Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1)[C:2]([CH3:4])=O.C(=O)(O)O.[OH:23][CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH2:25][NH2:26].O>C1C=CC=CC=1>[Cl:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH:24]([OH:23])[CH2:25][NH:26][CH:2]([CH3:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: O=C(O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(COc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 18 h

Procedure:
A mixture of 4,5-dihydro-6-(4-acetonyloxyphenyl)3(2H)-pyridazinone (0.3 g) and 2-hydroxy-2-(3-chlorophenyl) ethanamine carbonate (0.26 g) in dry benzene (80 ml) was heated under reflux, with azeotropic removal of water, for 3 hr. The solvent was evaporated and the residue dissolved in methanol (80 ml) and treated with sodium cyanoborohydride (0.5 g). After 18 hr. the methanol was evaporated and the residue partitioned between ethylacetate and brine. The organic phase was washed with water, dried (MgSO4) and evaporated to a gum which was chromatographed on silica gel. Elution with methanol-chloroform (4:96) gave 6-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyloxy]-phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white crystalline solid, m.p.t. 140°-158° C., as a 1:1 mixture of diastereoisomers.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].C(O)(=O)C(O)=O.[CH2:25]1[C:28]2([CH2:31][NH:30][CH2:29]2)[CH2:27][O:26]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:25]1[C:28]2([CH2:31][N:30]([S:2]([C:5]3[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=3)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3])[CH2:29]2)[CH2:27][O:26]1
Reactant: C1NCC12COC2
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CC3(COC3)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (1 g, 1.33 mmol, Buttpark Ltd.) in CH2Cl2 (10 mL) was added N,N-ethyldiisopropylamine (1.28 g, 1.73 mL, 9.91 mmol, Eq: 3) and 2-oxa-6-aza-spiro[3.3]heptane oxalate (524 mg, 1.82 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL CH2Cl2 and the layers were separated. The aqueous layer was extracted a second time with 30 mL CH2Cl2. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Colorless solid (460 mg, 38.1%). MS (ESI): m/z=365 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([I:9])=[CH:4][N:3]=1.Br[CH2:11][C:12](=[CH2:22])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:14][CH2:13][C:12](=[CH2:11])[CH2:22][NH:8][C:6]1[C:5]([I:9])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C(CBr)COCc1ccccc1
Reactant: Nc1cc(Cl)ncc1I
Product: C=C(CNc1cc(Cl)ncc1I)COCc1ccccc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
The title compound was prepared from 2-chloro-5-iodo-pyridin-4-yl-amine and (2-bromomethyl-allyloxymethyl)-benzene following a similar method to that described in Preparation 108. The reaction was stirred at 55° C. for 3 h. MS: [M+H]+=415.
Reaction SMILES: [Br:1][C:2]1[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:28]Br.BrC1N(COCC[Si](C)(C)C)C2C=NNC(=[O:39])C=2C=1CBr>>[Br:1][C:2]1[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])[C:9](=[O:10])[C:4]=2[C:3]=1[CH:28]=[O:39]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: C[Si](C)(C)CCOCn1c(Br)c(CBr)c2c(=O)[nH]ncc21
Product: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(Br)n2COCC[Si](C)(C)C)c1=O
Yield: 67 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 24-(g) except for using 5.70 g (10.0 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) in place of 2-bromo-3-bromomethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 3.38 g of the title compound was obtained as a white solid. (Yield: 67%)
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].Br[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[O:10][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH:2]=[CH2:3]
Reactant: CC(Br)c1ccccc1
Reactant: C=CCc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C(C)=O)ccc1OC(C)c1ccccc1

Procedure:
A solution of 3′-allyl-4′-hydroxyacetophenone (3.46 g, 19.66), (1-bromoethyl)-benzene (3.05 mL, 21.63 mmol)), and K2CO3 (4.07 g, 29.49 mmol) in acetone (100 mL) is refluxed 20 hours. The mixture is then filtered and the filtrate is concentrated in vacuo. The residue is dissolved in EtOAc (100 mL) and then washed with H2O (1×100 mL) and brine (1×100 mL), dried over MgSO4, and concentrated in vacuo. Chromatography (5:1 hexane/EtOAc) yields 3′-allyl-4′-(1-phenylethoxy)-acetopbenone. To a solution of sodium hydride (0.54 g, 13.5 mmol) in THF (20 mL) is added a solution of ethyl [2-(diethylamino)-2-oxoethyl]-phosphonate (3.13 g. 12.5 mmol) in THF (20 ml). After stirring this mixture for 5 minutes. at room temperature, a solution of 3′-allyl-4′-(1-phenylethoxy)-acetophenone (2.91 g, 10.4 mmol) in ThF (30 mL) is added, and the solution is refluxed 18 hours. After cooling, the mixture is then quenched with saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (4×75 mL). The combined organic phase is washed with water (1×100 mL) and brine (1×100 mL), dried over MgSO4, concentrated in vacuo, chromatographed (silica, 2:1 EtOAc/hexane) to yield N,N-diethyl (E)-3-[3-allyl 4-(1-phenylethoxy)-phenyl)-but-2-enamide.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[C:25](F)=[N:26][CH:27]=[CH:28][CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[CH2:32]([SH:34])[CH3:33].[H-].[Na+]>O1CCCC1>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[C:25]([S:34][CH2:32][CH3:33])=[N:26][CH:27]=[CH:28][CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCS
Reactant: OC1(c2cccnc2F)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCSc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 90.4 %

Procedure:
To a solution of the 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-fluoro-3-pyridyl)piperidin-4-ol (described in example 58) (2.00 g, 5.00 mmol, 1 eq) in tetrahydrofuran (50 mL) under nitrogen was added the sodium salt of ethanethiol (0.90 g, 10.7 mmol, 2.2 eq). The thiolate salt was prepared from ethanethiol and sodium hydride under standard conditions. The reaction was heated to reflux for 18 h and quenched by pouring into water (100 mL). The aqueous phase was extracted with diethyl ether (2×100 mL). Combined organic extracts were washed with water (2×100 mL), dried over anhydrous sodium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (200 mL, eluent: 50% ether in hexane) to yield 2.00 g (90%) of the title compound. TLC analysis (Rf 0.29, 50% ether in hexane). 1H NMR (CDCl3, 250 HHz) 8.35 (dd, J=1.6, 4.7 Hz, 1H), 7.58 (dd, J=1.7, 7.7 Hz, 1H), 7.22 (m, 4H), 6.95 (m 5H), 4.27 (s, 1H), 3.58 (s, 1H), 3.48 (s, 2H), 3.28 (q, J=7.3 Hz, 2H), 2.89 (m, 2H), 2.80 (ddd, J=9.3, 14.9, 10.7 Hz, 2H), 2.62 (d, J=1.5 Hz, 2H), 2.12 (m, 4H), 1.35 (t, J=7.2 Hz, 3H) MS (CI, CH4) m/z 443 (M+1,100), 471 (M+29,16), 425 (25) The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (room temperature, 10 pascal, 18 h) to yield a white solid, mp 176°-179° C. (dec).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:36]1[C:40]2[C:41]([CH:45]=O)=[CH:42][CH:43]=[CH:44][C:39]=2[CH2:38][CH2:37]1>C1COCC1.O>[O:36]1[C:40]2[C:41]([CH:45]=[CH:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:42][CH:43]=[CH:44][C:39]=2[CH2:38][CH2:37]1
Reactant: O=Cc1cccc2c1OCC2
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC=Cc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2-carboxyethyl)triphenylphosphonium bromide (617 mg, 1.5 mmol) in THF (20 mL) was added NaHMDS (1.5 mL, 3.0 mmol) at −20° C., and the reaction was stirred for 20 min. 2,3-Dihydro-1-benzofuran-7-carbaldehyde (200 mg, 1.4 mmol) was added to the reaction at −78° C., and the reaction was stirred overnight while warming to rt. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). Organics were washed with brine (30 mL), dried (Na2SO4), and concentrated to give the crude title compound as a yellow solid. [M+H] Calc'd for C12H12O3, 205. Found, 205.
Reaction SMILES: Cl[O-].[Na+].[CH3:4][C:5]1([CH3:28])[C@@H:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:8][C@H:7]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[NH:6]1.C(Cl)[Cl:30]>O>[Cl:30][N:6]1[C@@H:7]([C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)[CH2:8][C@H:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]1([CH3:28])[CH3:4]
Reactant: COc1cc([C@H]2C[C@H](c3ccncc3)C(C)(C)N2)cc(OC)c1OC
Reactant: ClCCl
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: COc1cc([C@H]2C[C@H](c3ccncc3)C(C)(C)N2Cl)cc(OC)c1OC
Temperature: 50 °C

Procedure:
30 Ml. of sodium hypochlorite (Cl2 = 10%) are added to a solution of 5.1 g. of 4-[trans-2,2-dimethyl-5-(3,4,5-trimethoxyphenyl)-3-pyrrolidinyl]-pyridine in 50 ml. of CH2Cl2. While stirring, the reaction mixture is heated at 50° C. for 2 hours. 10 Ml. of sodium hypochlorite are added and the reaction mixture is left to react for 2 more hours. After a further addition of 10 ml. of sodium hypochlorite and an additional 2 hours, the reaction mixture is treated with water and extracted three times with methylene chloride. The organic phase which results is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield crude 4-[trans-1-chloro-2,2-dimethyl-5-(3,4,5-trimethoxyphenyl)-3-pyrrolidinyl]-pyridine.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]>C1COCC1.C(O)C.[C].[Rh]>[CH3:1][CH:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)[CH2:3][CH3:4]
Reactant: CCC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(C)c1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 86.9 %

Procedure:
A mixture of 5% rhodium-carbon (50% wet, 15 mg) and 9-[4-(1-methylpropyl)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF (30 mL) and ethanol (30 ml) was stirred under a hydrogen atmosphere (3 atm) at room temperature for 7 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (132 mg) as a brown solid. The obtained solid was crystallized from THF and diisopropyl ether to give a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH:28]([NH2:31])([CH3:30])[CH3:29].CCCP(=O)=O>O1CCCC1>[CH:28]([NH:31][C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26])([CH3:30])[CH3:29]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CC(C)N
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 83.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), isopropylamine (119 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 ul, 318.8 mmol) in tetrahydrofurane (7.00 ml) is stirred for 20 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4-isopropyl-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (93 mg, 83.8%) as a white solid. mp.: >250° C. MS: m/z=404.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5](=[O:12])[C:6]2=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a stirred solution of 5-fluoroisatin (6.00 g, 36.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.60 g, 40.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h followed by the addition of bromodiphenylmethane (10.0 g, 38.0 mmol). The mixture was stirred at 60° C. for 7 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness, the residue was recrystallized from ethyl acetate and hexanes to give 1-(diphenylmethyl)-5-fluoro-1H-indole-2,3-dione (6.30 g, 52%): 1H NMR (300 MHz, CDCl3) 7.39-7.27 (m, 11H), 7.04-6.97 (m, 2H), 6.46-6.42 (m, 1H); MS (ES+) m/z 354.2 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=1)=[O:4].[CH2:18]([OH:21])[CH2:19][OH:20]>O>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:20][CH2:19][CH2:18][OH:21])=[O:16])=[CH:10][CH:9]=1)=[O:4]
Reactant: OCCO
Reactant: COC(=O)COC(=O)c1ccc(N=C=O)cc1
Solvent: O
Product: COC(=O)COC(=O)c1ccc(NC(=O)OCCO)cc1
Reaction time: 6 h

Procedure:
4-Isocyanato-benzoic acid methoxycarbonylmethyl ester 9 (5 grams, 21.09 mmol) is added to ethylene glycol (20 mL) at room temperature and stirred for 6 hours. Water (100 mL) is added, and crude 10 is filtered, dried, and purified by a suitable method.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[CH:13]3)[CH2:4][CH2:3]1.CCN(CC)CC.[CH2:37]([N:40]=[C:41]=[O:42])[CH2:38][CH3:39]>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:41]([NH:40][CH2:37][CH2:38][CH3:39])=[O:42])=[CH:27][CH:28]=2)=[CH:13]3)[CH2:6][CH2:7]1
Reactant: CCCN=C=O
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(N)cc4)nc32)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccc(-c2cn3c(n2)C(OC2CCN(C)CC2)c2ccccc2CC3)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 16) (100 mg, 0.258 mmole) in CH2Cl2 (2 mL) is added NEt3 (72 μL, 0.515 mmole) and propylisocyanate (36 μL, 0.387 mmole). The reaction mixture is stirred at room temperature for 24 hours. Solvent is removed under reduced pressure. AcOEt is added to the residue and the organic phase is washed with water and dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) as eluent with a gradient from (100:0) to (90:10) to afford 1-{4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-3-propyl-urea melting at 130° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=O)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]C#N)=[CH:14][CH:13]=1.[OH-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:8][O:10][C:18]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=3)=[C:6]2[CH:7]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2onc3ccc(Br)cc23)cc1

Procedure:
13 g 1-bromo-4-nitrobenzene, 7.68 mL 2-(4-fluorophenyl)acetonitrile and 3.9 g sodium hydroxide were stirred in 130 mL ethanol at 40° C. for 24 hours. After the reaction solution was left and cooled, water was added thereto and the reaction solution was extracted with ethylacetate. The organic solvent was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) and then recrystallized from hexane/ethyl acetate to give 2.9 g of the title compound as pale brown crystals.
Reaction SMILES: [CH2:1]=[O:2].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1>C1COCC1>[N:3]1([CH2:1][OH:2])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: C=O
Reactant: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Product: OCn1cnc2ccccc21
Reaction time: 0.17 h

Procedure:
Formaldehyde (37% in water, 1 mL, 13.3 mmol) was added to a solution of 1H-benzo[d]imidazole (1.57 g, 13.3 mmol) in THF (60 ml). After 10 minutes, the solvent was removed and dried to give 1H-benzo[d]imidazol-1-ylmethanol as a brown solid which was used without any further purification. 1H NMR (DMSO-d6) δ 5.60 (d, J=7.09 Hz, 2H), 6.70 (m, 1H), 7.25 (m, 2H), 7.65 (d, J=9.13 Hz, 2H), 8.26 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Cl)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)([O-:21])=[O:20].O>CN1C(=O)CCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:31]2[CH2:30][CH2:29][CH:28]([C:25]3[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)[CH2:33][CH2:32]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cc1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
To a solution of 1-benzyl-4-chloro-phthalazine (1.08 g, 4.04 mmol) in 8 mL NMP is added 4-(4-nitro-phenyl)piperidine (1 g, 4.85 mmol), TEA (1.68 mL, 12.12 mmol). The reaction mixture was heated to 150° C. for 45 min in a microwave reactor. Water was added to the reaction mixture to form a precipitate and the solid is collected by filtration and dried under vacuum. The resulting solid is purified by HPLC with acetonitril in water (from 20% to 100% with 3% 1-propanol) at 220 nm wavelength detection to provide the title compound (1.4 g, 78%).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:10][CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[CH2:4]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[F:21].C(N(CC)C(C)C)(C)C>C(#N)C>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[N:8]1[CH2:9][CH:5]2[CH2:4][CH:3]([OH:2])[CH2:10][CH:6]2[CH2:7]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OC1CC2CNCC2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CC3CC(O)CC3C2)c(F)c1

Procedure:
The octahydro-5-hydroxycyclopenta[c]pyrrol hydrochloride (44.4 mmol) prepared in the step 1 was dissolved in 100 ml of acetonitrile, and 4.91 ml (44.4 mmol) of 1,2-difluoro-4-nitrobenzene and 23.20 ml (133.2 mmol) of N,N-diisopropylethylamine were added, and the mixture was heat to reflux for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was concentrated under reduced pressure to remove the solvent. The solvent-free concentrate was dissolved in ethyl acetate, and washed with distilled water, and then, the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound, of which NMR data is as follow.
Reaction SMILES: [C:1]([CH2:3][C:4](Cl)=[O:5])#[N:2].[CH3:7][NH:8][CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14].N1C=CC=CC=1>C(OCC)C>[CH3:7][N:8]([CH2:9][CH2:10][CH2:11][Si:12]([O:15][CH3:16])([O:17][CH3:18])[O:13][CH3:14])[C:4](=[O:5])[CH2:3][C:1]#[N:2]
Reactant: N#CCC(=O)Cl
Reactant: CNCCC[Si](OC)(OC)OC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CO[Si](CCCN(C)C(=O)CC#N)(OC)OC
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a 1 L reactor equipped with a thermometer, a condenser and a loading glass were added 200 mL of diethylether and 11 g of cyanoacetylchloride, followed by stirring at room temperature in the presence of nitrogen. To the reactor were slowly added 20 g of N-methylaminopropyl trimethoxysilane (0.104 mol) and 11 g of pyridine (0.14 mol) in 100 mL of diethylether by using the loading glass. The reaction mixture was stirred for 2 hours at room temperature and then the precipitated pyridine salt was eliminated. After removing the solvent and non-reactants, the reaction mixture was distilled under reduced pressure to give 21 g of N-methyl-N-(3-trimethoxysilylpropyl)cyanoacetamide (formula 3). The yield was 75%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C@H:37]1[OH:49]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[CH2:38][C@H:37]4[OH:49])=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and tert-butyl(3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2) the title compound is obtained as pale yellow foam.