Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:22])([CH3:21])[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:20])=[O:29])=[CH:26][CH:25]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(F)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(F)cc1)C(C)(C)O2
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 140-142° C. (Ethyl acetate-hexane)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([F:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[Na+].[I-:12].C(Cl)(=O)C>C(#N)C>[F:10][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([I:12])[CH:7]=1)[CH3:9]
Reactant: CC(F)c1ccnc(Cl)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: CC(F)c1ccnc(I)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-(1-fluoroethyl)pyridine (70 g, 439 mmol, 1.00 equiv), NaI (661 g, 4.41 mol, 10.00 equiv), ACN (700 mL) and acetyl chloride (56 g, 713 mmol, 1.60 equiv) were combined in a 2000-mL 4-necked round-bottom flask. The resulting solution was stirred overnight at 80° C. in an oil bath and then cooled to r.t, diluted with ice aqueous saturated sodium carbonate (500 mL) and extracted with dichloromethane (3×500 mL). The combined organic layer was washed with NaS2O3 (10%, 3×300 mL) and the aqueous phase was extracted with dichloromethane (2×200 mL). The combined organic layer was washed with brine (2×500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel column (1:10 ethyl acetate/petroleum ether) to afford 4-(1-fluoroethyl)-2-iodopyridine as yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13]S(O)(=O)=O.O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH:10]([O:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CN(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Temperature: 0 °C
Yield: 77 %

Procedure:
To an ice-cooled solution of 1-benzyl pyrroline (0.01 mol), 98% H2SO4 (0.012 mol), water (1.5 g), and acetone (10 mL) in a round bottom flask was added 77% m-CPBA (0.013 mol) with stirring, and allowed to react for about 50 h at room temperature. After completion of the reaction (TLC monitor), acetone was evaporated under reduced pressure, and the mixture was neutralized by 1M NaOH, and extracted with toluene (30 mL×3). The precipitates that appeared were filtered, and the filtrate was repeatedly washed with water (30 mL×2). After the solvent was evaporated under reduced pressure, pure product was obtained in 77% yield via column chromatography (silica gel, CH2Cl2:EtOAc:MeOH, 7.5:2.00:0.5).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([O:9][CH2:10][C:11]1[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH:26]([F:28])[F:27])=[N:13][O:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[CH2:2]2.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34]>>[CH:16]1([C:15]2[O:14][N:13]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH:26]([F:27])[F:28])[C:11]=2[CH2:10][O:9][CH:3]2[CH2:2][CH:1]3[N:8]([C:37]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=4[F:29])[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH2:17][CH2:18]1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: FC(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Product: N#Cc1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)F)noc2C2CC2)C3)c(F)c1

Procedure:
4-(3-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzonitrile (26-A) was prepared from 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole and 3,4-difluorobenzonitrile according to the procedure described for the preparation of example 23.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: S=C=NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCc1ccccc1)Nc1nccs1
Temperature: 25 °C
Yield: 46.1 %

Procedure:
A solution of benzyl isothiocyanate (1.5 g, 10 mmol) and 2-aminothiazole (1.0 g, 10 mmol) in N,N-dimethyl-formamide (25 mL) was heated at 100° C. for 12 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 1.15 g (46%) of the title product:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][CH:19]\2O)=[CH:11][N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([OH:43])(=[S:42])[CH3:41].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.O>C1(C)C=CC=CC=1>[C:40]([S:42][CH:19]1[CH2:18][CH2:17][N:16]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:15]/[C:14]/1=[CH:13]\[C:12]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=[N:10][CH:11]=1)(=[O:43])[CH3:41]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)n1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cncn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{[1-(t-butoxycarbonyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (6.00 g) in toluene (100 ml) were added successively thioacetic acid (1.64 ml) and N,N-dimethylformamide dineopentyl acetal (6.40 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane and dichloromethane (1:3:1) as the eluent to afford (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (including impurities) as a yellow amorphous solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:18]=[C:17]2[C:8]([CH2:9][C:10]3([C:16]2=[O:19])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH2:21].C([O-])(=O)C.[Na+].O>CO>[N+:2]([C:5]1[CH:18]=[C:17]2[C:8]([CH2:9][C:10]3([C:16]2=[O:19])[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:12][CH2:11]3)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CC12CCNCC2
Reactant: C=Cc1ccccn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1c2cc([N+](=O)[O-])ccc2CC12CCN(CCc1ccccn1)CC2
Yield: 66 %

Procedure:
A solution of 0.150 g (0.53 mmole) 1,3-dihydro-6-nitro-1-oxospiro[2H-indene-2,4'-piperidine] hydrochloride, 0.116 g (1.1 mmoles) 2-vinylpyridine, and 0.090 g (1.1 mmoles) sodium acetate in 1.5 ml of 1:1 methanol: water was heated at reflux for 8 hours. Ethanol was removed in vacuo. The aqueous residue was diluted with 3 ml saturated sodium bicarbonate solution and extracted with 2×10 ml ethyl acetate. The combined extracts were washed with 3 ml water brine, dried, and the solvent was removed in vacuo to give 0.195 g crude product. This was recrystallized from ethyl acetate to give 0.123 g (66%) product, m.p. 142°-144° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CCN=C=NCCCN(C)C.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:15](=[O:17])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:19][CH2:18][C:5]1=2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: CCN=C=NCCCN(C)C
Product: Cc1ccc2c(c1)c1c(n2CC(=O)NCc2ccccc2)CCN(C)C1
Reaction time: 16 h

Procedure:
2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (CD58) was mixed with EDCI and benzylamine and the reaction mixture was stirred for 16 h to obtain N-benzyl-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([O:48]CC4C=CC=CC=4)=[C:43]([CH3:56])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:57]=[CH:58][CH:59]=[CH:60][C:4]=2[NH:3]1.[H][H]>CCO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([CH3:56])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:57]=[CH:58][CH:59]=[CH:60][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
340 mg (0.41 mmol) (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-ethoxycarbonyl methoxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 20 mL EtOH were combined with 100 mg 10% Pd/C and hydrogenated at 50° C. and 50 psi hydrogen for 2 h. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i.vac.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[CH3:8][C@@H:9]1[N:12]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)[C:11](=[O:18])[C@H:10]1[NH:19][C:20](=[O:59])/[C:21](/[C:34]1[N:35]=[C:36]([NH:39]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:37][CH:38]=1)=[N:22]\[O:23][C:24](C(C)(C)C)([CH2:26]C(O)=O)[CH3:25].ClCCl>C1(C)C=CC=CC=1>[CH3:8][C@@H:9]1[N:12]([C:13]2[NH:14][N:15]=[N:16][N:17]=2)[C:11](=[O:18])[C@H:10]1[NH:19][C:20](=[O:59])/[C:21](/[C:34]1[N:35]=[C:36]([NH2:39])[S:37][CH:38]=1)=[N:22]\[O:23][C:24]([C:3]([OH:5])=[O:4])([CH3:25])[CH3:26]
Reactant: C[C@H]1[C@H](NC(=O)/C(=N\OC(C)(CC(=O)O)C(C)(C)C)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)N1c1nnn[nH]1
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1c1nnn[nH]1
Reaction time: 1 h
Yield: 16 %

Procedure:
Trifluoroacetic acid (0.50 ml) was added to a -15° solution of 39 (0.047 g, 0.065 mmol) and 0.5 ml dichloromethane. After one hour, the solution was warmed to 23° and stirred for an additional hour before 2 ml toluene was added and volatiles were removed under a stream of nitrogen. Dilution with 10 ml water and washing with 20 ml of 1:1, ethyl acetate: diethyl ether was followed by evaporation under vacuum and chromatography by reverse phase preparative TLC (10% ethanol in water). Elution of a band of Rf 0.9 with 80% acetonitrile in water gave 0.0043 g (16%) 40 as a white solid after lyophilization:
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOC)(=O)C.[C:13]([O:16][C@:17]1([C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[C:27](=[CH:28][C:29](=[O:39])[CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)[C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]>C(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O>[C:13]([O:16][C@:17]1([C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[C:27](=[CH:28][C:29](=[O:39])[CH2:30][CH2:31]2)[C:26]([CH3:1])=[CH:25]3)[CH2:22][CH2:21]1)[C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: COCOC(C)=O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 70 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A suspension of 0.5 g of sodium acetate in 60 ml of anhydrous chloroform and 2 ml of distilled phosphorus oxychloride is refluxed under agitation for 30 minutes at a bath temperature of 70° C. After adding 15 ml of methoxymethyl acetate and 2.0 g of 17α-acetoxy-4-pregnene-3,20-dione, the reaction solution is further stirred for 5 hours at 70° C. Subsequently such an amount of a saturated soda solution is added dropwise at room temperature that the aqueous phase remains alkaline. The organic phase is separated, washed with water, and dried over sodium sulfate. After concentration, the crude product is purified on 100 g of silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 1.26 g of 17α-acetoxy-6-methyl-4,6-pregnadiene-3,20-dione, mp 217°-219° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].Cl.[OH-].[Na+]>COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc(N2CCOCC2)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(N3CCOCC3)cc2OC)ncc1Cl
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a suspension of 2-(2,5-dichloro-pyrimidin-4-yl-amino)-N-methyl-benzamide (5.05 g, 17.0 mmol) in 90 mL of 2-methoxyethanol are added 2-methoxy-4-morpholinoaniline dihydrochloride (4.56 g, 16.2 mmol) and 17.0 mL of 1N ethanolic solution of hydrogen chloride (17.0 mmol). After the reaction mixture is stirred at 110° C. for 4 hours and cooled to room temperature, the mixture is neutralized with 1N aqueous NaOH solution and extracted with EtOAc (100 mL×3). The organic layer is washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting black solid is washed with EtOH (90 mL), then purified with silica gel column chromatography (CH2Cl2 to CH2Cl2:AcOEt=1:2) to give 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a pale yellow solid.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][S:6][CH2:5][CH2:4]2)[CH2:2]1.[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=2)=[C:12]([CH3:25])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][C:3]1([CH2:2][O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=3)=[C:12]([CH3:25])[CH:11]=2)[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: C1CC2(CCS1)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(C=O)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
To a solution of 1-oxa-6-thiaspiro[2.5]octane (6.33 g, 48.6 mmol) and 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (10.0 g, 44.2 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (6.11 g, 44.2 mmol) at room temperature, and the mixture was stirred at 100° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (12.3 g, yield 78%) as colorless crystals.
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].C(O)(=O)C.[N:12]#[C:13][NH2:14]>CO>[O:5]=[C:4]([CH2:3][N:1]([C:13](=[NH:12])[NH2:14])[CH3:2])[OH:6]
Reactant: N#CN
Reactant: CNCC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(=O)O)C(=N)N
Temperature: 15 °C

Procedure:
674.5 g (2.43 moles) of 40% by weight aqueous sodium sarcosinate solution were taken and a pH value of 8.5 adjusted at 70° C. with 99% by weight acetic acid. After the addition of 500 ml methanol, 491.1 g (2.92 moles) of a 25% by weight aqueous cyanamide solution were added thereto with vigorous stirring at reflux temperature in the course of 2 hours. After ending of the addition of the cyanamide solution, the reaction mixture was further stirred for 2 hours under reflux while stirring. After cooling to 15° C., the crystalline precipitate was filtered off with suction, washed twice with, in each case, 250 ml of water and subsequently recrystallised from water. After drying in a vacuum drying cabinet at 80° C. and 15 mbar pressure, there were obtained 176.7 g (48.8% by weight) of anhydrous creatine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-(2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].CC(C)=O.[OH:9][N:10]=[C:11]([CH3:26])[CH2:12][N:13]([S:22]([CH3:25])(=[O:24])=[O:23])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21]>C(N(CC)CC)C>[CH3:1][NH:2][C:3]([O:9][N:10]=[C:11]([CH3:26])[CH2:12][N:13]([S:22]([CH3:25])(=[O:24])=[O:23])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:4]
Reactant: CC(CN(c1c(C)cccc1C)S(C)(=O)=O)=NO
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)ON=C(C)CN(c1c(C)cccc1C)S(C)(=O)=O
Reaction time: 8 h

Procedure:
Methyl isocyanate (1.2 ml) was added to an acetone solution of N-[2-hydroxyiminopropyl]-2',6'-dimethylmethanesulphonanilide (2.7 g) containing triethylamine (0.05 ml). The mixture was allowed to stand at room temperature overnight, then evaporated to a viscous oil which slowly solidified on standing. Recrystallisation from ethylacetate/60°-80° petrol gave colourless crystals of N-[2-(methylcarbamoyloxyimino)propyl]-2',6'-dimethylmethanesulphonanilide. Yield 3.0 g (91%). Melting point 130°-134°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=12
Reactant: Ic1ccnc2cn[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2nccc(I)c21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
7-Iodo-1H-pyrazolo[4,3-b]pyridine (1.5 g, 6.12 mmol) was dissolved in dry DMF (51.0 mL), cooled to 0° C. and NaH (0.245 g, 60% in oil, 6.12 mmol) was added. After 15 minutes and (2-(chloromethoxy)ethyl)trimethylsilane (1.080 mL, 6.12 mmol) was added and the mixture was warmed to room temperature over 2 hours then poured into ice water (350 mL) to give a solid which was filtered off. The filtrate was combined with dichloromethane and evaporated onto silica gel. Silica gel chromatography eluted with 0-5% MeOH in DCM gave 7-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([NH:13][CH2:12][CH:9]1[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CNCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of benzaldehyde (3 mL, 29.55 mmol), cyclopropanemethylamine (2.53 mL, 29.55 mmol), AcOH (1.7 mL, 29.55 mmol) in 1,2-dichloroethane (150 mL) is stirred at RT for 25 minutes. Sodium triacetoxyborohydride (8.8 g, 41.37 mmol) is added and the mixture further stirred overnight at RT. Sodium triacetoxyborohydride (3.13 g, 15 mmol) is again added to complete the reaction. The mixture is quenched by the addition of NaOH 1N (50 mL), the layers are separated and the aqueous phase is extracted twice with ether. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 95:5 to 80:20+5% NH3) to give the title product. tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.91 min.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:19])[CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.CO.O>CO>[C:9]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][C:5]([OH:19])=[O:4])[CH:8]=1
Reactant: COC(=O)Cc1cccc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.5 mL of a 2 M LiOH solution in methanol was added to a solution of compound 91B in 3:1 MeOH/H2O solution. The reaction was stirred at room temperature for 20 hours. The mixture was concentrated under vacuum and the residue dissolved in water. 10% HCl was then added leading to a white precipitate. The solids were collected, washed thoroughly with water and dried (125 mg, 95%). NMR 1H (ppm, MeOD): 7.58 (d., J3=7.26 Hz, 2H), 7.52-7.47 (m, 2H), 7.43-7.37 (m, 3H), 7.34-7.24 (m, 2H), 3.66 (s, 2H). MS (−ESI): M−H+: 211.