Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=[O:12])(=O)([OH:10])[OH:9].O.[C:14](O)(=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>>[C:14]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:8]([OH:10])(=[O:12])=[O:9])(=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: O=S(=O)(O)O
Reactant: CC(C)CCCCCC(=O)O
Reactant: Oc1ccccc1
Solvent: O
Product: CC(C)CCCCCC(=O)Oc1ccccc1S(=O)(=O)O
Temperature: 110 °C

Procedure:
94 parts by weight of phenol are dissolved in 166 parts by weight of isononanoic acid. 107 parts by weight of 96% sulfuric acid are then added to this solution and the mixture is heated for 30 minutes to 100° to 110° C. The water of reaction is then largely distilled off under reduced pressure (20 mm) within 30 minutes. After cooling, 134 parts by weight of thionylchloride are added dropwise at 45° to 50° C., with addition of an antifoam. The mixture is stirred for one further hour. This gives a stable isononanoyloxybenzenesulfonic acid havingan AS content of 81%, and the Na salt as the end product, which is obtained in virtually quantitative yield (relatative to phenol), has an AS content of 85%.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)[CH3:2].[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.Cl>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:8]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: c1ccsc1
Agent: Cl
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cccs2)cc1

Procedure:
To a stirred mixture of 26.7 parts of p-ethylbenzoyl chloride, 13.3 parts of thiophene in 80 parts of methylene chloride are added 41.1 parts of stannic chloride in 40 parts of methylene chloride at 30° C. Upon completion, stirring is continued for 3h.30 at reflux temperature. The reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid. The layers are separated and the aqueous phase is extracted with methylene chloride. The combined organic layers are washed with water, dried, filtered and evaporated. The residue is evaporated once more from benzene. The latter residue is distilled, yielding p-ethylphenyl 2-thienyl ketone; b.p. 200°-205° C at 12 mm. pressure.
Reaction SMILES: [P:1]([O-:6])([O:4]C)[O:2]C.O.[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH3:9]>CO>[CH3:8][P:1](=[O:6])([O-:4])[O-:2].[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][NH3+:14])[CH3:9].[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][NH3+:14])[CH3:9]
Reactant: CCOCCCN
Reactant: COP([O-])OC
Solvent: O
Solvent: CO
Product: CCOCCC[NH3+]
Product: CP(=O)([O-])[O-]
Yield: 98.9 %

Procedure:
A mixture of 11 g. (0.1 moles) of dimethyl phosphite, 20 ml. of water and 20 ml. of methanol is reacted with a mixture of 10.31 g. (0.1 moles) of 3-ethoxypropyl amine and 30 ml. of methanol as described in Example 1. 19.7 g. of 3-ethoxypropyl-ammoniummethyl phosphonate are obtained. Yield: 98.9%. nD30 1.4425.
Reaction SMILES: [H-].[Na+].C(O)C.[C:6](OCC)(=[O:13])[CH2:7][C:8](OCC)=[O:9].Cl.[O:18]1[CH2:23][CH2:22][CH:21]([C:24](=[NH:26])[NH2:25])[CH2:20][CH2:19]1>CCCCCC>[O:18]1[CH2:23][CH2:22][CH:21]([C:24]2[N:25]=[C:8]([OH:9])[CH:7]=[C:6]([OH:13])[N:26]=2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)C1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: Oc1cc(O)nc(C2CCOCC2)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (3.0 g, 60% in oil, 75 mmol) in hexane (4 mL) was added ethanol (60 mL) slowly at rt. After 30 min at rt, diethyl malonate (4 g, 25 mmol) were added, followed by tetrahydro-2H-pyran-4-carboximidamide-HCl (4.12 g, 25 mmol). The mixture was heated at 90° C. overnight. Dry molecular sieves (2.5 g) were added, and additional ethanol was added to help stirring. The reaction was heated at 90° C. for 4 days. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was removed in vacuo to give 2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,6-diol as a solid, which was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.C(O)[CH:32]1[O:36][CH2:35][CH2:34][CH2:33]1>>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH:35]3[O:36][CH2:32][CH2:33][CH2:34]3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: OCC1CCCO1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCC4CCCO4)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 60 %

Procedure:
A solution of mitomycin A (100 mg or 0.286 mmole) in 4 ml of tetrahydrofurfuryl alcohol was stirred at room temperature and under nitrogen for 45 minutes with 480 mg of a 1.6% solution of KOH in tetrahydrofurfuryl alcohol. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. The product was chromatographed on a silica gel column using CHCl3 -MeOH 9.5:0.5 as solvent. Further purification of the product was done by preparative thin layer chromatography (silica gel, CHCl3 -MeOH 9.5:0.5). This procedure resulted in 72 mg (60%) of the desired product having a melting point of 128°-133° C. (decomposition) and providing the following analysis:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:36])=[C:10]([CH:35]=1)[C:11]([C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([CH3:34])=[CH:15][N:14]=1)=[O:12]>C1COCC1.CC(O)=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:18]2[C:13]([C:11](=[O:12])[C:10]3[CH:35]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=[CH:8][C:9]=3[Cl:36])=[N:14][CH:15]=[C:16]([CH3:34])[CH:17]=2)(=[O:22])=[O:21])=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CN=C=O
Reactant: Cc1cnc(C(=O)c2cc(N)ccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=O)Nc1ccc(Cl)c(C(=O)c2ncc(C)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
Methylisocyanate (17 μL, 0.235 mmol) was added to N-[2-(5-amino-2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzene sulfonamide (59 mg, 0.117 mmol) in THF (2 mL) and AcOH (0.5 mL) and stirred at room temperature for 4 h. The reaction mixture was directly purified by preparative HPLC (20-80% acetonitrile in water) to afford 4-chloro-N-{2-[2-chloro-5-(3-methyl-ureido)-benzoyl]-5-methyl-pyridin-3-yl}-3-trifluoromethyl-benzene sulfonamide (25 mg) in 38% yield. 1H NMR (400 MHz, CDCl3+CD3OD) δ 8.14 (m, 2H), 7.95 (m, 2H), 7.63 (d, 1H), 7.58 (dd, 1H), 7.41 (dd, 1H), 7.19 (d, 1H), 2.76 (s, 3H), 2.42 (s, 3H); ESMS m/z (relative intensity): 561 (M+H)+ (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3=[N:14][C:15]([CH3:22])=[C:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[Br-].[H-].[Na+].O.[CH:27]([O:29][CH3:30])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3=[N:14][C:15]([CH3:22])=[C:16]([C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:27][O:29][CH3:30])[N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COC=O
Reactant: COC(=O)Cc1c(C)nc2sc(-c3ccc(OC)cc3)nn12
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1c(C)nc2sc(-c3ccc(OC)cc3)nn12
Reaction time: 8 h

Procedure:
A solution of 10 g of 2-(4-methoxyphenyl)-5-methoxycarbonylmethyl-6-methylimidazolo-[2,1-b]-1,3,4-thiadiazole in 50 cm3 of methyl formate is dripped into a solution of 1.8 g of sodium hydride bromide in 10 cm3 of anhydrous dimethylformamide (DMF). The solution is left under agitation overnight at ambient temperature and is then poured into water and extracted twice with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[Cl:11].[CH2:13]([NH2:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[Na+].[Na+].[ClH:23]>C(OCC)C.C(O)C>[OH2:2].[ClH:11].[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[NH:16][CH2:13][CH:14]=[CH2:15].[CH2:13]([NH:16][C:5]1[N:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:12])[CH:14]=[CH2:15].[ClH:23]
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: C=CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: C=CCNc1nc(C)ccc1C(=O)OC
Product: O

Procedure:
A stirred mixture of 9.25 g. (0.05 mole) of methyl-2-chloro-6-methylnicotinate, 2.85 g. (0.05 mole) of allylamine and 5.3 g. (0.05 mole) of sodium carbonate in 50 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was diluted with 50 ml. of water and was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated. The residue was passed through a neutral aluminum oxide column using ethyl acetate as the eluent. Evaporation of the ethyl acetate gave 3.1 g. of product. A small amount of this oil was dissolved in diethyl ether containing a few drops of ethanol and this solution was acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was recrystallized from ethyl acetate to give 2-allylamino-6-methylnicotinic acid methyl ester hydrochloride hemihydrate, m.p. 140°-142° C.
Reaction SMILES: [OH:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH:8]3[CH2:13][CH:12]([C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][NH:10][CH2:9]3.C(N(C(C)C)CC)(C)C.[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C(Cl)Cl>[OH:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH:8]3[CH2:13][CH:12]([C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][N:10]([C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:39])[CH2:9]3
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CNCC2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CC2CN(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
To ethyl 3-hydroxy-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,11-methanopyrimido[1,2-a][1,5]diazocine-2-carboxylate (0.26 g, 0.661 mmol) in CH2Cl2 (5 mL) was added diisopropylethylamine (0.576 mL, 3.31 mmol) and benzylchloroformate (0.102 mL, 0.727 mmol). The reaction mixture was stirred at 23° C. for 16 hours. HCl (1N, 15 mL) was then added to the reaction mixture and the organic material extracted with CH2Cl2 (3×15 mL) and ethyl acetate (3×15 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The organic material was purified by Silica gel column chromatography (Biotage flash chromatography system) eluting with gradient of ethyl acetate 100% to ethyl acetate methanol (1:9) to afford 0.036 g (13% yield) of the title compound. 1H NMR (400 MHz, MeOD) δ ppm 7.36 (5 H, s), 4.95-5.10 (2 H, m) 3.95-4.40 (2 H, br m), 2.75-3.30 (5 H, br m), 1.75-2.50 (4 H, m), 0.95-1.45 (4 H, m). LCMS (+ESI, M+H+) m/z: 414.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:41])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[CH2:9][CH2:8][N:7]([CH2:19][CH2:20][CH:21]=[C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[N:32][C:27]=3[CH2:26][O:25][C:24]3[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]2=3)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2([OH:11])[CH2:9][CH2:8][N:7]([CH2:19][CH2:20][CH:21]=[C:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[N:32][C:27]=4[CH2:26][O:25][C:24]4[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]3=4)[CH2:6][C:5]2([CH2:3][OH:2])[CH3:41])=[CH:13][CH:14]=1
Reactant: COC(=O)C1(C)CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(CO)C1)c1cccnc1CO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
4-(4-Chloro-phenyl)-4-hydroxy-1-{3-[7-(hydroxyl-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-3-methyl-piperidine-3-carboxylic acid methyl ester (0.250 g, 0.43 mmol) was dissolved in tetrahydrofuran and cooled to 0° C. To the solution was added LiAlH4 (1.3 mL, 1.3 mmol) dropwise and the reaction was allowed to stir at 0° C. for 3 h. The reaction was quenched with ice water slowly and diluted with ethyl acetate. The reaction mixture was allowed to stir at room temperature for 45 min. to break up any aluminum complexes. The organics were separated and the aqueous layer was extracted (2×) more. All of the organics were collected, dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/50% hexane to 75% ethyl acetate/25% hexane) to yield the title compound (0.103 g, 43%). 1H-NMR (CDCl3): δ 0.53 (s, 3H), 1.55 (d, 6H), 1.62 (m, 1H), 2.40 (q, 2H), 2.55 (q, 3H), 2.72-2.86 (m, 4H), 3.19 (dd, 1H), 3.24 (d, 1H), 3.41 (d, 1H), 5.33 (bs, 2H), 6.17 (t, 1H), 6.44 (bs, 1H), 6.79 (d, 1H), 7.17 (d, 1H), 7.26-7.59 (m, 7H), 8.50 (d, 1H). ESI-MS m/z: 549 (M+1), retention time 1.39.
Reaction SMILES: [CH:1]1([N:7]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Cl:29])C(=O)C1.O>C(Cl)Cl>[Cl:29][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1nccs1)N(C1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ncc(Cl)s1)N(C1CCCCC1)N1CCCCC1

Procedure:
1-Cyclohexyl-1-piperidin-1-yl-3-thiazol-2-yl-urea (50 mg, 0.16 mmol), prepared in an identical manner to Example 94 was dissolved in DCM (1 mL) and NCS (26 mg, 0.19 mmol)) was added. The reaction mixture was stirred for 3 days before DCM (20 mL) and water (20 mL) was added. The organic phase was dried (MgSO4) and the solvent was removed in vacuo. MeCN (1 mL) was added whereupon the product precipitated. The product was filtered off and dried. Yield: 20 mg.
Reaction SMILES: [C:1]1([NH2:12])[C:6](F)=[C:5](F)[C:4](F)=[C:3](N)C=1F.Cl.Cl.[CH2:15]([N:17](CC)CC)[CH3:16].[C:22]1([CH:32]([N:34]=[C:35]=[O:36])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>C1COCC1>[N:12]12[CH2:3][CH2:4][CH:5]([CH2:6][CH2:1]1)[CH:15]([NH:17][C:35]([NH:34][CH:32]([C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[CH3:33])=[O:36])[CH2:16]2
Reactant: CCN(CC)CC
Reactant: CC(N=C=O)c1cccc2ccccc12
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: C1CCOC1
Product: CC(NC(=O)NC1CN2CCC1CC2)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
3-Aminoquinculidene dihydrochloride (150 mg, 0.753 mmol) was mixed with THF (3 mL) and triethylamine (152 mg, 1.50 mmol) before adding 1-(1-naphthyl)ethylisocyanate (149 mg, 0.752 mmol). The mixture was stirred 48 h at room temperature. The reaction solution was concentrated and purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the title compound as an off-white solid (46 mg, 19%). 1H NMR (400 MHz, CDCl3) δ 8.20-8.05 (m, 1H), 7.85 (dd, J=7.9, 1.5 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.59-7.34 (m, 4H), 5.55 (hept, 1H), 5.35-5.19 (m, 1H), 4.84 (dd, 1H), 3.70-3.53 (m, 1H), 3.09 (ddd, 1H), 2.74-2.28 (m, 4H), 2.17 (ddd, J=1.8, 4.5, 14.1 Hz, 1H), 1.75-1.62 (m, 1H), 1.55 (dd, J=1.8, 6.8 Hz, 3H), 1.52-1.06 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.7, 140.0, 134.1, 130.9, 129.2, 128.3, 126.8, 126.7, 126.7, 126.0, 125.6, 123.2, 123.1, 122.8, 122.7, 56.9, 56.7, 47.4, 47.3, 46.7, 46.4, 26.1, 25.9, 22.7, 22.6, 20.1, 20.0 ppm. Purity: 97% UPLCMS (210 nm); retention time 0.68 min; (M+1) 324.2
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[Cl:21][C:22]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][N:23]=1.[CH:29](=[O:33])[CH:30]([CH3:32])[CH3:31]>O1CCCC1>[Cl:21][C:22]1[N:27]=[C:26]([Cl:28])[C:25]([CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])=[CH:24][N:23]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)C(O)c1cnc(Cl)nc1Cl
Reaction time: 0.67 h

Procedure:
A solution of diisopropylamine (1.1 mL; 7.85 mmol) (Aldrich) and freshly distilled tetrahydrofuran (15 mL) was cooled to −78° C. n-Butyllithium (2.5M in hexanes; 3.1 mL; 7.75 mmol) (Aldrich) was added dropwise and stirring continued for 40 minutes to prepare a LDA solution. 2,4-Dichloropyrimidine (0.50 g; 3.37 mmol) (Aldrich) in tetrahydrofuran (3 mL) was then added dropwise to this freshly prepared LDA solution over 15 minutes. After stirring for 40 minutes, isobutyraldehyde (0.61 mL; 6.72 mmol) (Aldrich) was added over 6 minutes and stirring continued for another 30 minutes. The reaction was quenched with the addition of 25% aqueous ammonium chloride solution (20 mL) and then diluted with ethyl acetate and water. The organic phase was washed with a second portion of aqueous ammonium chloride solution and then brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (Biotage 40S; 10:90 to 15:85 ethyl acetate-hexanes gradient) to give (±)-1-(2,4-dichloro-pyrimidin-5-yl)-2-methyl-propan-1-ol. (Yield 0.25 g; 33.4%).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:24])=[CH:6][CH:5]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O1CCC[CH2:33]1>>[CH3:24][C:12]1[N:13]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14]2[C:19]([C:11]=1[S:10][C:7]1[CH:8]=[CH:9][C:4]([CH3:33])=[CH:5][CH:6]=1)=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2
Reactant: CCOC(=O)CBr
Reactant: C1CCOC1
Reactant: Cc1[nH]c2cc(S(C)(=O)=O)ccc2c1Sc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(C)cc2)c2ccc(S(C)(=O)=O)cc21
Reaction time: 1 h

Procedure:
To a stirred solution of sodium hydride (45 mg of 60% dispersion in mineral oil) in dry tetrahydrofuran (10 ml) was added 3-[(4-chlorophenyl)thio]-2-methyl-6-(methylsulfonyl)-1H-indole (160 mg) (the product of Example 20 step i). After 30 minutes the reaction was treated with ethyl bromoacetate (78 μl) and stirring continued for 1 hour. Reaction was quenched with ethanol, the solvent was removed in vacuo, the residue redissolved in ethyl acetate, washed with water, dried (MgSO4), and evaporated in vacuo and the residue purified by flash column chromatography eluting with 30% ethyl acetate and iso-hexane mixture. The sub-title compound was obtained as a white solid (180 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][CH2:26][CH2:27][C:28](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.C(OCC)C.CCOC(C)=O>[CH3:24][O:25][CH2:26][CH2:27][C:28]1[N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1
Reactant: COCCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COCCc1nc2cnc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 15 h
Yield: 151.6 %

Procedure:
To the product of example 1 step (iii) (1.9 g) in NMP (25 mL), 3-methoxypropanoic acid (0.678 mL, 7.21 mmol) was added followed by HATU (2.74 g) and TEA (0.837 mL) under nitrogen. The resulting solution was stirred at 60° C. for 15 h. The reaction mixture was diluted with diethyl ether (300 mL) and EtOAc (300 mL), and washed with water (300 mL), sat. NaHCO3 (200 mL), and saturated brine (200 mL). The organic was dried, filtered and evaporated to afford the subtitle product (3.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1.[O-:24][C:25]#[N:26].[K+].C(O)(=O)C>O1CCCC1>[NH2:26][C:25]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1)=[O:24]
Reactant: N#C[O-]
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(N)cc2[nH]1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(NC(N)=O)cc2[nH]1

Procedure:
One gram (3.0 mmol) of 5-amino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole were dissolved in 20 ml of pure tetrahydrofuran, and then 2.0 gm of potassium cyanate and 5 ml of 2M acetic acid were added successively. After the mixture refluxed for eight hours, the solvent was evaporated off in vacuo, and the residue was mixed with 10 ml of water and neutralized with 5% sodium bicarbonate solution. The crude product precipitated was subjected to suction filtration and chromatographed over 200 gm of silica gel (eluant: methylene chloride with 8% ethanol).
Reaction SMILES: [I-:1].Cl[C:3]1[N:4]([CH3:15])[N+:5]([CH3:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[O-]C1C=CC=CC=1.[Na+].[CH3:24][N:25](C)[CH:26]=O>>[I-:1].[CH3:14][N+:5]1[N:4]([CH3:15])[C:3]([N:25]([CH3:26])[CH3:24])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cn1c(Cl)cc(-c2ccccc2)[n+]1C
Reactant: CN(C)C=O
Agent: [I-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CN(C)c1cc(-c2ccccc2)[n+](C)n1C
Reaction time: 21 h

Procedure:
3-Chloro-1,2-dimethyl-5-phenylpyrazolium iodide (10.0 g, 0.03 mole) is treated with sodium phenoxide (5.64 g, 0.06 mole) in dimethylformamide (100 ml) and the mixture heated and stirred at 110° C. to 120° C. for 21 hours. The dimethylformamide is then removed in vacuo, the residual oil dissolved in aqueous sodium bicarbonate solution and is extracted with ether. The ether fraction yields some brown oil which is not further examined. Next the aqueous sodium bicarbonate solution is extracted with chloroform (2× 150 ml). Evaporation of the chloroform solution yields a white solid which is dried by azeotropic distillation of toluene. Crystallization from a chloroform/ether mixture yields a white solid, m.p. 181.5° C. to 182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH:20]([CH3:28])[CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH:20]([CH3:28])[CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1cc2c(cc1OC)CC(C)NC2
Product: COc1cc2c(cc1OC)CN(C(=O)c1cc3ncc(Cl)cn3n1)C(C)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a colorless solid.