Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].[CH3:31][O:32][C:33]1[C:34](=O)[C:35](=[O:39])[C:36]=1[O:37]C.CCN(C(C)C)C(C)C>CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:34]2[C:35](=[O:39])[C:36](=[O:37])[C:33]=2[O:32][CH3:31])[CH2:4]1)[CH3:2]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C[C@H](Nc2c(OC)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 71.5 %

Procedure:
To a solution of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.40 g, 0.942 mmol, Example #8 Step M) in MeOH (3 mL) was added 3,4-dimethoxycyclobut-3-ene-1,2-dione (0.14 g, 0.98 mmol) and DIEA (0.18 mL, 1.0 mmol). The reaction was stirred at rt for about 16.5 h. Then the solid from the reaction mixture was collected via vacuum filtration, while washing with cold MeOH (about 4° C., 10 mL), and dried in a vacuum oven at about 60° C. to give crude 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione (0.36 g, 73%, 90% purity): LC/MS (Table 1, Method a) Rt=2.13 min; MS m/z: 535 (M+H)+.
Reaction SMILES: [CH2:1]=O.[N:3]1([C:9]([S:11][CH3:12])=[S:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>C(O)C>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][C:17]=1[CH2:1][N:6]1[CH2:7][CH2:8][N:3]([C:9]([S:11][CH3:12])=[S:10])[CH2:4][CH2:5]1
Reactant: CSC(=S)N1CCNCC1
Reactant: C=O
Reactant: COc1ccc(O)cc1
Solvent: CCO
Product: COc1ccc(O)c(CN2CCN(C(=S)SC)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To 20 ml of ethanol was 1.05 g of 37% formalin, and to the mixture was added under chilling with ice 2.29 g of methyl 1-piperazinecarbodithioate.The mixture was then stirred for 30 min. at room temperature, and, after addition of 1.24 g of 4-methoxyphenol, refluxed overnight under heating. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained oil was crystallized from 10 ml of ethanol. The crystals were collected by filtration and subsequently washed with ethanol to give 1.06 g of the desired compound as white crystals, m.p. 112° C., yield 34%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[I:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Cl>C1COCC1>[I:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:28])[CH:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CC(=O)c2ccc(I)cc2)cc1
Reactant: COc1cccc(CCl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(Cc2cccc(OC)c2)C(=O)c2ccc(I)cc2)cc1
Reaction time: 3.5 h
Yield: 82.9 %

Procedure:
Potassium bis(trimethylsilyl)amide (2.5 g, 12.5 mmol) was added to a solution of 1-(4-iodophenyl)-2-(4-methoxyphenyl)ethanone (4.225 g, 12.00 mmol) and THF (60 mL) at rt under N2. After 3.5 h, 3-methoxybenzyl chloride (2.2 mL, 15 mmol) was added. After 2.5 days, the reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (150 mL). The ethyl acetate extract was dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (99:1→4:1; hexanes:ethyl acetate) to give 4.7 g of 1-(4-iodophenyl)-3-(3-methoxyphenyl)-2-(4-methoxyphenyl)propan-1-one as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.76 (d, 2H), 7.20 (d, 2H), 7.09 (t, 1H), 6.81 (d, 2H), 6.76-6.65 (m, 3H), 5.13 (t, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.35 (dd, 1H), 2.93 (dd, 1H).
Reaction SMILES: [N:1]1([CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[S:13][C:14]4[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:19]=4[N:20]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.N1CCC(N2CC[O:37][CH2:36]C2)CC1>>[Cl:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:19]2[N:20]=[C:12]([CH2:11][N:8]3[CH2:9][CH2:10][CH:5]([N:1]4[CH2:4][CH2:3][O:37][CH2:36][CH2:2]4)[CH2:6][CH2:7]3)[S:13][C:14]=2[N:15]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCOCC4)CC3)sc2n1

Procedure:
Prepared according to the method used in the preparation of 2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine using 4-piperidin-4-ylmorpholine in place of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (104 mg, 67%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].O>CS(C)=O.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][C:1]#[N:2])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
0.22 g of dibenzo-18-crown-6-ether and 1.57 g of sodium cyanide were suspended in 20 ml of DMSO, and 5.00 g of 4-tert-butylbenzyl bromide was dropwise added thereto with cooling with water. After having been stirred overnight at room temperature, the resulting mixture was further stirred at 50° C. for 5 hours. After this was left to be at room temperature, water was added thereto and extracted with ether. The organic layer was washed with water, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 1.19 g of 4-tert-butylphenylacetonitrile was obtained from the fraction eluted with n-hexane:ethyl acetate=5:1.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[N:11]1([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: C1CNC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=Cc1c(Cl)ncnc1N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloropyrimidine-5-carbaldehyde (1.00 g, 5.65 mmol) in chloroform at 0° C. were added azetidine (99%, 0.392 mL, 5.71 mmol) and triethylamine (5 drops). The reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. The reaction mixture was filtered, and the filtrate was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to provide the product. Yield: 880 mg, 4.45 mmol, 79%. LCMS m/z 198.1, 200.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.34-2.43 (m, 2H), 4.12-4.33 (br m, 4H), 8.30 (s, 1H), 10.28 (s, 1H).
Reaction SMILES: [Cl-].[NH4+].[B-](F)(F)(F)F.CCOC(C(C#N)=[N:14]OC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63]([OH:65])=O)[N:52]=3)=[O:50])[CH:41]=2)[N:36]=1>CN(C=O)C>[CH3:34][C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63]([NH2:14])=[O:65])[N:52]=3)=[O:50])[CH:41]=2)[N:36]=1
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(N)=O)c4)c4ccccn34)cc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
0.107 g (2 mmol) of ammonium chloride, 0.328 g (1 mmol) of TOTU and 0.517 g (4 mmol) of N,N-diisopropylethylamine are added, at ambient temperature under an inert atmosphere, to 0.233 g (0.5 mol) of 3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 30 ml of DMF. The reaction medium is stirred for 5 hours at ambient temperature and then concentrated under reduced pressure. 50 ml of a saturated solution of sodium hydrogen carbonate are added to the residue. The precipitate obtained is filtered off, and then dried under reduced pressure at 50° C. overnight. 0.230 g of a yellow solid is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.ClCCl.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>C(N(CC)CC)C>[CH3:21][Si:22]([CH3:24])([CH3:23])[O:1][CH2:2][C:3]1([CH2:16][O:17][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: C[Si](C)(C)Cl
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCC1(CO[Si](C)(C)C)c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 88 %

Procedure:
1 g of 9,9-bis(hydroxymethyl)-fluorene was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, and 1.9 ml of triethyl amine was added thereto. Then 1.4 ml of trimethylsilyl chloride was added drop-wise, and the mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.41 g of concentrate (yield 88%). The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound. MS (El) m/e: 370(M+).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[CH3:32][O:33][N:34]=[C:35]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[CH2:36][CH2:37][CH2:38]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:46][C:43]1[CH:42]=[CH:41][C:40]([C:35](=[N:34][O:33][CH3:32])[CH2:36][CH2:37][CH2:38][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:45][CH:44]=1
Reactant: CON=C(CCCI)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(CCCN1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OC(C)(C)C)c1)CN2c1ccccc1)c1ccc(F)cc1
Yield: 76.8 %

Procedure:
tert-Butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 1-(4-fluorophenyl)-4-iodobutan-1-one O-methyl oxime (0.19 g, 0.593 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.28 g, 78%); MS for C36H43FN4O4 m/z 615 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:33](=[O:41])[C:32]=1[C:42]#[N:43]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:38]1([CH2:37][N:34]2[CH:35]=[CH:36][C:31]([C:6]3[CH:5]=[CH:4][C:3]([NH:17][CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[C:2]([F:1])[CH:7]=3)=[C:32]([C:42]#[N:43])[C:33]2=[O:41])[CH2:39][CH2:40]1
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)c(F)c2)OC1(C)C
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(NC3CCOCC3)c(F)c2)ccn(CC2CC2)c1=O
Yield: 28.4 %

Procedure:
To a solution of intermediate 15 (0.8 g, 2.55 mmol) in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml) was added intermediate 8 (0.58 g, 2.31 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.26 mg, 0.23 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 1 (0.241 g, 30%).
Reaction SMILES: C(#N)C.[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1.[C:10]([O:18]OC(C)(C)C)(=[O:17])[C:11]1C=CC=CC=1>[Cu+2].[Cu].C(O)(=O)C>[C:10]([O:18][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:17])[CH3:11]
Reactant: C1=CCCCC1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Cu+2]
Agent: [Cu]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)OC1C=CCCC1
Reaction time: 3 h

Procedure:
A mixture of 0.6 g of di-L-prolinato Copper (II), 0.7 g of copper powder, 15 ml of acetonitrile, 5 ml of acetic acid, 15 ml of cyclohexene and 5 ml of t-butyl peroxybenzoate was stirred at 20° to 25° C for 3 hours in a nitrogen atmosphere. After it was confirmed on TLC (thin layer chromatography) that the residual t-butyl peroxybenzoate was no longer present, the remaining copper powder was filtered off and the filtrate was admixed with 50 ml of benzene. The organic layer was successively washed with a 2N hydrochloric acid, an aqueous solution saturated with sodium chloride, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. After removing the solvent, the residue was distilled under reduced pressure to obtain 1.40 g of 2-cyclohexenyl acetate. B.P. 75°-76° C/21 mmHg.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[O:7]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.[OH-].C[N+](C)(C)CC1C=CC=CC=1>O1CCCC1.C(Cl)Cl>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=1)=[O:5]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CSC(=Cc1cccc(Oc2ccccc2)c1)S(C)=O
Yield: 61.2 %

Procedure:
FAMSO (1.27 g) and 2.00 g of m-phenoxybenzaldehyde were dissolved in 10 ml of tetrahydrofuran, and 1 ml of a 40% methanol solution of trimethylbenzylammonium hydroxide was added. The mixture was heated under reflux for 26 hours. Methylene chloride (50 ml) was added, and the reaction mixture was washed with 3N dilute sulfuric acid. The product was dried over anhydrous potassium carbonate, concentrated under reduced pressure, and chromatographed on a silica gel column using methylene chloride as an eluant to afford 1.88 g of 1-methylsulfinyl-1-methylthio-2-(m-phenoxyphenyl)ethylene as a colorless oily substance.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:14])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CCC(C(=O)O)CC1
Solvent: ClCCl
Product: O=C1CCC(C(=O)Cl)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-oxo-cyclohexanecarboxylic acid (commercially available) (115 mg, 0.81 mmol) in CH2Cl2 (3 ml) was added oxalyl chloride (205 mg, 1.61 mmol). The reaction mixture was stirred at RT over night, and then concentrated under vacuo. The product was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(OC)(C)(C)C>[OH:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)=[O:6]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1c(O)cc(O)c(C)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: Cc1c(O)cc(O)c(C)c1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
To a solution of 91.1 g of 3,5-dihydroxy-2,6 -dimethylbenzoic acid and 108.0 g of p-nitrobenzyl bromide were added 165.9 g of potassium carbonate. The mixture was heated at reflux under stirring for 4 hours. After cooling to room temperature, the mixture was filtered, and the unsoluble material was washed with 0.5 l of ethyl acetate. The filtrate was diluted with 0.5 l of ethyl acetate and washed with ice-cold 3N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. To the remaining, crystallizing oil were added 0.6 1 of tert-butylmethylether, and the suspension was stirred for 1 hour. Unsoluble material was filtered off and the filtrate was evaporated in vacuo. The remaining oil was dissolved in 300 ml of methylene chloride. Upon crystallization, 200 ml of hexane were added and the crystals isolated by filtration. This material was suspended once more in 400 ml of tert-butylmethylether and the unsoluble material was removed by filtration. Evaporation of the filtrate in vacuo and crystallization of the residue from methylene chloride/hexane afforded 98.8 g of p-nitrobenzyl 3,5-dihydroxy-2,6-dimethylbenzoate as yellow crystals of m.p. 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:19]=[N:20][C:21](F)=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:14]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:19]=[N:20][C:21]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:14]=1
Reactant: C1COCCN1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccc(F)nc3)cnc12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccc(N4CCOCC4)nc3)cnc12
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
A mixture of 6-(2,4-dichloro-phenyl)-3-(6-fluoro-pyridin-3-yl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (64 mg, 0.14 mmol) and morpholine (0.06 mL, 0.70 mmol) in DMSO (1 mL) was heated at 180° C. and stirred for 30 min. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2×10 ml). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to yield the crude 6-(2,4-dichloro-phenyl)-8-isobutoxy-3-(6-morpholin-4-yl-pyridin-3-yl)-imidazo[1,2-a]pyridine-7-carbonitrile intermediate (67.8 mg) as a brown solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[N:11]=1>CN(C=O)C>[Br:1][C:13]1[CH:14]=[CH:15][C:10]([NH2:9])=[N:11][C:12]=1[Cl:16]
Reactant: Nc1cccc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
N-bromosuccinimide (16.45 g; 92.41 mmol; 1.10 eq.) was added portionwise to a solution of 2-amino-6-chloropyridine (10.80 g; 84.01 mmol; 1.0 eq.) in DMF (200 mL) at rt. The reaction mixture was stirred at rt for 2 hours. Solvents were removed under reduced pressure and the residue was taken up in EtOAc and aqueous ammonia. The organic phase was washed again with aqueous ammonia and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The black solid obtained was washed with pentane and dried under vacuum to give the title compound as a beige powder (12.5 g, 72%). HPLC, Rt: 2.81 min. (purity 95.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]=[CH:6][C:5]3=[O:12])=[O:22])=[CH:16][CH:15]=1
Reactant: Nc1ccc2occc(=O)c2c1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc2occc(=O)c2c1
Yield: 99.1 %

Procedure:
To a stirred and heated (80° C.) slurry of 6-aminochromone (3.0 g, 18.6 mmol) in toluene (200 mL) was added 4-chlorophenyl isocyanate (3.2 g, 20.5 mmol) and the mixture was refluxed further for 18 hours. The reaction mixture was cooled and the precipitate was filtered and washed with methanol. The residue was dried in vacuo to afford 1-(4-chloro-phenyl)-3-(4-oxo-4H-chromen-6-yl)-urea (5.8 g, 99%) as a yellow powder. LCMS m/z (%)=315 (M+H35Cl, 100), 317 (M+H37Cl, 32.2) 1H NMR (400 MHz, DMSO-d6) δ: 9.09 (bs, 1H), 8.94 (bs, 1H), 8.29 (d, J=5.99 Hz, 1H), 8.20 (d, J=2.69 Hz, 1H), 7.81 (dd, J=9.0, 2.75 Hz, 1H), 7.62 (d, J=9.07 Hz, 1H), 7.52 (dd, J=6.84, 2.16 Hz, 2H), 7.35 (dd, J=6.85, 2.11 Hz, 2H), 6.33 (d, J=5.98 Hz, 1H).
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (100 mg, 0.22 mmol) and propionic acid (17 mg, 0.23 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (31 mg, 35%), MS (ISP) m/z=401.3 [(M+H)+].