg, 0.290 mmol, from Step 2), 6-chloropyridazine-3-carbonitrile (81 mg, 0.581 mmol) and N,N-diisopropylethylamine (0.152 mL, 0.871 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed tube at 90° C. for 2.5 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic extract was concentrated and purified by silica gel chromatography, eluting with 0-100% ethyl acetate in hexanes, to give the title compound as a brown glassy solid (0.0711 g, 52% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 10.70 (1 H, d, J=9.02 Hz), 7.89 (1 H, s), 7.64 (1 H, d, J=1.76 Hz), 7.45 (1 H, d, J=9.68 Hz), 6.90 (1 H, d, J=9.46 Hz), 6.82 (1 H, d, J=1.54 Hz), 5.51 (2 H, br. s.), 4.39 (1 H, d, J=13.64 Hz), 4.18 (1 H, d, J=13.42 Hz), 4.09 (1 H, td, J=9.35, 3.96 Hz), 3.54 (1 H, ddd, J=13.75, 10.34, 3.41 Hz), 3.28 (1 H, d, J=13.86 Hz), 2.18-2.28 (1 H, m), 1.93 (1H, dddd, J=14.09, 10.01, 9.90, 4.29 Hz), 1.14 (3 H, s), 1.13 (3 H, s); MS (ES+) m/z: 469.2, 471.2 (M+H); LC retention time: 3.871 min (analytical HPLC Method H).
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C:11]([F:14])([F:13])[F:12])[NH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.CC(C)([O-])C.[K+].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>O1CCCC1>[Br:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C:11]([F:14])([F:12])[F:13])[N:4]([CH2:32][O:31][CH2:29][CH3:30])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1
Reactant: CCOCCl
Reactant: FC(F)(F)c1[nH]c(-c2ccc(Cl)c(Cl)c2)c(Br)c1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCn1c(-c2ccc(Cl)c(Cl)c2)c(Br)c(C(F)(F)F)c1C(F)(F)F
Yield: 93.8 %

Procedure:
To a chilled solution of 3-bromo-2-(3,4-dichlorophenyl)-4,5-bis(trifluoromethyl)pyrrole (0.854 g, 2 mmol) and tetrahydrofuran is added potassium tertbutoxide (0.247 g, 2.2 mmol). After stirring at ice bath temperature for 15 minutes chloromethyl ethyl ether (0.208 g, 2.2 mmol) is added to the reaction mixture and the ice bath is removed. Stirring is continued for 1 1/2 hours then the reaction mixture is diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow liquid (0.91 g, 94%). Identified by IR and NMR spectral analyses.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:26][N:12]2[C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15](=[O:16])[N:11]2[CH2:10]1)(C(C)(C)C)(C)C>F.C(#N)C>[Cl:23][C:21]1[CH:22]=[C:17]([N:14]2[C:15](=[O:16])[N:11]3[CH2:10][CH:9]([OH:8])[CH2:26][N:12]3[C:13]2=[O:25])[CH:18]=[C:19]([Cl:24])[CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OC1Cn2c(=O)n(-c3cc(Cl)cc(Cl)c3)c(=O)n2C1
Agent: F
Solvent: CC#N
Product: O=c1n(-c2cc(Cl)cc(Cl)c2)c(=O)n2n1CC(O)C2
Temperature: 55 °C
Yield: 79.8 %

Procedure:
A solution of 6-(tert-Butyl-dimethylsilyloxy)-2-(3,5-dichlorophenyl)-dihydro-pyrazolo[1,2-α][1,2,4]triazole-1,3-dione (1.9 g, 4.56 mmol) (Preparation 5) in a mixture of 50% hydrofluoric acid (2 ml) and acetonitrile (80 ml) was heated for 7 h at 50-60° C. in a Teflon flask. The solvent was removed under vacuum and the residue crystallized in diethyl ether to yield the above compound as a white solid (1.1 g, mp=160° C.). 1H NMR (CDCl3):7.49 (2H, m), 7.38 (1H, m), 4.54 (1H, br s), 3.98 (2H, d, J=12 Hz), 3.49 (2H, dd, J1=12 Hz, J2=2.1 Hz), 3.10 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[C:6]([F:12])[N:5]=[C:4](F)[N:3]=1.[CH3:14][NH2:15]>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[C:6]([F:12])[N:5]=[C:4]([NH:15][CH3:14])[N:3]=1
Reactant: Fc1nc(F)c(OC(F)F)c(Cl)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(F)c(OC(F)F)c(Cl)n1
Reaction time: 1 h

Procedure:
20.3 g (0.0938 mol) of 4-chlorodifluoromethoxy-2,6-difluoropyrimidine in 150 ml of tetrahydrofuran were initially taken, and 5.8 g (0.188 mol) of gaseous methylamine were added at from -70° to -60° C. in the course of 30 minutes while stirring. Stirring was continued for 1 hour in each case at -70° C., 0° C. and 25° C. The reaction mixture was evaporated down under reduced pressure, after which the residue was stirred with water, the solution was extracted twice with ethyl acetate and the extract was dried over magnesium sulfate. It was partially evaporated down under reduced pressure and then subjected to fractional chromatography over silica gel using 1:5 ether/petroleum ether. The first fractions contained the title compound of melting point 57°-61° C. in a yield of 12.5 g (58.5%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH3:16])[C:11]([O:15][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([CH3:14])[N:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution containing 1.62 g (7.46 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-hydroxy-4,6-dimethylpyrimidine (5) in 30 mL of anhydrous THF were added 440 mg (11.00 mmol) of 60% sodium hydride suspension in mineral oil followed by 1.20 mL (10.10 mmol) of benzyl bromide. The reaction mixture was stirred at room temperature under argon atmosphere for 48 h. The reaction mixture was poured into 150 mL of water and extracted with two portions of 100 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 4:1 gave the expected product as light yellow oil: yield 2.20 g (96%). 1H-NMR (CDCl3) δ 7.42 (m, 5H), 5.86 (s, 2H), 4.92 (s, 2H), 2.47 (s, 6H), 2.29 (s, 6H); 13C-NMR (CDCl3) δ 161.59, 152.34, 147.66, 136.05, 129.16, 128.59, 128.26, 107.90, 75.29, 19.10, 14.10.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH2:12][C:13]3[N:17]([CH2:18][C:4]1=2)[C:16]([CH3:19])=[C:15]([C:20](OC)=[O:21])[C:14]=3[C:24](OC)=[O:25])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH2:12][C:13]3[N:17]([CH2:18][C:4]1=2)[C:16]([CH3:19])=[C:15]([CH2:20][OH:21])[C:14]=3[CH2:24][OH:25])[CH3:2]
Reactant: CCn1c2c(c3ccccc31)Cc1c(C(=O)OC)c(C(=O)OC)c(C)n1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCn1c2c(c3ccccc31)Cc1c(CO)c(CO)c(C)n1C2

Procedure:
Compound BO-1972 was prepared from dimethyl 6-ethyl-3-methyl-6,11-dihydro-5H-indolizino-[6,7-b]indole-1,2-dicarboxylate (3.6 g, 10 mmol) and LiAlH4 (0.92 g, 25 mmol). Yield 2.5 g (80%); mp 216-217° C. 1H NMR (DMSO-d6) δ 1.29 (3H, t, J=7.1 Hz, Me), 2.30 (3H, s, Me), 4.00 (2H, s, CH2), 4.21 (2H, q, J=7.1 Hz, CH2), 4.38 (3H, br s, CH2 and exchangeable, OH), 4.44 (3H, br s, CH2 and exchangeable, OH), 5.13 (2H, s, CH2), 7.04-7.07 (1H, m, ArH), 7.14-7.18 (1H, m, ArH), 7.47-7.49 (1H, m, ArH), 7.53-7.55 (1H, m, ArH). Anal. Calcd for (C19H22N2O2): C, 73.52; H, 7.14; N, 9.03. Found: C, 73.68; H, 6.93; N, 8.66.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C@H:10]([CH3:11])[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH3:12].[Li].[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:12][C@H:6]1[CH2:7][CH2:8][CH2:9][C@@H:10]([CH3:11])[N:5]1[CH2:4][CH2:3][CH2:2][C:18]([C:17]1[CH:4]=[CH:3][CH:2]=[CH:15][CH:16]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)[OH:14]
Reactant: C1CCOC1
Reactant: C[C@@H]1CCC[C@H](C)N1CCCCl
Agent: [Li]
Product: C[C@@H]1CCC[C@H](C)N1CCCC(O)(c1ccccc1)c1ccccn1
Reaction time: 4 h

Procedure:
A solution of 18.9 g. of cis-1-(3-chloropropyl)-2,6-dimethylpiperidine in 50 ml. of tetrahydrofuran is added dropwise under a nitrogen atmosphere to a stirred mixture of 1.4 g. of lithium wire and 50 ml. of tetrahydrofuran over a period of 2 hours. After the addition is complete, the mixture is stirred another 4 hours under nitrogen, the excess lithium metal removed manually and a solution of 18.3 g. of 2-benzoylpyridine in 100 ml. of tetrahydrofuran is added dropwise with stirring over a period of 2 hours. The mixture is stirred for 16 hours, then treated with 5 ml. of water. The organic phase is decanted from the precipitated solid and evaporated at reduced pressure to about one-fourth its previous volume. This solution is poured into 400 ml. of water, the solution is acidified with acetic acid and washed with ether. The aqueous acid solution is basified with aqueous sodium hydroxide and extracted with ether. The ether extract is washed with water, dried and evaporated to give (+,-)-cis-α-[3-(2,6-dimethyl-1-piperidinyl)propyl]-α-phenyl-2-pyridinemethanol; m.p. (monohydrate) 100°-102° C. after crystallization from aqueous methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[C@@H:15]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]=2)=[N:6][C:7]=1[O:8][CH3:9].Cl.O1CCOCC1>CO>[C:17]([O:16][C@@H:15]1[C:10]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([O:8][CH3:9])[N:6]=2)=[CH:11][CH2:12][NH:13][CH2:14]1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1nc(C2=CCN(C(=O)OC(C)(C)C)C[C@@H]2OC(=O)C(C)(C)C)ccc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1nc(C2=CCNC[C@@H]2OC(=O)C(C)(C)C)ccc1Cl
Yield: 127.8 %

Procedure:
To a methanol solution (1.0 mL) of tert-butyl (R)-5-chloro-6-methoxy-5′-(pivaloyloxy)-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (1.35 g, 3.18 mmol) synthesized in Reference Synthesis Example 142, 4 M hydrogen chloride/1,4-dioxane (15 mL) was added and the resultant mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and saturated sodium bicarbonate aqueous solution and water were added to the concentrated solution, followed by extraction from the resultant mixture with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of the title compound (1.32 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([Cl:19])=[N:16]3)=[CH:11][CH:10]=2)[C:4]1=[O:20].[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([S:33](Cl)(=[O:35])=[O:34])=[CH:30]2)=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:19][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:33]([C:29]4[CH:28]=[CH:27][C:26]5[C:31](=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=5)[CH:30]=4)(=[O:35])=[O:34])[C:4]3=[O:20])=[CH:10][CH:11]=2)[N:16]=1
Reactant: N[C@H]1CCN(Cc2ccc3ccc(Cl)nc3c2)C1=O
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccc(Cl)nc5c4)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. The crude product is triturated in 20% EtOAc/hexanes and filtered to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[I:17](O)(=O)=O.II>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([I:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][I+2]([O-])O
Reactant: CC(=O)Nc1cc(-c2cccc(F)c2)n[nH]1
Agent: II
Solvent: CCO
Product: CC(=O)Nc1[nH]nc(-c2cccc(F)c2)c1I
Temperature: 60 °C
Yield: 368.2 %

Procedure:
A suspension of N-[3-(3-fluorophenyl)-1H-pyrazol-5-yl]acetamide (7.6 g, 34.7 mmol), iodic acid (1.5 g, 8.5 mmol) and iodine (4.4 g, 17.3 mmol) in ethanol (200 mL) was heated at 60° C. for 1 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 and 2 M Na2S2O3 aq. solution. The layers were separated and the organic washed with brine, dried (MgSO4), and concentrated in vacuo to provide the title compound as a solid (10.8 g).