Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:20][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC(CC1CCCCC1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)C(CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid (3.0 g, 11.1 mmol) and potassium carbonate (1.5 g, 11.1 mmol) in N,N-dimethylformamide (20 mL) was added methyl iodide (0.795 μL; 12.1 mmol). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (100 mL) and the solution was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title intermediate as an oil (3.1 g) which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([O:4][C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6])[CH3:3].C(N(CC)CC)C.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[NH2:45][CH2:46][C:47](=[O:73])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:56]([NH:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[N:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>O1CCCC1.C(OCC)(=O)C>[CH3:64][C:61]([CH3:62])([O:60][C:58]([NH:57][C:56]([NH:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][NH:48][C:47](=[O:73])[CH2:46][NH:45][C:33](=[O:34])[O:23][CH2:22][CH2:21][CH2:20][CH2:19][N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:18])[CH2:10][CH2:9][CH2:8][NH:7][C:5]([O:4][C:2]([CH3:24])([CH3:1])[CH3:3])=[O:6])=[N:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[O:59])[CH3:63]
Reactant: CC(C)(C)OC(=O)N=C(NCCCCCCNC(=O)CN)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCO)C(=O)OC(C)(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCCCCCCNC(=O)CNC(=O)OCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1 g (2.89·10-3 mol) of [3-[[(1,1-dimethyl-ethoxy)carbonyl]amino]propyl](4-hydroxybutyl)carbamic acid, 1,1-dimethylethyl ester is dissolved in 20 ml of tetrahydrofuran (THF), and 0.45 g (4.5·10-3 mol) of triethylamine is added followed by a solution of 0.58 g (2.89·10-3 mol) of 4-nitrophenyl chloroformate in 5 ml of THF. The reaction mixture is stirred for 15 hours at room temperature, a solution of 1.2 g (2.89·10-3 mol) of 13-amino-3-[[(1,1-dimethylethoxy)carbonyl]-amino]-12-oxo-2,4,11-triazatridec-2-enoic acid, 1,1-dimethylethyl ester in 6 ml of THF is then added and the reaction mixture is heated to 40° C. and stirred for 5 hours. After concentration of the reaction medium under reduced pressure, the residue is purified by medium pressure chromatography on silica gel using a methylcyclohexane/ethyl acetate mixture (7/3; v/v) and then pure ethyl acetate as the eluent to give 1 g of the expected product in the form of a transparent oil (yield=44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([N:22]=[C:23]=[O:24])[C:3]=1[CH3:25].C(N(CC)CC)C.[C:33]1([OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([NH:22][C:23]([O:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:24])[C:3]=1[CH3:25]
Reactant: Oc1ccccc1
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N=C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 45.4 %

Procedure:
3-(4-Chloro-6-fluoro-2-isocyanato-3-methylphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1.4 mmol) and triethylamine (0.14 g, 1.4 mmol) were dissolved in toluene (15 ml) and the solution was treated with phenol (0.13 g, 1.4 mmol). Solution was stirred for 0.3 hr at ambient temperature and water was added. Product was extracted with ethyl acetate. Removal of the solvent followed by column chromatography on silica gel (eluent, methylene chloride) afforded the title compound (0.3 g).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][N:8]([CH3:34])[C:9](=[O:33])[CH2:10][CH:11]([C:13]1[C:14]([CH:30]2[CH2:32][CH2:31]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)O.C(N(CC)CC)C>ClCCl>[CH3:6][O:7][N:8]([CH3:34])[C:9](=[O:33])/[CH:10]=[CH:11]/[C:13]1[C:14]([CH:30]2[CH2:31][CH2:32]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: CON(C)C(=O)CC(O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 79.9 %

Procedure:
A dichloromethane (10 ml) solution of methanesulfonyl chloride (1.44 g, 12.6 mmol) was added to a dichloromethane (40 ml) solution of N-methoxy-N-methyl-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3-hydroxypropanamide (3.30 g, 8.38 mmol) and triethylamine (1.27 g, 12.6 mmol). The resulting mixture was stirred at 0° C. for 30 minutes and at room temperature for 3 hours before treatment with triethylamine (1.27 g, 12.6 mmol). The mixture was heated to reflux for 3 hours, quenched with saturated NaHCO3 aq solution, and extracted with dichloromethane. The organic layer was washed with saturated NaCl aq solution, dried over magnesium sulfate, and then concentrated. The residue was purified by column chromatography (hexane:ethyl acetate=3:1) to give N-methoxy-N-methyl-(E)-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}propenamide (2.52 g, 80% yield). mp=141° C. Rf =0.52 (hexane:ethyl acetate=2:1) IR (CHCl3): 3000, 1650, 1610, 1515, 1490, 1415, 1385, 1220, 1090, 1025, 840, 760 cm-1.
Reaction SMILES: C(OC([N:8]([C:19]1[CH:24]=[C:23]([N:25](C(OC(C)(C)C)=O)[C:26]([NH2:35])=[N:27]C(OC(C)(C)C)=O)[CH:22]=[C:21]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][N:44]=2)[C:20]=1[CH3:51])[C:9]([NH2:18])=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:52]>ClCCl.O1CCOCC1>[ClH:52].[ClH:52].[ClH:52].[NH:8]([C:19]1[CH:24]=[C:23]([NH:25][C:26]([NH2:35])=[NH:27])[CH:22]=[C:21]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][N:44]=2)[C:20]=1[CH3:51])[C:9]([NH2:18])=[NH:10]
Reactant: COc1ccnc(-c2cc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)cc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)c2C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccnc(-c2cc(NC(=N)N)cc(NC(=N)N)c2C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2,4-bis(N,N′-bis(tert-butoxycarbonyl)guanidino)-6-(4-methoxypyridin-2-yl)toluene (0.15 g) in dichloromethane (3 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 3 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (50 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 2,4-diguanidino-6-(4-methoxypyridin-2-yl)toluene trihydrochloride (85 mg).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]([CH3:14])=[C:10]([CH2:12][CH3:13])[N:11]=1.Cl.N([O-])=[O:20].[Na+]>O>[OH:20][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]([CH3:14])=[C:10]([CH2:12][CH3:13])[N:11]=1
Reactant: CCc1nc(/C=C/c2cccc(N)c2)sc1C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCc1nc(/C=C/c2cccc(O)c2)sc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
An amount of 3.0 g of 2-(trans-3-aminostyryl)-4-ethyl-5-methylthiazole was added to 18 ml of 20% hydrochloric acid and to the mixture was added dropwise slowly 3 ml of an aqueous solution of 0.86 g of sodium nitrite while maintaining the inner temperature at 4° to 5° C. After the mixture was stirred at the above temperature for 1.5 hours, the reaction mixture was added into 50 ml of boiling water over 20 minutes. After the mixture was cooled to room temperature, the precipitates formed were collected by filtration, washed with aqueous saturated sodium hydrogen carbonate solution and with water, followed by drying under reduced pressure. The crude product was washed with toluene and dried under reduced pressure to obtain 2.1 g (yield 70%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C(O[N:26]1N=[N:33][C:28]2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1([C:15]([NH:33][CH2:28][C:27]#[N:26])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)C1(Sc2ccccc2Br)CCCCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1(Sc2ccccc2Br)CCCCC1
Reaction time: 8 h

Procedure:
To a mixture of 1-[(2bromophenyl)sulfanyl]cyclohexanecarboxylic acid (77 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and aminoacetonitrile hydrochloride (33 mg, 0.35 mmol) in DMF (3 mL) was added Et3N (0.1 mL, 0.72 mmol). The mixture was stirred overnight, then partitioned between ethyl acetate and 1 M HCl. The organic phase was washed with water, 1 M NaOH and brine, then dried over MgSO4 and concentrated to give 1-[(2-bromophenyl)sulfanyl]-N-(cyanomethyl)cyclohexanecarboxamide.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4].[H-].[Na+].[C:16]([O:19][C@H:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][Br:25])(=[O:18])[CH3:17].O>CS(C)=O>[C:16]([O:19][C@H:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][Br:25])(=[O:18])[CH3:17].[C:16]([O:19][C@H:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][N:5]1[C:6]2[N:7]=[CH:8][N:9]([CH3:13])[C:10]=2[C:11](=[O:12])[N:2]([CH3:1])[C:3]1=[O:4])(=[O:18])[CH3:17]
Reactant: Cn1c(=O)[nH]c2ncn(C)c2c1=O
Agent: CC(=O)O[C@H](C)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)n(C)c(=O)c2c1ncn2C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 120.5 %

Procedure:
To a stirring solution of 1,7-dimethylxanthine (0.30 g, 1.67 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (42 mmg, 1.75 mmol) in one portion. After stirring for 30 minutes, (R)-5-acetoxy-1-bromohexane (0.31 g, 1.75 mmol) was added neat. (R)-5-Acetoxy-1-bromohexane was prepared according to methods described in U.S. patent application Ser. No. 09/002,345, which is incorporated herein by reference. After heating at 80° C. for 18 hours, water (25 ml) was added and the aqueous solution was extracted with dichloromethane (3×20 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate to give (R)-3-(5-acetoxyhexyl)-1,7-dimethylxanthine (0.34 g, 64% yield) as a colorless oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[CH2:40][C@@:38]4([CH3:39])[C@@H:34]([CH2:35][CH2:36][C:37]4=[O:41])[C@H:33]4[C:24]3=[C:25]3[C:30]([CH2:31][CH2:32]4)=[CH:29][C:28](=[O:42])[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].[Cl-].C1CCCCC1>CN(C)C=O>[Cl:1][C:29]1[C:28](=[O:42])[CH2:27][CH2:26][C:25]2[C:30]=1[CH2:31][CH2:32][C@@H:33]1[C:24]=2[C@@H:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:22][CH:21]=2)[CH2:40][C@@:38]2([CH3:39])[C@H:34]1[CH2:35][CH2:36][C:37]2=[O:41]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@]12C[C@H](c3ccc(OCc4ccccc4)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: C[C@]12C[C@H](c3ccc(OCc4ccccc4)cc3)C3=C4CCC(=O)C(Cl)=C4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.17 h

Procedure:
5.295 g of N-chlorosuccinimide is added at 60° C. under an inert atmosphere to a solution of 13.6 g of 11β-[4-(phenylmethoxy)phenyl]-estra-4,9-diene-3,17-dione in 120 ml of dimethylformamide, agitation is carried out for 10 minutes then the reaction medium is poured into a saturated aqueous solution of NaCl, followed by extraction, washing, drying and evaporating under reduced pressure until the crude product is obtained (m=19.128 g). A second trial is carried out, the crude products are collected and purified by chromatography eluting with an ethyl acetate-cyclohexane mixture 30/70. 23.28 g of expected pure product is obtained. (Rf ACOET/cyclohexane 30/70=0.19).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 22, step a) (2.3 g) in a mixture of dichloromethane (40 mL) and trifluoroacetic acid (10 mL) was allowed to stand at 20° C. for 30 minutes. Toluene (50 mL) was added and the solvents were evaporated, then this process was repeated with further toluene (50 mL). The residue was triturated with ether. The gum was then dissolved in acetonitrile and the solvent evaporated to afford the subtitled compound. Yield 1.64 g.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc2ccccn2c1=O
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(Cl)c1cnc2ccccn2c1=O

Procedure:
In a similar manner to that of Example 1--1), 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonyl chloride, which was prepared from 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (1.8 g) and thionyl chloride (36 ml), was treated with a solution of 7-(D-2-phenylglycinamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid formate (2.5 g) and bis(trimethylsilyl)acetamide (4.0 g) in methylene chloride (50 ml). Thus obtained reaction mixture was worked up in a similar manner to that of Example 1-4) to give powder (650 mg) of 7-[D-2-(4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamido)-2-phenylacetamide]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, mp 103° to 105° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH2:23])=[S:22])[CH:15]=1.[CH3:24][C:25]1N=C(NC2C=NC=CN=2)SC=1C1C=CC(SC)=CC=1.CSC1C=CC(C=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[S:22][C:21]([NH:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[N:23][C:24]=2[CH3:25])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: NC(=S)Nc1cccnc1
Reactant: CSc1ccc(-c2sc(Nc3cnccn3)nc2C)cc1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1Cl
Agent: CSc1ccc(C=O)cc1
Product: Cc1nc(Nc2cccnc2)sc1-c1ccc(S(C)(=O)=O)c(Cl)c1

Procedure:
The title compound is prepared starting from 3-chloro-4-methanesulfonyl-benzaldehyde (prepared as described in WO 01/49660 A1) and 3-pyridylthiourea following an analogous sequence of reactions described for the preparation of [4-Methyl-5-(4-methylsulfanyl-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine (27c) from 4-methylsulfanyl-benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:34](=[O:37])[CH2:35][CH3:36])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide produced in Example C52(v) in pyridine (1.0 mL) was added propionyl chloride (29 μL, 0.332 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (46.7 mg, 52%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3c(C)cccc3c(Oc3ccc(Cl)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenoxy)-5-methyl-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 366(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Cl.[NH:27]1[CH2:30][CH2:29][CH2:28]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:25])=[O:24])=[C:6]([CH2:8][C:9]([N:27]2[CH2:30][CH2:29][CH2:28]2)=[O:11])[CH:7]=1
Reactant: C1CNC1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)N2CCC2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (500 mg, 1.4 mmol) and azetidine hydrochloride (470 mg, 5 mmol) in DMF (5 ml), added PyBOP (730 mg, 1.4 mmol) then triethyl amine (1.1 ml, 8 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The compound was obtained as white powder. MS calcd for (C18H20BN3O5S): 401.12. MS found (ESI negative): (M−H)−=400.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 7.04 (dd, J=8.4 Hz, 1H), 6.34 (d, J=2.4 Hz, 1H), 6.30 (dd, J=8.8 Hz, 1H), 4.81 (s, 2H), 4.01 (t, J=7.2 Hz, 1H), 3.81 (t, J=7.6 Hz, 1H), 3.57 (s, 2H), 2.11 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[NH:6][C:7]2[CH:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][C:8]=2[N:9]=1)[CH3:3].[S:16](Cl)(Cl)=O.S[CH:21]([CH3:24])[C:22]#[N:23].[Na].[O-]CC.[Na+]>CO>[C:22]([CH2:21][CH2:24][S:16][CH2:14][C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[NH:6][C:7]=2[CH:13]=1)#[N:23]
Reactant: CN(C)Cc1nc2ccc(CO)cc2[nH]1
Reactant: CC(S)C#N
Reactant: O=S(Cl)Cl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CN(C)Cc1nc2ccc(CSCCC#N)cc2[nH]1
Temperature: 25 °C

Procedure:
5-Chloromethyl-2-dimethylaminomethylbenzimidazole, 2hydrochloride (melting point 248.4° C., 3.64 g) was produced by subjecting 2-dimethylaminomethyl-5-hydroxymethylbenzimidazole (3 g) and thionylchloride (10.5 ml) to a 4-hour refluxing with heat. 2-Mercaptopropionitrile (1.05 g) was changed into sodium salt by sodium ethoxide and, at a temperature of 0° C., methanol solution of the above-mentioned chloromethyl compound was added gradually and the mixture was stirred through one whole night at the room temperature to yield 5-[(2-cyanoethyl)thiomethyl]-2-dimethylaminomethylbenzimidazole (3.2 g).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=1[F:24]>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([F:24])[CH:19]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(I)cc1F
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(F)c(F)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=312.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 1,2-difluoro-4-iodobenzene.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:24]1([CH2:30][CH2:31][CH2:32][C:33]#[CH:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.[Cu]I>[CH3:9][C:7]1[N:8]=[C:4]([N:1]2[CH:34]=[C:33]([CH2:32][CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:3]=[N:2]2)[S:5][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Reactant: C#CCCCc1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-n2cc(CCCc3ccccc3)nn2)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of ethyl 2-azido-4-methylthiazole-5-carboxylate (5.31 g, 25.02 mmol) in tetrahydrofuran (50 mL) was added copper(I) iodide (4.76 g, 25.02 mmol), N,N-diisopropylethylamine (13.07 mL, 75.06 mmol) and 5-phenyl-1-pentyne (3.97 g, 27.52 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:4 ratio) to afford the title compound in 79% yield (7.04 g): 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.31-7.16 (m, 5H), 4.33 (q, J=6.0 Hz, 2H), 2.82 (t, J=9.0 Hz, 2H), 2.77-2.69 (m, 5H), 2.10-2.04 (m, 2H), 1.38 (t, J=6.0 Hz, 3H); MS (ES+) m/z 357.3 (M+1).