Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[N:3]=[CH:4][CH:5]=[C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[C:9]1([C:7]2[NH:3][CH:4]=[CH:5][C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)N=CC=C(C(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cc[nH]c2-c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 3.1 g (0.011 mole) of 4-dimethylhydrazono-1,2-diphenyl-2-buten-1-one, 11.2 g (0.064 mole) sodium hydrosulfite in 75 ml ethanol and 37.5 ml water was heated at reflux for three hours. The mixture was cooled and poured into 300 ml ice water. The white crystalline produce was collected, washed with water and air dried to give 1.9 g (79%), m.p. 130°-1°, identical to product obtained via the decarboxylation, Method A.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.C(N(CC)CC)C.[NH2:20][CH2:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=2)=[O:30])[CH2:24]1>CCO>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:20][CH2:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=2)=[O:30])[CH2:24]1)[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1c(NCCC2CN(C(=O)OCc3cc(Cl)cc(Cl)c3)CCO2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising of 3,4-diethoxycyclobut-3-ene-1,2-dione (77 mg, 0.453 mmol) and triethylamine (253 μl, 1.813 mmol) in EtOH (1511 μl) was stirred at 40° C. for 20 minutes under nitrogen. After cooling to room temperature, 3,5-dichlorobenzyl 2-(2-aminoethyl)morpholine-4-carboxylate (step 2) (151 mg, 0.453 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for a further 30 minutes. The resulting reaction mixture was concentrated under reduced pressure and diluted with EtOAc. The organic portion was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was dried loaded using silica onto an ISCO 4 g column, eluting with 0-100% EtOAc in iso-hexane. The product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(O)CC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCO
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCCN1CCOCC1

Procedure:
To a clear solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (60.1 g, 178 mmol) in a mixture of n-propanol/ethyl acetate (600/200 mL) at 30-35° C. was added 3-trifluoromethyl benzoyl chloride slowly with stirring. The reaction mixture became turbid initially and solids were separated after the mixture was stirred at ambient temperature for 3 to 5 hours. The solids were filtered, washed with n-propanol, and dried in vacuo at 40° C. overnight to produce N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide as a white solid in 72% yield (as the HCl salt). LCMS m/z (%)=509 (M+H35Cl, 100), 511 (M+H37Cl, 33) 1H NMR (400 MHz, DMSO-d6) δ: 10.7 (bs, 1H), 8.39-8.44 (m, 2H), 8.01 (d, J=2.61 Hz, 1H), 7.98 (s, 1H), 7.75-7.83 (m, 2H), 7.69 (s, 1H), 7.35 (d, J=9.01, 1H), 4.45-4.65 (m, 2H), 3.79-3.89 (m, 4H), 3.69 (s, 3H), 3.36-3.53 (m, 4H with water), 3.05-3.25 (m, 2H), 2.99-3.05 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:34])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:31][CH2:32][CH3:33])=[C:20]([S:23]([NH:26][C:27]([NH:29][CH3:30])=S)(=[O:25])=[O:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[OH:35]O>>[CH2:1]([C:3]1[C:4](=[O:34])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:31][CH2:32][CH3:33])=[C:20]([S:23]([NH:26][C:27]([NH:29][CH3:30])=[O:35])(=[O:25])=[O:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCOc1cc2c(cc1S(=O)(=O)NC(=S)NC)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2
Reactant: OO
Product: CCOc1cc2c(cc1S(=O)(=O)NC(=O)NC)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(methylaminocarbonylaminosulfonyl)-7-ethoxychroman ##STR56## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(methylaminocarbonylaminosulfonyl)-7-ethoxychroman is prepared analogously to Example 18 by oxidation of 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-ethoxychroman using hydrogen peroxide solution. Melting point: 187°-188° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:3]1.[C:20]([CH2:22][C:23](O)=[O:24])#[N:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:8]1([C@@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:23](=[O:24])[CH2:22][C:20]#[N:21])[CH2:3]2)[N:12]2[C:13]3[CH:19]=[CH:18][NH:17][C:14]=3[N:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: c1cc2c(ncc3nnc([C@@H]4CCCNC4)n32)[nH]1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CCC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a suspension of (R)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.074 g, 0.265 mmol; Example #I1.1) and 2-cyanoacetic acid (0.034 g, 0.398 mmol) in DMF (3 mL) was added HOBt (0.041 g, 0.265 mmol), EDC.HCl (0.051 g, 0.265 mmol) and DIEA (0.093 mL, 0.531 mmol). The reaction mixture was stirred at ambient temperature for about 16 h. The crude reaction mixture was purified by RP-HPLC (Table 2, Method f). The appropriate fractions were concentrated in vacuo and lyophilized to afford (R)-3-(3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile as a white solid (0.052 g, 63%): LC/MS (Table 2, Method a) Rt=1.30 min; MS m/z: 310 (M+H)+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)[CH3:8]>O.CO>[CH2:7]([S:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:24][CH2:25]2)=[O:19])=[CH:16][CH:15]=1)=[O:2])[CH3:8]
Reactant: CCSCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCS(=O)CCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
Sodium metaperiodate (0.28 g) is dissolved in water (4 ml) and thereto is added a solution of 1-{1-[4-(3-ethylthiopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.4 g) in methanol (15 ml) and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is extracted with chloroform. The extract is dried with magnesium sulfate and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:2→ethyl acetate:methanol=20:1) to give 1-{1-[4-(3-ethylsulfinylpropoxy)benzoyl]-4-piperidinyl]-3,4-dihydrocarbostyril (0.12 g).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11]O)=[C:6]([F:13])[CH:5]=1.C(O)(=O)C.C(OCC)C.C(=O)([O-])O.[Na+].[BrH:29]>>[Br:29][CH2:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([O:3][CH:2]([F:14])[F:1])=[CH:5][C:6]=1[F:13]
Reactant: Br
Reactant: OCc1c(F)cc(OC(F)F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Fc1cc(OC(F)F)cc(F)c1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.76 g of [4-(difluoromethoxy)-2,6-difluorophenyl]methanol (3.62 mmol, 1 eq.) were dissolved in 1.72 ml of 33% hydrogen bromide in glacial acetic acid (9.97 mmol, 2.75 eq.) and stirred at room temperature for 2 hours. 25 ml of diethyl ether were added and the mixture was stirred at room temperature for 15 min. The reaction mixture was added dropwise to 80 ml of aqueous saturated sodium hydrogen carbonate solution and stirred again at room temperature for 15 min. The separated aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo to yield 991 mg (3.56 mmol, 98.4%) of the analytically pure target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 1.00 g (3.25 mmol) of 5-(Benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 630 μL (2.16 mmol) of 1-bromopentadecane in 20 mL of anhydrous THF were added 2.70 mL (4.32 mmol) of a 1.60 M solution of n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 70 mL of water. The mixture was then extracted with two 70-mL portions of diethyl ether. The combined organic layer was then washed with a 100-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-diethyl ether afforded the expected product as a colorless oil: yield 269 mg (24%); silica gel TLC Rf 0.5 (4:1 hexanes-diethyl ether); 1H NMR (CDCl3) δ0.89 (t, 3H, J=7.2 Hz), 1.20-1.30 (m, 26H), 1.75 (quint, 2H, J=7.2 Hz), 2.29 (s, 6H), 2.47 (s, 3H), 2.76 (dd, 2H, J=8.0, 8.0 Hz), 4.89 (s, 2H), 5.85 (s, 2H) and 7.30-7.42 (m, 5H); 13C NMR (CDCl3) δ 14.08, 14.30, 14.30, 19.27, 22.66 27.72, 29.33, 29.40, 29.50, 29.55, 29.63, 29.63, 29.63, 29.67, 29.67, 29.67, 29.67, 31.61, 31.89, 75.72, 107.91, 128.01, 128.22, 128.72, 129.30, 129.30, 136.22, 147.35, 147.35, 152.59, 161.59 and 165.09; mass spectrum (APCI), m/z 518.4113 (M+H)+ (C34H52N3O requires 518.4110).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH:13](=O)[CH2:14][CH2:15][CH3:16]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)[CH2:14][CH2:15][CH3:16])([O-:3])=[O:2]
Reactant: CCCC=O
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Product: CCCC(c1c[nH]c2ccc([N+](=O)[O-])cc12)c1c[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
ST 1429 was prepared from 5-nitroindole and butyraldehyde prepared using the method described in example 2/1.
Reaction SMILES: [N:1]1[CH:6]=[C:5](C(O)=O)[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=O.[CH3:13][O:14]C1C=C(C=C(OC)C=1OC)C(O)=O>>[N:1]1[C:2]([CH2:10][OH:12])=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:13][OH:14]
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Product: OCc1cccc(CO)n1

Procedure:
Pyridine 2,5-dicarboxylic acid is reacted in a process similar to that utilized in the reaction of 3,4,5-trimethoxybenzoic acid set forth in the first two portions of the procedure of Example I so as to produce the corresponding mixed anhydride that is subjected to the catalytic hydrogatation to obtain pyridine 2,6-dimethanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1>>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])[CH:26]=[CH:25][C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNCc1cccc2[nH]ccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CN(Cc1cccc2[nH]ccc12)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 73.7 %

Procedure:
According to the procedure of Example 35g, (1H-indol-4-ylmethyl)-methyl-amine (223 mg, 1.39 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (359 mg, 1.41 mmol), were coupled to give crude product. Purification by column chromatography gave the title compound (369 mg, 73%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 11.20-11.14 (m, 1H), 10.65-10.62 (m, 1H), 8.38-8.32 (m, 1H), 8.08-7.99 (m, 1H), 7.59-7.53 (m, 1H), 7.37-7.21 (m, 3H), 7.09-7.03 (m, 1H), 6.89-6.76 (m, 1H), 6.51 (s, 1H), 5.06-4.88 (m, 2H), 3.04-2.83 (m, 5H), 2.56-2.52 (m, 2H); ESI MS m/z 361 [C21H20N4O2+H]+.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:23])[C:15]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1>C1COCC1>[F:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:13])[N:23]([CH2:14][C:15]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1)[CH2:11]2
Reactant: COC(=O)c1ccc(F)cc1CBr
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(F)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a stirred solution of 2-bromomethyl-4-fluoro-benzoic acid methyl ester (17 g, 68.8 mmol) in THF (200 mL) was added PMBNH2 (23.6 g, 172 mmol) at 0° C. After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo to give a crude product which was then purified by column chromatography to give the title compound (13 g, yield 69%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].C(C1C=C(C=C(C)C=1O)[C:16]([NH:18][OH:19])=[NH:17])C>>[OH:10][C:4]1[C:5]([CH3:9])=[CH:6][C:7]([C:16]([NH:18][OH:19])=[NH:17])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C)c1O
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Product: COc1cc(C(=N)NO)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-methoxy-6-methyl-phenol in analogy to literature procedures (e.g B. Roth et al. J. Med. Chem. 31 (1988) 122-129; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.50 min; [M+1]+=197.23.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6](=[O:15])[C:7]([C:13]#[N:14])=[C:8]([S:11][CH3:12])SC.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=1[NH:25][NH2:26]>O>[CH3:4][O:5][C:6]([C:7]1[C:8]([S:11][CH3:12])=[N:26][N:25]([C:18]2[C:19]([Cl:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])[C:13]=1[NH2:14])=[O:15]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(SC)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Reaction time: 8 h

Procedure:
An ethanol (3.5 l) solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid methyl ester (454.3 g, 2.23 mol) and 2,4,6-trichlorophenylhydrazine (472.7 g, 2.23 mol) was vigorously refluxed for 1.5 hours. The reaction mixture was allowed to stand overnight at ambient temperature. Water (850 ml) was added, and the resulting mixture was briskly stirred for 30 minutes. The granular precipitate was filtered and washed with a water/ethanol(1:3 in volume)solution (1 l). The air-dried product was further dried under vacuum (45° C.) for 2 days to afford the title compound as a yellow crystalline solid, m.p. 160°-162° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[N:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(O)(C(F)(F)F)=O.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3ncccc23)CC1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CCCN3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of 4-pyrido[2,3-d]pyrimidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (0.24 g, 0.76 mmol) in MeOH (10 mL) and TFA (1 mL) was added PtO2 (10 mg). The mixture was stirred under H2 (1 atm) at room temperature overnight. The catalyst was filtered off and the solvent was removed. The residue was subject to column chromatography, eluted by DCM/MeOH (20:1) to afford 4-(5,6,7,8-Tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.15 g, 62%). 1H NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 5.92 (s, 1H), 3.50 (m, 4H), 3.40 (m, 2H), 3.25 (m, 4H), 2.55 (m, 2H), 1.85 (m, 2H), 1.48 (s, 9H). MS (APCI+) [M+H]+320.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1.CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Reactant: Cc1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc(CCCN[C@H]2CC[C@@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Reaction time: 48 h
Yield: 9.8 %

Procedure:
A mixture of cis and trans 4-(4-benzyloxy-phenyl)-cyclohexyl-amine (preparation see under example 43a, 1.25 g, 4.44 mmol), K2CO3 (1.23 g, 8.88 mmol), 1-(3-Bromo-propyl)-4-methyl-benzene (1.18 g, 4.44 mmol) and 2-butanone was stirred at 80° for 48 h. Water was then added and the products were extracted with EtOAc. The organic layer was dried (Na2SO4), evaporated and the residue was purified by chromatography (SiO2, CH2Cl2—MeOH—aq. NH3 140:10:1) to give cis-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-p-tolyl-propyl)-amine (180 mg; 10 %) as a light yellow solid (MS: m/e=414.4 (M+H+))and trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-p-tolyl-propyl)-amine (38 mg; 2%) as a light yellow solid (MS: m/e=414.4 (M+H+)).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([C:15]3[NH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:20].CC(C)([O-])C.[Li+].F[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[CH:30][N:29]=1>CN(C)C=O.C1COCC1>[CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([C:15]3[CH:16]=[CH:17][N:18]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][O:39]5)=[CH:30][N:29]=4)[N:19]=3)[CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:20]
Reactant: COCn1c(=O)sc2cc(C(C)c3ccn[nH]3)ccc21
Reactant: Fc1ccc(OCCOC2CCCCO2)cn1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCn1c(=O)sc2cc(C(C)c3ccn(-c4ccc(OCCOC5CCCCO5)cn4)n3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
Dissolve 3-(methoxymethyl)-6-[1-(1H-pyrazol-5-yl)ethyl]-3H-1,3-benzothiazol-2-one (7.7 g, 26.6 mmoles) in dimethylformamide (0.2 M; 133 mL). Add lithium t-butoxide ((1.5 Eq of a 1.00 molar solution in THF), 39.9 mmoles; 39.9 mL)) and stir 15 min. Add 2-fluoro-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (2.00 Eq; 53.2 mmoles; 12.8 g). Heat the reaction in an oil bath to 140° C. and purge with N2 to remove THF. Heat the mixture at reflux for 5 hr. Cool the mixture to room temperature and quench with saturated ammonium chloride. Extract into EtOAc (2×200 mL), wash with water (2×100 mL), followed by brine (200 mL). Dry over sodium sulfate, filter and concentrate. Purify by HPLC (silica) eluting with 40% EtOAc/hexanes to give 3-(methoxymethyl)-6-{1-[1-(5-{2-(tetrahydro-2H-pyran-2-yloxy)ethoxy}pyridine-2-yl)-1H-pyrazol-3-yl]ethyl}-3H-1,3-benzothiazol-2-one as a pale yellow oil (10 g; 19.6 mmoles, 74% yield). LCMS (low) rt=2.6, M+1=511.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.[CH2:13]([O:15][CH:16]([O:19][CH2:20]C)[CH2:17][NH2:18])C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH3:13][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:18][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: CCOC(CN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(CNCc1nc2ccccc2n1C)OC
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A solution of 1-methyl-2-formylbenzimidazole (1 g) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 equivalent) and NaCNBH3 (0.85 g, 2 equivalents) at 25° C., stirred for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with saturated NaHCO3 and brine, and concentrated. The residue was purified by eluting with 8% methanol/dichloromethane to give 1.2 g (64%) of the title compound.
Reaction SMILES: [C:1]([CH:4]([CH2:17][C:18]#[C:19][C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt]>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][C:20]1([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C(CC#CC1(O)CCCCC1)CCCc1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(=O)C(CCCc1ccc(C(=O)O)cc1)CCCC1(O)CCCCC1

Procedure:
4-[4-Acetyl-7-(1-hydroxycyclohexyl)-6-heptyn-1-yl]benzoic acid (5.1 g., 0.014 mole) in ethyl acetate (55 ml.) is hydrogenated over 2.0 g. of a 5% Pt on charcoal catalyst at 1 atmosphere pressure and room temperature. The theoretical amount of hydrogen (0.028 mole) is absorbed in 25 minutes. The catalyst is filtered off, the solvent is evaporated and the residue (5 g.) is chromatographed on 75 g. of silica gel with 2% methanol in chloroform as eluant. The title compound is obtained as a colorless viscous oil.
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>CN(C=O)C.O>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[C:9]([Br:35])=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of 506 mg of 19d in 4 ml of DMF was treated with 210 mg of NBS. The reaction was stirred for 45 min, then diluted with water, and stirred for an additional 15 min. The white precipitate was filtered and dried, to provide 543 mg of dibromide 25a.