Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([CH:9]([C:20](=O)[CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:25]([C:27]1[N:28]([NH2:32])[CH:29]=[CH:30][CH:31]=1)[CH3:26].C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]2[C:29]3[N:28]([C:27]([CH2:25][CH3:26])=[CH:31][CH:30]=3)[N:32]=[C:20]([CH3:21])[C:9]=2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1cccn1N
Reactant: CCOC(=O)CCCCCC(C(C)=O)C(=O)c1ccc(C#N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCc1c(C)nn2c(CC)ccc2c1-c1ccc(C#N)cc1
Yield: 82 %

Procedure:
A mixture of ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.2 g), 2-ethyl-1H-pyrrol-1-amine (809 mg), and p-toluenesulfonic acid monohydrate (64 mg) in toluene (40 ml) was refluxed for 20 minutes. The mixture was partioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give the product, which was triturated with hexane to give ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo-[1,2-b]pyridazin-3-yl]hexanoate (2.21 g) as an yellow crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[C:12]1(=[O:22])[N:16]([CH2:2][CH2:3][C@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[OH:5])[C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@H](CCCl)c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC[C@@H](O)c1ccccc1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
To a solution of 10.09 g of (R)-(+)-3-chloro-1-phenylpropanol in 80 ml of dimethylformamide were added 13.14 g of potassium phthalimide in 80 ml of dimethylformamide. The mixture was heated at 100° C. for 8 hours, allowed to cool to room temperature, and filtered. The filtrate was diluted with water, and the solution extracted 3 times with ethyl acetate. The combined organic extracts were washed once with water, once with 0.2 N sodium hydroxide, once again with water, and once with a saturated solution of sodium chloride, dried over sodium sulfate, and concentrated in vacuo to provide an opaque oil that solidified. Crystallization from ethyl acetate/hexanes provided 11.09 g of the title intermediate as clear pale yellow needles, m.p. 81°-83° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH2:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:45]=2)[CH2:40][CH2:39]1)=[O:37].C([O-])(O)=O.[Na+]>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.O1CCOCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:43]3[CH:42]=[C:41]4[C:46](=[CH:45][CH:44]=3)[N:38]([C:36](=[O:37])[CH2:35][C:29]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=3[F:27])[CH2:39][CH2:40]4)=[CH:9][N:8]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cc(Br)c3c(N)ncnc32)CC1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
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
Product: CC(C)(C)OC(=O)N1CCC(CCn2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c3c(N)ncnc32)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
To 1,1-dimethylethyl 4-[2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (220 mg, 0.518 mmol) and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (290 mg, 0.726 mmol) in a 5 ml sealable vial was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL). The mixture was then bubbled with N2 for 10 minutes then Pd(Ph3P)4 (59.9 mg, 0.052 mmol) was added and N2 was bubbled for 5 minutes. The mixture was then capped and heated at 100° C. After 4 hours the reaction was complete. The reaction was diluted with water (5 ml) then extracted with EtOAc (3×10 ml). The organics were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude oil was then dissolved in 3 mL of DMSO and then purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 2% ACN/H2O, 0.1% TFA to 32% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then the material was transferred to a 40 mL vial with MeCN, then water was added and it was freeze-dried to isolate 1,1-dimethylethyl 4-[2-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (151 mg, 47.2% yield) as a white powder. LC-MS (ES) m/z=617.6 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:12]([CH3:14])=[CH2:13])=[N:5][C:6]([N+:9]([O-])=O)=[CH:7][CH:8]=1>C(O)C.[Pd]>[CH:12]([C:4]1[N:5]=[C:6]([NH2:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:14])[CH3:13]
Reactant: C=C(C)c1nc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)nc1C(C)C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To a solution of 3-methoxy-6-nitro-2-(prop-1-en-2-yl)pyridine (824 mg, 4.24 mmol) in ethanol (14.1 mL) was added 10% palladium on carbon (45.2 mg, 424 μmol). The reaction mixture was evacuated and back filled with hydrogen. This was repeated two more times. The reaction was stirred under hydrogen at 1 atm for 16 h. The mixture was then filtered reaction through a pad of celite, the filtrate concentrated in vacuo, and then purified by chromatography (silica, 10 to 60% ethyl acetate in hexanes) to give 6-isopropyl-5-methoxypyridin-2-amine (562 mg, 3.38 mmol, 80%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 7.04 (d, J=8.7 Hz, 1H), 6.33 (d, J=8.7 Hz, 1H), 4.12 (br. s, 2H), 3.78 (s, 3H), 3.36 (m, 1H), 1.22 (d, J=7.0 Hz, 6H); MS (EI/CI) m/z: 166.8 [M+H].
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]3=[N:8][N:7]=2)=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[Cl:22][C:23]1[C:24]([CH3:32])=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(OCC)(=O)C>[Cl:22][C:23]1[C:24]([CH3:32])=[C:25]([C:26]([N:13]2[CH2:12][CH2:11][N:10]3[C:6]([C:5]4[S:1][N:2]=[CH:3][N:4]=4)=[N:7][N:8]=[C:9]3[CH2:14]2)=[O:27])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(Cl)cccc1C(=O)Cl
Reactant: c1nsc(-c2nnc3n2CCNC3)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1C(=O)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I115) (50 mg, 0.240 mmol) and triethylamine (0.050 mL, 0.360 mmol) in DCM (1.5 ml) was treated with 3-chloro-2-methylbenzoyl chloride (I130) (49.9 mg, 0.264 mmol) in DCM (0.5 ml) and stirred at room temp for 1 h. After 1 h, 2 drops of methanol and then NaHCO3 solution (5 ml) and ethyl acetate (30 ml) were added. The product was extracted into the ethyl acetate which was dried (Na2SO4) and concentrated. Purification by high pH MDAP gave the desired product as a white solid in 66 mg.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:32])[N:14]([CH3:31])[N:15]=[C:16]([O:26][CH2:27][C:28](O)=[O:29])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].S(Cl)(Cl)=O.C[N:38](C=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:32])[N:14]([CH3:31])[N:15]=[C:16]([O:26][CH2:27][C:28](=[O:29])[NH2:38])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(OCC(=O)O)nn(C)c1=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(OCC(N)=O)nn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 839.2 %

Procedure:
A solution of (4-(2,6-diethyl-4-methylphenyl)-5-benzyloxy-2-methyl-3(2H)-pyridazinone-6-yl)oxyacetic acid (530 mg, 1.53 mmol), thionyl chloride (290 mg, 2.43 mmol) and DMF (10 mg) in toluene (15 ml) was stirred at 50° C. for 45 minutes. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in THF (5 ml), and aqueous ammonia (2 ml) was slowly added under ice-cooling. After the reaction solution was stirred at room temperature for 30 minutes, the reaction solution was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated under reduced pressure to give 500 mg of Compound (I-35-1) (yield: 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[O:22]1[C:26]2[CH:27]=[CH:28][C:29](B(O)O)=[CH:30][C:25]=2[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd]Cl>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[C:4]4[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=3)[NH:7][CH:6]=[C:5]4[CH:14]3[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]3)=[CH:30][C:25]=2[CH2:24][CH2:23]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccc3c(c2)CCO3)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Reaction time: 0.3 h
Yield: 20.5 %

Procedure:
A mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (30 mg, 0.081 mmol), 2,3-dihydro-1-benzofuran-5-ylboronic acid (26.5 mg, 0.162 mmol), and K2CO3 (33.7 mg, 0.242 mmol) in 1,4-dioxane (0.36 mL) and water (0.180 mL) was degassed in a Biotage microwave vial for 10 min. PdCl2 (dppf) (5.91 mg, 8.08 μmol) was added, the vial was sealed, and the reaction was heated at 100° C. (bath temp) for 5 min in a Biotage microwave oven at high absorption. EtOAc (3 mL) and water (1 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (4×2 mL). The combined organic layers were washed with saturated NaCl (1×2 mL), dried (Na2SO4), and concentrated under a stream of nitrogen at 50° C. The crude product was dissolved in DMSO (1.2 mL), filtered through a 0.2 mm acrodisc, and purified on a Gilson HPLC (XBridge C18 5 mm OBD 19×100 mm preparatory column), eluting at 15 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% NH4OH) to 70% CH3CN/H2O (0.1% NH4OH) over 18 min. The desired fractions were concentrated under a stream of nitrogen at 50° C., giving 6.8 mg (20%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:13]([CH:14]=2)[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[S:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:24](=O)([O-])[O-:25].[Na+].[Na+]>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH:24]=[O:25])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[S:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(-c2cn3c4c(sc3n2)CCCC4)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccccc2)nc2sc3c(n12)CCCC3
Temperature: 60 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
3.35 g of 5,6,7,8-tetrahydro-2-phenylimidazo[2,1-b]benzothiazole was suspended in 20 ml of dimethylformamide. To the resultant mixture, 3 ml of phosphorus oxychloride was added dropwise at 0° C. over 10 minutes. The solution was gradually returned to room temperature, then heated and stirred at 60° C. for 3 hours, poured onto an aqueous sodium carbonate solution, then extracted with chloroform. The solvent was distilled off, the residue was then recrystallized from ethanol to obtain the desired substance in an amount of 2.31 g (yield of 82.0%) (melting point:150-150.5° C.).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][CH2:17][CH2:18][OH:19]>C(OCC)(=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:16][CH2:17][CH2:18][OH:19])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: Fc1ccc(OCCBr)c(C(F)(F)F)c1
Reactant: NCCO
Solvent: CCOC(C)=O
Product: OCCNCCOc1ccc(F)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromoethoxy)-4-fluoro-2-(trifluoromethyl)benzene (C35) (600 mg, 2.09 mmol) and 2-aminoethanol (2.20 mL, 52.4 mmol) was heated to 80° C. for 1.5 hours. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (75 mL) and washed with aqueous sodium hydroxide solution (1 N, 4×50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as a white solid. Yield: 550 mg, 2.06 mmol, 99%. LCMS m/z 268.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.80 (br dd, J=5.5, 5.4 Hz, 2H), 3.04 (dd, J=5.4, 5.2 Hz, 2H), 3.68 (br dd, J=5.6, 5.4 Hz, 2H), 4.20 (dd, J=5.3, 5.3 Hz, 2H), 7.22 (br dd, J=8.8, 4.2 Hz, 1H), 7.30-7.37 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])=[O:6])[CH2:3][CH2:2]1.[C:16]([CH2:18][C:19](O)=[O:20])#[N:17].CN(C)C=O.CS(Cl)(=O)=O>O.C(O)(C)C.O>[C:16]([CH2:18][C:19]([N:4]([CH:1]1[CH2:2][CH2:3]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[F:15])=[O:6])=[O:20])#[N:17]
Reactant: N#CCC(=O)O
Reactant: O=C(Nc1ccc(I)cc1F)NC1CC1
Agent: CS(=O)(=O)Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC(=O)N(C(=O)Nc1ccc(I)cc1F)C1CC1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
Under a nitrogen atmosphere, to 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 48 (167 g) and cyanoacetic acid 73 (80.0 g), was added N,N-dimethylformamide (836 ml), and methanesulfonyl chloride (72.8 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 4 hrs. The reaction mixture was cooled with water, and water-isopropanol [2:1 (volume ratio), 1670 ml] was added dropwise. The mixture was stirred under water-cooling for 1 hr, and the precipitated crystals were collected by filtration and dried to give 1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 74 (192 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[C:6]([C:8]1[N:13]([CH2:14][CH2:15][O:16]C(=O)C)[C:12](=[O:20])[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:10](=[O:30])[C:9]=1[CH:31]([CH3:33])[CH3:32])=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO>[OH:16][CH2:15][CH2:14][N:13]1[C:8]([C:6]([C:5]2[CH:4]=[C:3]([CH:36]=[C:35]([CH3:37])[CH:34]=2)[C:1]#[N:2])=[O:7])=[C:9]([CH:31]([CH3:33])[CH3:32])[C:10](=[O:30])[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:12]1=[O:20]
Reactant: COc1ccc(Cn2c(=O)c(C(C)C)c(C(=O)c3cc(C)cc(C#N)c3)n(CCOC(C)=O)c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(Cn2c(=O)c(C(C)C)c(C(=O)c3cc(C)cc(C#N)c3)n(CCO)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
Acetic acid 2-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-3-(4-methoxy-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-ethyl ester (88 mg, 0.175 mmol, 1.2 eq.) was dissolved in 1.5 mL MeOH. Potassium carbonate (48 mg, 0.349 mmol, 2 eq.) was added and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated down and purified (silica gel, 0-10% MeOH/DCM) to give a white powder (76 mg, 94%). LC-MS shows 462.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[N:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[N:11]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)nc2)n1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cc(N)n(-c2ccc(=O)n(CCN3CCOCC3)c2)n1

Procedure:
To a solution of 5-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)pyridin-2-ol (Abraham, S. et al., WO 2009/117080, 24 Sep. 2009) (4.04 g, 17.4 mmol) in MeCN (50 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (3.88 g, 20.9 mmol) and K2CO3 (5.29 g, 38.3 mmol)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.F[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[CH:26]=[O:27])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NC1CCCNC1
Reactant: O=Cc1ccccc1F
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NC1CCCN(c2ccccc2C=O)C1
Yield: 16.9 %

Procedure:
Using N-(piperidin-3-yl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (67.2 mg, 0.200 mmol) and 2-fluorobenzaldehyde (0.211 mL, 2.00 mmol), the same procedure was followed as in Step 6c of Example 6 to give 14.9 mg (17%) of the desired compound as a colorless powder.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=O)=O>N1C=CC=CC=1>[CH:1]1([CH2:7][C:8]([O:10][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=3)[CH:32]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)CC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)CC3CCCCC3)ccc2c1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 2.5 g of cyclohexylacetic acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture, and stirred for 24 hours at room temperature. The insolubles were removed by filtration and ethyl ether was added to the filtrate. The precipitate was collected by filtration and recrystallized from a dimethylformaldehyde-ether mixture to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl cyclohexylacetate methanesulfonate.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([NH:26][NH2:27])=[CH:24][CH:25]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH:29](=O)[CH:30]([CH3:32])[CH3:31]>>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([NH:26][N:27]=[CH:29][CH:30]([CH3:32])[CH3:31])=[CH:24][CH:25]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(CCNCC(O)COc2ccc(NN)nn2)cc1OC
Reactant: CC(C)C=O
Agent: Cl
Product: COc1ccc(CCNCC(O)COc2ccc(NN=CC(C)C)nn2)cc1OC
Yield: 71 %

Procedure:
In a similar manner to Example 8 reaction of 2 g of (RS)-3-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]-6-hydrazinopyridazine dihydrochloride with (1.1 ml) of isobutyraldehyde afforded the title compound in 71% yield, m.p. 150°-152° C. (with decomp).
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:25]([N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:37][CH2:38][CH:39]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+].[OH-].[Na+]>C(O)C.C(#N)C>[CH2:25]([N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:37][CH2:38][CH2:39][NH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:4])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=CCCc1nccn1Cc1ccccc1
Reactant: COc1ccc(S(=O)(=O)NCCc2ccc(C(C)(C)N)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: COc1ccc(S(=O)(=O)NCCc2ccc(C(C)(C)NCCCc3nccn3Cc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-{2-[4-(1-amino-1-methylethyl)phenyl]ethyl}-4-methoxybenzenesulphonamide (0.97 g), 3-(1-benzylimidazol-2-yl)propionaldehyde (0.66 g), 4A molecular sieves (0.7 g) and acetonitrile (15 ml) was stirred at ambient temperature for 18 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to give a residue which was dissolved in absolute ethanol (15 ml). Sodium borohydride (0.18 g) was added to the ethanolic solution and the mixture was boiled under reflux for 3 hours. The solvent was removed under reduced pressure and water was added to the residue followed by dilute hydrochloric acid to give an acidic mixture. After 20 minutes the mixture was basified with dilute sodium hydroxide solution and extracted with ethyl acetate to give an oil which was purified with flash column chromatography on silica to give N-[2-(4-{1-[3-(1-benzylimidazol-2-yl)propylamino]-1-methylethyl}phenyl)ethyl]-4methoxybenzenesulphonamide. A mixture of this product (0.61 g), absolute ethanol (30 ml), ammonium formate (0.42 g) and 10% palladium on carbon (0.91 g) was boiled under reflux for 1 hour. The mixture was filtered and the filtrate was evaporated under reduced pressure to give a residue which was purified by flash column chromatography on silica using ethyl acetate/methanol/triethylamine (18:1:1) as the mobile phase to give N-[2-(4-{1-[3-(imidazol-2-yl)propylamino]-1-methylethyl}phenyl)ethyl]-4-methoxybenzenesulphonamide as an oil.