Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH:12]=O)=[CH:7][CH:6]=2.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([NH2:19])=[O:18].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[NH:19][C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([O:24][CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])[N:14]=1)=[CH:7][CH:6]=2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc2[nH]c(CO)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CO)cc4c3)nc2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 2-hydroxymethyl-1H-indole-5-carbaldehyde (90 mg, 0.51 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.15 g, 0.77 mmol) in N,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt %) (0.14 g, 0.77 mmol) and p-toluenesulfonic acid (20 mg, 0.10 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen, cooled to room temperature, and concentrated under reduced pressure. Water (20 mL) was added. The separated solid was filtered, washed with water (20 mL) and ether (20 mL), and dried under vacuum. Crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent), to give the title compound as an off-white solid. Yield: 0.06 g (33%). MP 264-265° C. 1H NMR (400 MHz, DMSO-d6): δ 11.85 (br s, 1H), 11.36 (s, 1H), 8.39 (s, 1H), 7.93 (dd, J=8.6 and 1.6 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 6.41 (s, 1H). 5.34 (t, J=5.8 Hz, 1H), 4.63 (d, J=5.5 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=3[O:11][C:10]=2[CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:23][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=2[O:11][C:10]=1[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(C(O)C3CCCCC3)c(C)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(C(Cl)C3CCCCC3)c(C)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution (10 mL) of cyclohexyl(6-methoxy-2-methyl-1-benzofuran-3-yl)methanol (499 mg) synthesized above in toluene was added thionyl chloride (159 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (530 mg, 99%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[C:16]1([Mg][Cl:23])[CH:21]=[CH:20]C=[CH:18][CH:17]=1.[Cl-].[NH4+].Cl[Si](C)(C)C>C1COCC1>[ClH:23].[CH3:1][N:2]([CH3:15])[C:3]1([C:13]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Cl[Mg]c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (21 g, 0.1 mole), dissolved in THF (210 ml), was added within 15 minutes while cooling with ice and under argon to a 1.82 M phenylmagnesium chloride solution in THF (109 ml, 0.198 mole) and the mixture was then stirred for 16 hours at room temperature. To work up the reaction mixture saturated ammonium chloride solution (150 ml) was added while cooling with ice and extracted with diethyl ether (3×100 ml). The organic phase was extracted by shaking with water (100 ml) and saturated NaCl solution (100 ml) and concentrated by evaporation. A yellow oil (25.2 g) remained. The crude product was dissolved in ethyl methyl ketone (280 ml) and ClSiMe3 (18.8 ml, 0.15 mole) was added while cooling with ice. After a reaction time of 6 hours dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)amine hydrochloride was isolated as a white solid in a yield of 35% (10.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][NH:25][CH:26]2[CH3:29])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][C:19]([C:15]5[O:14][CH:18]=[CH:17][CH:16]=5)=[CH:20][CH:21]=4)[CH:26]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3ccco3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(-c3ccco3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: NC1N=C2C(N=CN2)=C(OCC2C=CC(C[NH:18][C:19](=[O:34])[C:20]3[CH:25]=[CH:24][C:23](CNC(=O)C(F)(F)F)=[CH:22][CH:21]=3)=CC=2)N=1.CO.C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)C(O)=O.[C:52](#[N:54])C>O>[NH2:54][CH2:52][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:19]([NH2:18])=[O:34]
Reactant: Nc1nc(OCc2ccc(CNC(=O)c3ccc(CNC(=O)C(F)(F)F)cc3)cc2)c2nc[nH]c2n1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: NCc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Weighed into a 50 ml round-bottomed flask were 25 mg (50 μmol) of N-(4-((2-amino-9H-purin-6-yloxy)methyl)benzyl)-4-((2,2,2-trifluoroacetamido)methyl)benzamide. 10 ml of methanol, 2 ml of an aqueous solution saturated with Na2CO3 and 4 ml of water were added. It was left stirring overnight at ambient temperature. The deprotection was monitored by HPLC on a Merck Lichrospher RP °18, 5 μm, 125×4.6 column with a gradient of acetonitrile in water containing 0.2% of trifluoroacetic acid.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCOC(=O)CC#N
Temperature: 105 °C

Procedure:
Cyanoacetic acid (85.5 g; 1.0 mol), 1-propanol (120 g; 2.0 mol) and p-toluenesulfonic acid monohydrate (1.00 g; 0.005 mol) were introduced into a 500 ml flask. The mixture was slowly heated to a maximum of 105° C. while collecting distillates at 88-90° C. The pressure was reduced so that the flask was maintained at 105-110° C. and the distillates were collected continuously, and the propanol was returned to the flask. After distilling off the unreacted propanol, the n-propyl cyanoacetate (bp 100° C./23 mm Hg) was collected as a clear liquid. The yield was 122 g (96% of theoretical) and its purity was >99% (GC assay).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([C:16]1[CH:31]=[CH:30][C:19]([O:20][CH2:21][CH:22]([OH:29])[CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[CH2:8]([C:16]1[CH:31]=[CH:30][C:19]([O:20][CH2:21][C:22](=[O:29])[CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2cccn2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.154 g (1.51 mmol) acetic anhydride is mixed with 5 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.050 g (0.152 mmol) 1-(4-octylphenoxy)-3-(pyrazol-1-yl)propan-2-ol in 10 ml absolute DMSO. Having stirred at room temperature for 18 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellowish solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a white solid.
Reaction SMILES: ClC1C=CC(C2C(C3C=CN=C(N[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:21]=4)N=3)=CNN=2)=CC=1.[CH3:35][C:36]([O:39][C:40]([NH:42]C1C=CC(O)=CC=1)=[O:41])([CH3:38])[CH3:37]>>[C:36]([O:39][C:40](=[O:41])[NH:42][C:25]1[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[CH:23][CH:24]=1)([CH3:38])([CH3:37])[CH3:35]
Reactant: CN1CCC(COc2cccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)c2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Product: CN1CCC(COc2ccc(NC(=O)OC(C)(C)C)cc2)CC1

Procedure:
[4-(1-Methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester is prepared as described for [3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester (see Example 27) using 4-N-BOC-Aminophenol (AstaTech; B56686). Title compound: ES-MS: 321.1 [M+H]+; single peak at tR=4.55 min (System 1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:9]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:42]([CH2:46]I)([F:45])([F:44])[F:43]>CN(C=O)C>[F:43][C:42]([F:45])([F:44])[CH2:46][O:7][C:8]1[C:9]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@]12CC[C@@H]3c4cc(O)c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4cc(OCC(F)(F)F)c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Temperature: 110 °C
Yield: 96.1 %

Procedure:
Powdered K2CO3 (1.5 g, 11 mmol) was added to a solution of estradiol (6) (4.0 g, 8.5 mmol) in anhydrous DMF (50 mL) followed by dropwise addition of CF3CH2I (5.0 mL, 51 mmol) at room temperature. The resulting reaction mixture was heated at 110° C. for 3 h. Additional K2CO3 (2.5 g) and CF3CH2I (6 mL) were added, and the mixture was heated again at 130° C. for 2 h. The mixture was cooled in an ice bath and poured onto ice cold 3N HCl (125 mL). The aqueous layer was extracted with ether (2×200 mL). The combined ether layer was washed with 3N HCl (100 mL), water (100 mL), brine (100 mL), and dried over anhydrous MgSO4. The ether layer was evaporated under reduced pressure and the resulting crude product on purification on a silica gel column gave estradiol (7)(4.5 g, 95%) as a colorless oil: IR (neat) 2910, 2850, 1600, 1500, 730, 690 cm-1 ; 1H NMR (CDCl3) δ 0.9 (s, 3H), 1.1-2.4 (m, 13H), 2.65-2.85 (m, 2H), 3.50 (t, J=8.5 Hz, 1H), 4.40 (q, J=8.5 Hz, 2H), 4.56 (s, 2H), 5.05 (s, 2H), 6.70 (s, 1H), 6.98 (s, 1H), 7.2-7.55 (m, 10H). Anal. (C34H37F3O3) C, H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[CH:22][C:23]=2[C:24](=[O:34])[NH:25][C:26]2([C:32]#[N:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[N-:35]=[N+:36]=[N-:37].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[CH:22][C:23]=2[C:24](=[O:34])[NH:25][C:26]2([C:32]3[NH:37][N:36]=[N:35][N:33]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: N#CC1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1(c2nnn[nH]2)CCCCC1)c1cnn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 82.4 %

Procedure:
To a solution of the compound obtained in Example A1 (106 mg) in toluene (4 mL) and dimethylformamide (1.5 mL) were added sodium azide (86 mg) and triethylamine hydrochloride (183 mg), and the mixture was stirred at 120° C. for 24 hours. To the reaction mixture were further added sodium azide (90 mg) and triethylamine hydrochloride (183 mg), and the mixture was stirred for 21 hours. After cooling to room temperature, the reaction mixture was filtered through Celite to remove precipitates, and the filtrate was concentrated in vacuo. The resultant crude product was purified successively by column chromatography on silica gel (solvent; chloroform/methanol=100/0 to 95/5) and gel-permeation chromatography (solvent; chloroform) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-[1-(1,2,3,4-tetrazol-5-yl)cyclohexyl]carbamoyl]-pyrazolo[1,5-a]pyrimidine (95 mg, yield: 83%) as a powder.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:34][C:35]1[C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][O:37][N:36]=1.C(OCC)(=O)C.O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:39]1[C:35]([CH3:34])=[N:36][O:37][CH:38]=1
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1conc1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1nocc1-c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (25 mg, 0.042 mmol), tetrakis(triphenylphosphine) palladium (2.5 mg, 0.0022 mmol) and 3-methyl-4-(tributylstannyl)isoxazole [synthesized as described by D. Uchiyama in Heterocycles, 43, 6, 1301, 1996] (32 mg, 0.086 mmol) were mixed in DME (0.45 ml) in an argon filled vial. The vial was closed and heated with stirring at 100° C. for 24 h. The reaction mixture was poured into a mixture of ethyl acetate and water. The mixture was shaken, the water phase was removed and the organic phase was dried over sodium sulphate. The product was purified by preparative HPLC. Yield: 12 mg, 0.022 mmol (52%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2([CH3:23])[CH3:22])=[CH:10][N:9]=1)(C)(C)C.Cl>O1CCOCC1.CO>[CH3:22][C:16]1([CH3:23])[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][N:15]1[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=1
Reactant: CN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(C)(C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(Cc2ccc(N)nc2)C(C)(C)C1
Yield: 75 %

Procedure:
A mixture of [5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 110.2) (1.94 g, 5.8 mmol), a 4 N solution of HCl in dioxane (20 mL) and MeOH (5 mL) was stirred for 12 h at rt and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 95:4:1) to afford 1.02 g of the title compound as a white solid. Title compound: ESI-MS: 235.2 [M+H]+; TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:35][CH:34]2[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]2)[CH2:30]1>C(O)C>[CH:34]12[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]1)[CH2:30][N:29]([CH2:28][CH2:27][N:12]1[CH2:13][CH2:14][C:9]3[C:5]4[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=4[O:16][C:15](=[O:17])[C:10]=3[CH2:11]1)[CH2:35]2
Reactant: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCN(CCN1CC2CCC(CC2)C1)C3
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (6.0 g, 0.026 moles), triethylamine (6.1 g, 0.060 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (6.3 g, 0.028 moles) in absolute ethanol (150 ml) is stirred at reflux under a nitrogen atmosphere for 24 hours. The crude product precipitates as the free base as the reaction mixture is cooled slowly to room temperature. The product is filtered and recrystallized from absolute ethanol to yield the final product (4.6 g), mp 174°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH3:15][C:16]1[N:21]=[C:20]([NH:22][CH3:23])[N:19]=[C:18]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31](O)=[O:32])[CH2:26]2)[N:17]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:31]([CH:27]2[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:18]3[N:17]=[C:16]([CH3:15])[N:21]=[C:20]([NH:22][CH3:23])[N:19]=3)[CH2:26]2)=[O:32])=[C:4]([O:10][C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Reactant: NCc1ccc(Br)cc1OC(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(C)nc(NC2CCCC(C(=O)NCc3ccc(Br)cc3OC(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A mixture of ({4-bromo-2-[(trifluoromethyl)oxy]phenyl}methyl)amine (0.4 g, 1.041 mmol), 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.276 g, 1.041 mmol), 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.507 g, 1.146 mmol) and diisopropylethylamine (0.364 ml, 2.083 mmol) in N,N-Dimethylformamide (DMF) (5 ml) was stirred overnight at RT. The reaction mixture was treated with water which caused a precipitate to form. The precipitate was filtered and washed with water, and dried to give N-({4-bromo-2-[(trifluoromethyl)oxy]phenyl}methyl)-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (0.35 g, 0.543 mmol, 53%) as an off-white solid. MS (ES) m/e 517, 519 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:30][NH2:31]>C1COCC1.O.C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:7]3[CH2:8][C:2]4[S:1][CH:5]=[CH:4][C:3]=4[C:6]=3[NH:31][N:30]=2)=[CH:13][CH:12]=1
Reactant: NN
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: O=C1CCc2sccc21
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(Nc2n[nH]c3c2Cc2sccc2-3)cc1
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Chloro-4-isothiocyanato-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4-Chloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 35% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[S:16][C:17]4[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:18]=4[CH:19]=3)[C:9]([CH2:13][OH:14])=[C:10]([C:11]#[N:12])[N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:31][CH2:32]N(C(C)C)C(C)C>ClCCl.C(O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[S:16][C:17]4[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:18]=4[CH:19]=3)[C:9]([CH2:13][O:14][CH2:31][CH3:32])=[C:10]([C:11]#[N:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C)cc2cc(-c3c(CO)c(C#N)n4ncnc(N)c34)sc12
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOCc1c(-c2cc3cc(C)cc(OC)c3s2)c2c(N)ncnn2c1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of Example 68 (60 mg, 164 μmol) in dichloromethane (5 ml) was treated with thionyl chloride (18 μl, 246 μmol). The mixture was stirred at rt for 15 min and then evaporated. The residue was dissolved in ethanol (2 ml) and treated with DIPEA (57 μl, 328 μmol). The mixture was stirred at 60° C. overnight and then heated to 150° C. for 30 min in a microwave device. After this, the mixture was evaporated, and the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. TFA). The product thus obtained was dissolved in ethanol (2 ml) and again heated to 150° C. for 30 min in the microwave oven. DIPEA (57 μl, 328 μmol) was added, and heating to 150° C. in the microwave oven was continued for further 30 min. After evaporation, the residue was purified by column chromatography on silica gel (dichloromethane/methanol 95:5) affording 16 mg (23% of th.) of the title compound.
Reaction SMILES: [P:1]([O-:8])([O:5]CC)[O:2]CC.O.[CH2:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:10]([P:1](=[O:2])([O-:5])[O-:8])[CH3:11].[CH2:10]([O:14][CH2:15][CH2:16][CH2:17][NH3+:18])[CH2:11][CH2:12][CH3:13].[CH2:10]([O:14][CH2:15][CH2:16][CH2:17][NH3+:18])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOCCCN
Reactant: CCOP([O-])OCC
Solvent: CCO
Solvent: O
Product: CCCCOCCC[NH3+]
Product: CCP(=O)([O-])[O-]
Yield: 95.7 %

Procedure:
A mixture of 13.81 g. (0.1 moles) of diethyl phosphite, 20 ml. of water and 20 ml. of ethanol is reacted with a mixture of 13.12 g. (0.1 moles) of 3-butyloxypropyl amine and 30 ml. of ethanol as described in Example 1. 23.1 g. of 3-butyloxypropyl-ammoniumethyl phosphonate are obtained. Yield: 95.7%. nD30 =1.4438
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>ClCCCl>[Cl:18][CH2:14][CH:11]1[CH2:12][CH2:13][N:9]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:10]1
Reactant: O=S(Cl)Cl
Reactant: CC(c1ccccc1)N1CCC(CO)C1
Solvent: ClCCCl
Product: CC(c1ccccc1)N1CCC(CCl)C1
Yield: 100 %

Procedure:
A solution of 0.50 g (2.44 mmol) [3R-(R*,R*)]-1-(1-phenylethyl)-3-pyrrolidinemethanol in 5 ml 1,2-dichloroethane was treated with 2 ml thionyl chloride, refluxed two hours, evaporated, and crystallized by trituration with ether to afford 0.64 g (100%) of the title compound as the hydrochloride mp 140°-146 ° C., [α]D +27.8° C. (c, 1.07, methanol).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:15])=[CH:12][CH:11]=1>C(#N)C>[BrH:15].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([I:9])=[CH:11][CH:12]=2)[N:5]=1)[CH3:8]
Reactant: BrCc1ccc(I)cc1
Reactant: CCc1nnc(N)s1
Solvent: CC#N
Product: Br
Product: CCc1nn(Cc2ccc(I)cc2)c(=N)s1
Yield: 71.4 %

Procedure:
To acetonitrile (10 ml) was added 2-amino-5-ethyl-1,3,4-thiadiazole (645 mg) and 4-iodobenzyl bromide (1.49 g), followed by heating under reflux for 20 hours. After the reaction mixture was cooled, the crystals so precipitated were collected by filtration and dried, whereby 1.52 g of the title compound was obtained.