Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([N:13]([CH2:21][CH2:22]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[CH3:12].[Na].C(O)C>O>[CH2:21]([N:13]([CH2:11][CH2:12][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[CH3:22]
Reactant: Sc1nc2ccccc2s1
Reactant: CCN(CCCl)c1cccc(C)c1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCN(CCSc1nc2ccccc2s1)c1cccc(C)c1

Procedure:
73.5 Parts of 2-mercapto-benzthiazole and 79.0 parts of N-ethyl-N-(β-chloroethyl)-m-toluidine are successively added to a solution of 10.15 parts of sodium in 200 parts of absolute ethanol and the mixture is heated to the refluxing temperature for 6 hours. After cooling, the mixture is poured into 1,000 parts of water, the pH is adjusted to 9-10 and the oil which has separated out is taken up in chloroform. The chloroform solution is washed with water in the usual manner, dried over calcium chloride and evaporated. 127.2 Parts of crude N-ethyl-N-(β-benzthiazolylmercaptoethyl)-m-toluidine are obtained as an oily residue. 65.6 Parts of this toluidine base are dissolved in 43.8 parts of dimethylformamide, 34 parts of phosphorus oxychloride are added dropwise over the course of about one hour at below 50°, and the mixture is stirred for a further 15 hours, at 60°-65°. It is then allowed to cool to approx. 40° and a total of 150 parts by volume of methanol is added--initially dropwise, and whilst cooling externally to 40°-50° until the exothermic reaction has subsided--7 parts of emulsifier are introduced and the pH value is now adjusted to 7-8 by dropwise addition of approx. 55 parts by volume of concentrated aqueous ammonia whilst cooling with water. A solution of 13.8 parts of malodinitrile in 15 parts of methanol is then added, the reaction mixture is stirred for 2 hours at 55°-60° and after cooling the dyestuff of the formula ##STR17## which has precipitated is filtered off. The product is washed with 150 parts by volume of methanol and then with 750 parts of warm water, and after drying at 70° in a vacuum drying cabinet 70.6 parts of dyestuff (87.5% of theory) of melting point 190°-192° are obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:21][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH3:20].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:19]([O:21][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH3:20]
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCOC(=O)CCCCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 58 %

Procedure:
To a solution of 12.6 g (0.05 mole) 4,5-diphenyl-2-imidazolethiol in 125 ml dimethylformamide was added, dropwise, 14.2 g (0.05 mole) ethyl-11-bromoundecanoate in 40 ml dimethylformamide and the reaction mixture was stirred at reflux under nitrogen overnight. The cooled solution was poured into 5% sodium bicarbonate and ice and then extracted with ethyl acetate. The organic layer was backwashed with 5% sodium bicarbonate, water, and saturated sodium chloride solution, then dried over magnesium sulfate and the solvent was removed under vacuum. The residue was chromatographed using hexane:ethyl acetate (9:1). The resulting solid was triturated with hexane to give 13.58 g (0.029 mole) of the title compound as a white solid, mp=57°-59° C. 1HNMR(DMSO-d6): δ12.6(s,1H), 7.6-7.1(m,10H), 4.0(q,2H,J=8Hz), 3.5(t,2H,J=7Hz), 2.25(t,2H,J=7Hz), 1.8-1.1(m.21H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][OH:9].F[C:11]([C:13]([C:19]([F:22])([F:21])[F:20])([C:15]([F:18])([F:17])[F:16])[F:14])=[O:12]>>[C:13]([C:11]([O:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][O:9][C:11]([C:13]([C:15]([F:16])([F:17])[F:18])([C:19]([F:20])([F:22])[F:21])[F:14])=[O:12])=[O:12])([C:19]([F:22])([F:21])[F:20])([C:15]([F:18])([F:17])[F:16])[F:14]
Reactant: O=C(F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: OCCCOCCCO
Product: O=C(OCCCOCCCOC(=O)C(F)(C(F)(F)F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.1 %

Procedure:
HO(CH2)3O(CH2)3OH (10 g) was loaded into an autoclave and stirred in a sealed state, and FCOCF(CF3)2 (36.95 g) was fed over 7 hours at room temperature with occasional pauses for bubbling with nitrogen gas under unsealed conditions. After the feeding, the reaction solution was stirred at room temperature for 1 hour and bubbled with nitrogen gas under unsealed conditions. The reaction solution was neutralized with saturated aqueous NaHCO3 (100 mL) and extracted with R-225 (100 mL) in twice. The organic phase was washed with saturated aqueous NaHCO3 (50 mL) and further with saturated aqueous NaCl (50 mL). The organic phase was dried over magnesium sulfate and filtered to give 36.13 g of a crude liquid.
Reaction SMILES: [BH4-].[Li+].O1CCCC1.Cl.[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([C:41](OCC)=[O:42])[C:36](OCC)=[O:37])=[CH:19][CH:18]=1>>[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([CH2:36][OH:37])[CH2:41][OH:42])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(CCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(CO)CCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 71.6 %

Procedure:
First, 1.7 g of lithium borohydride and 20 ml of tetrahydrofuran were placed in a 100 ml flask. Then, 60 ml of tetrahydrofuran solution in which 4 g of 2,3-difluoro-4'-[12,12-bis(ethoxycarbonyl)dodecyl]oxybiphenyl was dissolved was added dropwise to the reaction mixture, and the resultant reaction mixture was stirred under reflux for 18 hours. The reaction mixture was poured into cold diluted hydrochloric acid, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/toluene=8/2) and recrystallized from acetone to obtain 2.4 g of 2,3-difluoro-4'-[12,12-bis(hydroxymethyl)dodecyl]oxybiphenyl (Y: 71.6%). The compound thus obtained had a purity of 99.6% by HPLC.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][NH2:11].[OH-].[Na+].C(O[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])C>CCOC(C)=O>[NH2:22][C:21]1[N:10]([C:4]2[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])[N:11]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1cnn(-c2c(Cl)cccc2Cl)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
(2,6-Dichlorophenyl)hydrazine hydrochloride (5 g, 23.42 mmol) was partitioned between EtOAc (100 mL) and NaOH (2M, aq) (40 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. The resultant oil was suspended in methanol (50 mL) under nitrogen at −5° C. 2-(Ethoxymethylene)malononitrile (2.86 g, 23.42 mmol) added portion-wise over 5 mins and the mixture stiffed at 0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (5.60 g, 94%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 4.47 (2H, s), 7.43-7.47 (1H, m), 7.51-7.53 (2H, m), 7.73 (1H, s); m/z (ES+) (M+H)+=253; HPLC tR=1.62 min. Alternatively the product was obtained by concentrating the reaction mixture to half volume and allowing the product to crystallise.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:8]=1[CH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16](O)[CH3:17])[C:11]=12.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.CN(C)C=O.O>[N:30]([CH:16]([CH3:17])[CH2:15][N:12]1[CH:13]=[CH:14][C:10]2[CH2:9][C:8]3[C:19]([C:11]1=2)=[CH:20][CH:21]=[CH:22][C:7]=3[CH3:6])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2c1Cc1ccn(CC(C)O)c1-2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2c1Cc1ccn(CC(C)N=[N+]=[N-])c1-2
Yield: 98.7 %

Procedure:
0.44 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.63 g of (RS)-1-(5-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 1.6 ml of triethylamine in 25 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 50 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green solid obtained was dissolved in 30 ml of anhydrous dimethylformamide, treated with 0.36 g of sodium azide and the reaction mixture was heated to 60° for 16 hours while stirring. After cooling, the solution was poured into 80 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.69 g (98%) of (RS)-1-(2-azido-propyl)-5-methyl-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a light yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([N:8]1[CH2:9][CH2:10][N:5]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(c4ccc(OCCN5CCNCC5)cc4)CC3)nn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.1 %

Procedure:
A solution of acetyl chloride (0.029 mL, 0.40 mmol) in DCM (0.5 mL) was added dropwise to 6-[4-[4-(2-piperazin-1-ylethoxy)phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 727) (160 mg, 0.34 mmol) and triethylamine (0.094 mL, 0.67 mmol) in DCM (1 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge and the organic layer evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (60.0 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[CH2:22]([CH:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH2:21][CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)sc2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 6-amino-3H-benzothiazole-2-one and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 206. Melting Point: 196-199° C. (diethylether)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH3:44])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[C:13]1[CH:25]=[CH:24][C:16]2[O:17]C(C)(C)[O:19][C:20](=[O:21])[C:15]=2[CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[CH2:1]([O:8][CH2:9][C:10]([N:12]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH3:44])=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)[C:13]1[CH:25]=[CH:24][C:16]([OH:17])=[C:15]([CH:14]=1)[C:20]([OH:21])=[O:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)COCc3ccccc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)COCc3ccccc3)c3ccc(O)c(C(=O)O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using 2-(benzyloxy)-N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)acetamide and NaOH 5M aq. in die presence of EtOH as a beige powder (67%). 1H NMR (CDCl3, 300 MHz) δ 10.76 (s, 1H), 7.53 (m, 1H), 7.43 (m, 4H), 7.28 (m, 5H), 7.17 (m, 4H), 6.98 (m, 1H), 6.90 (d, J=8.7 Hz, 1H), 4.88 (s, 2H), 4.56 (s, 2H), 3.91 (s, 2H), 2.62 (t, J=7.7 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.93 (t, J=7.4 Hz, 3H). M− (ESI): 546.2; M+ (ESI): 548.3. HPLC, Rt; 5.33 min (Purity: 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:4].C(N([CH2:29][CH3:30])CC)C>C(O)C1C=CC=CC=1>[CH2:1]([O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:4])[C:30]1[CH:29]=[CH:7][CH:6]=[CH:5][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: OCc1ccccc1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)C(=O)OCc2ccccc2)[C@@H](O)[C@H]1O
Temperature: 100 °C

Procedure:
5 g of adenosine-5'-carboxylic acid methyl ester are suspended in 200 ml of benzyl alcohol, with the addition of 7 g of triethylamine, and the reaction mixture heated to 100° C. for 5 hours, the methyl ester thereby going into solution. After termination of the reaction, the base and excess alcohol are stripped off in a vacuum, the residue is triturated with ether for the removal of traces of amine and solvent and, after filtering off with suction, the product is recrystallized from water. There are thus obtained 3.3 g (53% of theory) of adenosine-5'-carboxylic acid benzyl ester, which has a melting point of 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:11])[C:9]#[N:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:11][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]#[N:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: N#CC(O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC(C#N)c2ccccc2Cl)cc1
Yield: 90.6 %

Procedure:
2-(2-chlorophenyl)-2-hydroxyacetonitrile (16.8 g, 0.1 mol) and 4-toluene sulfonyl chloride (21 g, 0.11 mol) was dissolved in toluene (100 mL) in a suitable reaction flask. Aqueous 5% NaOH (100 g, 0.125 mol) was added dropwise at 0-5° C. and the reaction continued at 10-15° C. until the reaction was completed by TLC monitoring. The organic layer was separated and the aqueous layer was extracted with toluene (50 ml×2). The combined organic layer was washed with water. After removal of toluene under reduced pressure, the target product was obtained (29 g, yield 90.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][NH:57][CH:58]1[CH2:63][CH2:62][N:61]([CH3:64])[CH2:60][CH2:59]1>CN(C=O)C>[CH3:56][N:57]([CH:58]1[CH2:63][CH2:62][N:61]([CH3:64])[CH2:60][CH2:59]1)[C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: CNC1CCN(C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N(C)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), HOBt (33 mg, 1.2 eq.), EDAC.HCl (45 mg, 1.2 eq.) and methyl-(1-methyl-piperidin-4-yl)-amine (284 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.069 mL, 2.5 eq.). After stirring at rt for 2 days, the reaction was concentrated, diluted with DCM and added solid sodium bicarbonate. After stirring at rt for 15 mins, the suspension was loaded onto a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([CH2:16][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CNC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)Oc1ccc(OCc2ccc(C#N)cc2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 4-bromomethyl-benzonitrile in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-propionamide as a white solid; MS: m/e=311 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[CH:18]=[CH:19][CH:20]=[N:21][C:11]2=3)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>O1CCCC1>[CH3:29][N:30]([CH:32]=[C:14]1[CH2:15][CH2:16][N:10]([CH2:8][C:7]2[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]2[N:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]1=[O:17])[CH3:31]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ncccc21
Solvent: C1CCOC1
Product: CN(C)C=C1CCN(Cc2ccc([N+](=O)[O-])cc2)c2ncccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a slurry of 0.50 g of 6,7,8,9-tetrahydro-9-(4-nitrobenzoyl)-5H-pyrido[2,3-b]azepin-5-one in 10 ml of tetrahydrofuran under argon is added 0.70 g of tert-butoxy-bis(dimethylamino)methane and the mixture is stirred at room temperature overnight. The volatiles are removed under vacuum and the residue in ethyl acetate--CH2Cl2 (2:8) filtered through a short column of silica gel. The silica gel is washed with ethyl acetate (discard) and then with chloroform containing 3% methanol to give 0.51 g of the product as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([CH2:39][NH:40]C(OC(C)(C)C)=O)[CH:32]=2)[C:17]2[C:18]([F:29])=[C:19]3[C:24](=[C:25]([O:27][CH3:28])[CH:26]=2)[O:23][CH2:22][CH2:21][CH2:20]3)=[N:11]1)=[O:4].CO.[OH-].[Na+]>C(O)(=O)C>[F:29][C:18]1[C:17]([CH:16]([NH:30][C:31]2[CH:32]=[C:33]3[C:34](=[CH:35][CH:36]=2)[C:37](=[NH:38])[NH:40][CH2:39]3)[C:12]2[NH:13][C:14](=[O:15])[N:10]([C:6]3[N:7]=[CH:8][S:9][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)=[CH:26][C:25]([O:27][CH3:28])=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][O:23]2
Reactant: COC(=O)c1scnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a mixture of 4-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-(5-fluoro-8-methoxychroman-6-yl)methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiazole-5-carboxylic acid methyl ester (74 mg) and methanol (2.0 mL) there was added aqueous 5N sodium hydroxide (111 μL), and the mixture was stirred at room temperature for 3 hours and 15 minutes. After adding acetic acid (52 μL) to the mixture, the solvent in the mixture was distilled off under reduced pressure. Dichloromethane (2.0 mL) was added to the residue, TFA (400 μL) was added to the resulting solution and the mixture was stirred at room temperature for 5 hours. Dichloromethane (50 mL) was added to the mixture, which was then stirred at room temperature for 14 hours. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (21 mg).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([C:23](O)=[O:24])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:26])[N:3]1[CH2:27][CH2:28][CH3:29]>C1COCC1>[OH:24][CH2:23][C:18]12[CH2:22][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:26])[N:3]([CH2:27][CH2:28][CH3:29])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:15][CH2:16][CH2:17]1)[CH2:21][CH2:20][CH2:19]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C(=O)O)(CCC3)C4)nc2n(CCC)c1=O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CO)(CCC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carboxylic acid (700 mg) was taken in THF (25 ml). BH3. THF (1M, 3.5 ml) was added and stirred at rt overnight. Next day the reaction was quenched with MeOH. Solvent was removed by rotavap. Diluted with water and extracted with ethyl acetate, washed with water, brine, dried over Na2SO4 and concentrated. Yield 690 mg. Mass (ES+ 389)