Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)ccn1
Temperature: 80 °C
Yield: 44.3 %

Procedure:
6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (2.465 g, 4.72 mmol), 2-methylpyridine-4-boronic acid (0.966 g, 7.05 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.579 g, 0.709 mmol) and K2CO3 (1.959 g, 14.17 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL)/H2O (2.5 mL). The reaction mixture was degassed for 5 min, heated to 80° C. overnight, cooled to RT and diluted with EtOAc. Reaction was filtered through Celite and then partitioned between EtOAc and saturated NaHCO3. The organic layer was extracted with EtOAc (3×) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel over a gradient of 0-75% EtOAc in hexanes to yield 6-chloro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.02 g, 2.09 mmol, 44%) as a solid. MS ESI calc'd. for C31H24ClN4 [M+1]+487, found 487.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[S:46]([N:50]=[C:51](OC1C=CC=CC=1)OC1C=CC=CC=1)(=[O:49])(=[O:48])[NH2:47].O>ClCCl>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:51]([NH:50][S:46](=[O:49])(=[O:48])[NH2:47])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: NS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(NS(N)(=O)=O)nc12
Yield: 21.7 %

Procedure:
A mixture of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (150 mg) and diphenyl N-sulfamoylcarbonimidate (85 mg) in dichloromethane (8 ml) was refluxed for 24 hours under nitrogen. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water, driver over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1/chloroform:methanol=6:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(2-sulfamoylamino-1H-benzimidazol-4-yl)carbonylaminobenzamide (38 mg).
Reaction SMILES: [ClH:1].[CH:2]([CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:7]=1[F:16])O)=[CH2:3]>O1CCOCC1>[Cl:1][CH2:3][CH:2]=[CH:4][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:7]=1[F:16]
Reactant: Cl
Reactant: C=CC(O)c1cccc(C(F)(F)F)c1F
Solvent: C1COCCO1
Product: Fc1c(C=CCCl)cccc1C(F)(F)F

Procedure:
334 ml of concentrated HCl are added over 10 minutes to a solution of 404.5 g (1.84 mol) of α-ethenyl-2-fluoro-3-(trifluoromethyl)benzenemethanol (prepared according to Example I1) in 3.7 1 of dioxane and the mixture is then heated for 2 h at reflux. 83.5 ml of concentrated HCl are added and the mixture is heated for a further 2 h at reflux.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:13]=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 956 %

Procedure:
To a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.250 g, 0.104 mmol) in DMSO (3.0 mL) was added sodium azide (0.101 g, 0.156 mmol). The reaction mixture was stirred at RT for 3-4 h. The reaction mixture was quenched in water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.200 g of the desired product. 1HNMR (DMSO-d6): δ 4.63 (s, 2H), 7.60 (d, J=7.8 Hz, 1H), 7.70-7.80 (m, 3H).
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH:10][CH2:11][CH2:12][Cl:13])=[O:9])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(O)C.[N:17]([O-])=[O:18].[Na+]>Cl.O>[CH2:1]([NH:7][C:8]([N:10]([CH2:11][CH2:12][Cl:13])[N:17]=[O:18])=[O:9])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: O=N[O-]
Reactant: CC(C)(C)CCNC(=O)NCCCl
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)CCNC(=O)N(CCCl)N=O
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A 2.07 g (10 mmol) quantity of 1-neohexyl-3-(2-chloroethyl) urea was dissolved in 15 ml of concentrated HCl:ethanol, 2:1, at 10° C., and 690 mg (10 mmol) sodium nitrite dissolved in 3 ml of water was added. Stirring at 5° C. continued for 1.5 hrs. and the precipitate was washed with four 25 ml portions of distilled water. After drying in vacuo overnight, 1.7 g (74%) of the product was obtained which melted at 43.0°-43.5° C. (decomposes). IR analysis showed peaks at 1705/cm (C=O) and 1525/cm (C--N=O). NMR: singlet (9H) at 0.9 ppm, multiplet (2H) at 1.3 ppm, symmetrical multiplet (6H) at 3.8 ppm. No evidence of isomeric material was detected.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[NH:13][C:12](=[O:21])[C:11]1=[O:22])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].F[B-](F)(F)F.[O:28]=[N+:29]=[O:30].O>C(Cl)Cl>[CH2:6]([O:5][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:29]([O-:30])=[O:28])=[C:17]([F:20])[CH:18]=2)[NH:13][C:12](=[O:21])[C:11]1=[O:22])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: O=[N+]=O
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2ccc(F)cc21)OCC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
615 mg of (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is mixed in 60 ml of methylene chloride with 743 mg of nitronium tetrafluoroborate. The batch is stirred for 2 hours at room temperature. It is mixed with 50 ml of water and, after separation of the organic phase, it is extracted three times with methylene chloride. The collected organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 350 mg of (6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1)[CH3:3].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[C:9]1([C:4]2([CH:2]([NH:1][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:3])[O:5][CH2:6][CH2:7][O:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: CC(N)C1(c2ccccc2)OCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC(C)C1(c2ccccc2)OCCO1

Procedure:
A solution of 2-(1-aminoethyl)-2-phenyldioxolane (20 mmoles), triethylamine (24 mmoles), and ethyl chloroformate (22 (mmoles) in 100 ml of dichloromethane is stirred at 0°C for 2 hours, washed with water, dried, and evaporated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][CH:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][O:14][C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([F:41])[CH:47]=2)[CH:10]=[C:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Reactant: Oc1cccc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=CC(COc2cccc(F)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (Preparation 42, 500 mg, 1.66 mmol), triphenylphosphine (653 mg, 2.49 mmol) and 3-fluorophenol (0.23 ml, 2.49 mmol) in tetrahydrofuran (30 ml) at 0° C. under a nitrogen atmosphere was added diisopropylazodicarboxylate (0.49 ml, 2.49 mmol) dropwise over 5 minutes and stirred to room temperature over 72 hours. Solvent was removed under reduced pressure and the residue purified by chromatography on silica gel, eluting with 10-15% ethyl acetate/heptane to give the title compound as a mixture of diastereomers (˜5:1 2S,4S:2S,4R) as a colourless oil (370 mg, 51%)
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:28](Cl)(=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>O1CCCC1>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][N:25]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2noc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide (220 mg), benzoyl chloride (70 μL), and triethylamine (250 μL) in tetrahydrofuran (5 mL) is stirred for 30 min at room temperature before heating to 80° C. for 15 h. The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 93:7) to afford the title compound. LC (method 3): tR=2.09 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:17]([CH2:18][S:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4([C:43]([OH:45])=[O:44])[CH2:42][CH2:41]4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[O:15][N:14]=1>C(Cl)Cl>[CH3:12][C:13]1[C:17]([CH2:18][S:19]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:9])=[C:16]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][C:37]([C:40]4([C:43]([OH:45])=[O:44])[CH2:41][CH2:42]4)=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[O:15][N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCCc1ccccc1
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CS(=O)CCc1ccccc1
Reaction time: 0.25 h

Procedure:
m-Chloroperbenzoic acid (0.023 g, 0.11 mmol) was added to a solution of 1-[4′-(3-methyl-4-phenethylsulfanylmethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (0.050 g, 0.11 mmol) in CH2Cl2. After stirring for 15 minutes the mixture was concentrated and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[CH2:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:19][NH2:20]>>[CH2:13]([C:12]1[C:6]2[C:7](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:8](=[O:9])[NH:20][N:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: NN
Reactant: CCCCC(=O)c1ccc(OC)cc1C(=O)O
Solvent: O
Product: CCCCc1n[nH]c(=O)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-pentanoylbenzoic acid with hydrazine hydrate.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=1.C(=O)([O-])O.[Na+]>CC(O)C.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:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=3)[CH:7]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cn1
Temperature: 90 °C

Procedure:
N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 4, 3.2 g), methyl 6-chloronicotinate (1.73 g), tetrakis(triphenylphosphine)palladium (210 mg) and aqueous sodium hydrogen carbonate (1M, 30 ml) were mixed in propan-2-ol (100 ml) and heated at 90° C. for 18 hours. The reaction was allowed to cool and the propan-2-ol removed under vacuum. The residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (1M). The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ethyl acetate (×2). The organic extracts were washed with brine, dried (magnesium sulphate) and reduced to dryness under vacuum. The resulting foam was triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acid as a solid. LCMS: MH+315, retention time 2.87 mins.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.CC(C)([O-:34])C.[K+]>C(O)(C)(C)C.COCCOC>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C:17](=[O:21])[C:18]([OH:34])([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: C[C@H](CCC(=O)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 40 °C

Procedure:
248 mg (0.6 m mol) of 1α,3β-dihydroxy-24-oxo cholesta-5,7-dien and 101 mg (0.9 m mol) of potassium-t-butoxide was dissolved in a mixture of t-butyl alcohol and ethyleneglycol dimethyl ether (1:1 V/V) warming at 40° C., and while cooling the solution with icewater to about 0° C. and stirring violently.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]=[C:31]=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: COc1cc(N=C=O)cc(OC)c1
Product: COc1cc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)cc(OC)c1

Procedure:
59.2 mg of solid beige-coloured 3-{4-[3-(3,5-dimethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3,5-dimethoxyphenyl isocyanate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH2:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH3:16][C:17]#N>CO.[Rh]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH:15][CH2:16][CH3:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(CCN)cc1OCC
Reactant: CC#N
Agent: [Rh]
Solvent: CO
Product: CCNCCc1ccc(OCC)c(OCC)c1
Reaction time: 72 h

Procedure:
To a solution of 0.43 g of 2-(3,4-diethoxy-phenyl)-ethylamine in 3 mL MeOH were added 270 mg of 5 wt % Rh/C and 0.22 mL of MeCN. The reaction mixture was stirred under a H2 atmosphere (balloon) for 3 days and then filtrated over a pad of celite and washed with 100 mL MeOH. Concentration in vacuo afforded 0.4 g of [2-(3,4-diethoxy-phenyl)-ethyl]-ethyl-amine as yellow oil.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)SC)#[N:2].[NH3:25]>C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)=[NH:25])#[N:2]
Reactant: CSC(=NCCSCc1cc2ccc(CN(C)C)cc2o1)NC#N
Reactant: N
Solvent: CCO
Product: CN(C)Cc1ccc2cc(CSCCNC(=N)NC#N)oc2c1

Procedure:
A solution of N-cyano-N'-[2-(6-dimethylaminomethyl)-2-benzofuranylmethylthio)ethyl]-S-methylisothiourea (Example 1, Step F) (6.27 g., 0.0173 mole) and ammonia (12 g.) in ethanol (65 ml.) is heated in a sealed vessel for 36 hours at 55°-60° C. Volatile materials are then removed by distillation at reduced pressure. The residual oil consisting of the nearly pure product is purified by column chromatography on 85 g. of silica gel with elution by a 10% solution of methanol in chloroform affording N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]guanidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccc1C

Procedure:
From 3-methoxy-4-methylbenzoic acid, HATU and N-ethyldiisopropylamine in THP, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+23.0° (c=1.03, CHCl3), ES-MS m/e (%): 415 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([OH:17])=O)=[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH2:26].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN1C(=O)CCC1>[NH2:1][C:2]1[C:14]([C:15]([NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])=[O:17])=[C:5]2[N:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)O
Reactant: COc1ccncc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccncc1NC(=O)c1c(N)nn2ccc(C(F)(F)F)nc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a (100 mg, 0.4063 mmol), 4-methoxypyridin-3-amine (50.44 mg, 0.4063 mmol) and DIPEA (52.51 mg, 70.77 μL, 0.4063 mmol) were dissolved in dry NMP (812.6 μL) in a microwave tube. TBTU (130.5 mg, 0.4063 mmol) was added in one portion and the resulting mixture was stirred at RT for ˜10 minutes and at 100° C. for ˜2 h under microwave conditions. The reaction mixture was allowed to cool to RT and filtered through a SCX-2 cartridge (5 g). The cartridge was washed with MeOH/DCM and eluted with 2M NH3 in MeOH (3×10 mL). The eluate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (7.5% MeOH in DCM, ˜75 mL) to give the desired Compound I-O-1 as a bright yellow solid (87.9 mg, 61% Yield). LC-MS (M+H)+353.1; 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.55 (s, 1H), 9.26 (dd, 1H), 8.24 (dd, 1H), 7.50-7.51 (d, 1H), 7.17-7.18 (d, 1H), 6.99 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[C:25]([CH2:24][CH2:23][CH2:22][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]1[CH3:1])#[N:26]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1CCCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To the stirred solution of tert-butyl 3-methylpiperazine-1-carboxylate (prepared according to procedure reported in US200876758A1, 2008, 5 g, 24.97 mmol) in N,N-dimethylformamide (50 ml) were added potassium carbonate (17.25 g, 125 mmol) and 4-bromobutanenitrile (2.98 ml, 30.0 mmol) at 25° C. The resulting solution was stirred at 25° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction water (100 ml) was added and extracted with dichloromethane (3×60 ml). The combined extract was washed with brine (25 ml) and dried over sodium sulphate, filtered and concentrated to give crude compound. The crude compound was purified by column chromatography over silica gel (100-200) using 15% ethyl acetate in hexane to obtain the title compound (5 g, 75%).