Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[CH:4][CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:42]1([CH2:48][C:49]([N:51]=[C:52]=[S:53])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])O.[Na+]>C(O)C.CCCCCC.C(OCC)C>[CH3:23][N:15]([CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[C:14]([NH:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:25]=[CH:26][C:2]([NH:1][C:52]([NH:51][C:49](=[O:50])[CH2:48][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[S:53])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1)=[O:24]
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCCC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Yield: 2.2 %

Procedure:
3-[4-(4-Aminophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (60 mg) was dissolved in ethanol (1 ml) while stirring, and then D-10-camphorsulfonic acid (39.3 mg) was added thereto under a nitrogen atmosphere, followed by stirring for 5 min. Phenylacetyl isothiocyanate (toluene solution, 1.82 M, 0.074 ml) was added thereto, followed by stirring further for 1.5 hrs. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:5, then ethyl acetate). Fractions containing the crude product were concentrated to give a residue, which was then purified by LC-MS. The fractions containing the target compound were concentrated to give a residue, to which a saturated aqueous solution of sodium hydrogencarbonate was added to extract with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:ethanol=9:1). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (0.3 ml)-hexane (0.1 ml) was then added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (2.0 mg, 2.2%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([OH:14])=O)[N:10]=1)(=[O:4])=[O:3].[C:15]([O:18][CH2:19][C:20]1[CH2:21][S:22][C@@H:23]2C(N)C(=O)[N:24]2[C:25]=1[C:26]([OH:28])=[O:27])(=[O:17])[NH2:16].P(Cl)(Cl)(Cl)(Cl)Cl.C[Si]([CH2:43][C:44]([NH2:46])=[O:45])(C)C>>[C:15]([O:18][CH2:19][C:20]1[CH:21]([NH:46][C:44](=[O:45])[CH3:43])[S:22][C@@H:23]2[CH:11]([C:9]3[N:10]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[S:7][CH:8]=3)[C:12](=[O:14])[N:24]2[C:25]=1[C:26]([OH:28])=[O:27])(=[O:17])[NH2:16]
Reactant: CS(=O)(=O)Nc1nc(CC(=O)O)cs1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: C[Si](C)(C)CC(N)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CC(=O)NC1S[C@@H]2C(c3csc(NS(C)(=O)=O)n3)C(=O)N2C(C(=O)O)=C1COC(N)=O
Yield: 76.1 %

Procedure:
2-Methanesulfonamidothiazol-4-ylacetic acid (1.13 g.), 3-carbamoyloxymethyl-7-amino-3-cephem-4-carboxylic acid (1.37 g.), phosphorus pentachloride (2.08 g.) and trimethylsilylacetamide (4.58 g.) were treated in the similar manner to that of Example 12 to give 3-carbamoyloxymethyl-7-(2-methanesulfonamidothiazol-4-yl)-acetamido-3-cephem-4-carboxylic acid (1.79 g.)
Reaction SMILES: CO.[NH2:3][C:4]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:5]=1[CH:6]([OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=1.[CH3:27][C:28]([CH3:32])([CH3:31])[CH:29]=O.C([BH3-])#N.[Na+]>C(OC(=O)C)C.C(O)(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:4]([NH:3][CH2:27][C:28]([CH3:32])([CH3:31])[CH3:29])=[C:5]([CH:22]=1)[CH:6]([OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=1
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a methanol (4 ml) solution of 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminophenyl) benzyl alcohol (0.4 g) were added trimethyl acetaldehyde (109 mg) and acetic acid (76 mg). The mixture was stirred for 10 minutes at room temperature, to which was added sodium cyano borohydride (79 mg). The mixture was stirred for one hour at room temperature, to which was added acetic acid ethyl ester (50 ml). The mixture was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to give the object 5-chloro-α-(3-tert-butoxycarbonylaminophenyl)-2-neopentylaminobenzyl alcohol (0.43 g) as a colorless amorphous solid product.
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[CH:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]([CH:3]([O:5][C:15]1[CH:14]=[CH:19][N:18]=[C:17]([C:20]#[N:21])[CH:16]=1)[CH3:4])([F:10])[C:6]([F:9])([F:8])[F:7]
Reactant: N#Cc1ccc(Cl)cn1
Reactant: CC(O)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(Oc1ccnc(C#N)c1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.9 %

Procedure:
Add (±)-3,3,4,4,4-pentafluoro-2-butanol (710 mg, 4.3 mmol) slowly to a slurry of sodium hydride (104 mg, 1.2 equiv, 60% mineral oil, washed with hexane) in hexamethylphosphoramide (2 mL) under nitrogen at 0° C. Allow the slurry to warm to ambient temperature and stir for 5 min. Add 5-chloro-pyridine-2-carbonitrile (300 mg, 2.2 mmol), then heat the mixture in a sealed flask at 130° C. for 4 h (monitor reaction by GC/MS). Cool the reaction to room temperature, adjust the mixture to pH 9 with saturated aqueous Na2CO3, then extract with diethyl ether (2×50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 7:3 gradient) to obtain the desired intermediate (380 mg, 66%). GC-MS m/z: 266 (M+).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].C[N:7]1CCOCC1.Cl[C:14]([CH:16]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:15]>CN(C)C=O.C(#N)C>[O:5]=[C:2]1[C@@H:3]([NH:7][C:14]([CH:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:15])[CH2:4][NH:1]1
Reactant: O=C1CCN1
Reactant: O=C(Cl)C(C(=O)OCc1ccccc1)c1ccccc1
Reactant: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(N[C@H]1CNC1=O)C(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
The above azetidinone (3.0 g) is dissolved in 100 ml of dimethylformamide. The solution is cooled to 0° C. and 4.5 g of N-methylmorpholine is added followed (dropwise) by 10.8 g of α-(chlorocarbonyl)benzeneacetic acid, phenylmethyl ester in 50 ml of acetonitrile with stirring. The mixture is stirred for about 16 hours at 5° C. The solvent is distilled off in vacuo and 100 ml of water is added to the residue. The aqueous suspension is extracted twice with 100 ml portions of methylene chloride. The organic layers are combined, washed with sodium bicarbonate, 2N phosphoric acid and water, dried with sodium sulfate, filtered and evaporated to dryness. The residue is crystallized with ethyl acetate and petroleum ether, yielding 8.7 g, melting point 164°-166° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].O1CCCC1>O>[C:12]([NH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)cccc1C(=O)O
Temperature: 80 °C
Reaction time: 13 h
Yield: 38 %

Procedure:
A mixture of 1.51 g of 2-amino-3-methylbenzoic acid, 1.0 g of acetic anhydride and 20 ml of tetrahydrofuran was stirred at 80° C. for 13 hours. The reaction mixture was allowed to cool to room temperature, poured into water, and extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with ethyl acetate to obtain 0.72 g of 2-acetylamino-3-methylbenzoic acid of the formula:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.[C:14]1([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:21](=[O:22])[CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:6]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cn1nnc(N)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 56 %

Procedure:
To a stirred solution of 5-amino-2-methyl-2H-tetrazole (0.50 g, 5.05 mmol), pyridine (0.48 g, 6.06 mmol) and DMAP (0.06 g, 0.51 mmol) in dichloromethane (30 ml) was added at 0° C. diphenylacetyl chloride (1.16 g, 5.05 mmol). Stirring was continued at RT for 2 h, the reaction mixture was poured into sat. NaHCO3 solution (50 ml) and extracted with dichloromethane (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (Na2SO4) and evaporated. The crude product was crystallized from ethyl acetate/hexane to give the title compound (0.83 g, 56%) as a white solid, m.p. 218° C. (dec.) and MS: m/e=293.1 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[C:9](=[O:12])([O-:11])[O-:10].[K+].[K+]>C(#N)C>[C:2]([O:12][C:9]([O:11][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:10])([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)COC(=O)Cl
Agent: [K+]
Solvent: CC#N
Product: CC(C)COC(=O)OC(=O)OCC(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Isobutyl chloroformate (136.76 g, 1.0 mol.) was added dropwise to a stirred mixture of powered, anhydrous potassium carbonate (77 g, 0.56 mol) in acetonitrile at such a rate as to maintain a reaction temperature of 40° C. The reaction mixture was stirred for six (6) hours at ambient temperature and then allowed to stand overnight prior to work-up. The crude product was purified by vacuum distillation, and the fraction collected between 58° and 62° C. at 0.05-0.10 mmHg was found to be di-isobutyl dicarbonate. YIELD=86.93 g=80%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22](O)=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=1)[CH3:2].[NH2:27][CH:28]1[CH2:33][CH2:32][C:31]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)([OH:34])[CH2:30][CH2:29]1>>[OH:34][C:31]1([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH2:32][CH2:33][CH:28]([NH:27][C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([O:12][CH2:11][C:8]2[C:7]4[CH:25]=[CH:26][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=4[O:10][CH:9]=2)[CH:21]=[CH:20][CH:19]=3)=[O:23])[CH2:29][CH2:30]1
Reactant: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-ethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 30a and amine 14.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: CC(C)Nc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12

Procedure:
The title compound was prepared following procedure and work up described for example 85 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and isopropylamine (43 mg, 0.73 mmol; 5.0 eq.) as a white solid (8 mg, 15%). HPLC, Rt: 3.09 min. (purity 87.7%). LC/MS, M+(ESI): 365.0, M−(ESI): 363.0.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>C1COCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]([OH:21])[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Clc1cccnc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccncc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
Diisopropylamine (1.82 mL, 12.9 mmol) was dissolved in THF (40 mL) and cooled to −78° C. nBuLi (4.93 mL, 2.5 M in hexanes, 12.3 mmol) was added drop-wise and the solution was warmed to room temperature, stirred for 45 min and re-cooled −78° C. A solution of 3-chloropyridine (1.40 g, 12.3 mmol) in THF (6 mL) was added and the reaction mixture was stirred at −78° C. for 4 h. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.89 g, 13.6 mmol) in THF (6 mL) was added and the reaction mixture was warmed to r.t. and stirred for 2 h. The reaction mixture was quenched with water (60 mL) and extracted with DCM (100 mL and 2×30 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (2.94 g, 73%) as a yellow gum. LCMS (ES+): 271.0 (M+H-tBu)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].Cl[CH2:13][C:14]([CH3:17])([OH:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[OH:16][C:14]([CH3:17])([CH3:15])[CH2:13][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[CH3:10]
Reactant: CC(C)(O)CCl
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C#N)cc(C)c1OCC(C)(C)O
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.5 mmol) and 1-chloro-2-methyl propan-2-ol (8.85 g, 81.5 mmol) in ethanol (50 mL) was added potassium carbonate (7.5 g, 54 mmol) and water (5 mL). The reaction mixture was stirred at reflux for 24 h and cooled to room temperature. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.9 g, 97%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([CH3:18])([O:12][CH2:13][C:14](OC)=[O:15])[C:9](=[O:11])[CH3:10]>CCOCC>[CH3:7][C:8]1([CH3:18])[C:9](=[O:11])[CH2:10][C:14](=[O:15])[CH2:13][O:12]1
Reactant: COC(=O)COC(C)(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC1(C)OCC(=O)CC1=O
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide (1M in tert-butanol, 12.1 mL, 12.1 mmol) in ether (7.5 mL) at 0° C. under N2 gas was treated with the product from Example 43B in ether (3 mL). After 10 minutes, the reaction mixture was quenched into 2N HCl (25 mL) and extracted with ether (3×25 mL). The organic layers were combined, washed with brine, dried over Na2SO4, concentrated to an oil, treated with 10% dichloromethane in hexane (5 mL), and placed in the freezer for 1 hour. The resulting crystals were collected by filtration, washed with a cold solution of 10% dichloromethane in hexane, and dried to provide the title compound (431 mg). 1H NMR (CDCl3) δ 1.25 (s, 6H), 4.16 (s, 2H), 5.20 (s, 1H), 11.70 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)=[CH:2]1.Cl.Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C@@H:31]([N:33]2[CH2:38][CH2:37][C@H:36]([OH:39])[C@@H:35]([CH3:40])[CH2:34]2)[CH3:32])[CH2:26][CH2:25]1>>[OH:39][C@H:36]1[CH2:37][CH2:38][N:33]([C@@H:31]([CH3:32])[CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:29][CH2:28]2)[CH2:34][C@@H:35]1[CH3:40]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3ccoc3)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5ccoc5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid, 95 (see example 36) and amine 56.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1>>[ClH:24].[Cl:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:40][CH2:39][CH2:38][CH2:37][N:34]3[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]3)=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: NC(=O)c1c(OCc2c(F)cc(Cl)cc2F)nsc1NC(=O)Oc1ccccc1
Product: CN1CCN(CCCNC(=O)Nc2snc(OCc3c(F)cc(Cl)cc3F)c2C(N)=O)CC1
Product: Cl

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 6. 1H NMR (400 MHz, D2O) δ 6.86 (bm, 2H), 5.20 (s, 2H), 3.4-2.6 (bm, 8H), 3.10 (b, 2H), 2.63 (b, 5H), 1.67 (m, 2H) ppm; MS (APCI, m/z): 503 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:18]=O)[CH:13]=[N:14][C:15]=1[O:16][CH3:17].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:9][C:10]1[CH:11]=[C:12]([CH2:18][NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)[CH:13]=[N:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ncc(C=O)cc1F
Reactant: Nc1cccc(F)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ncc(CNc2cccc(F)n2)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To 6-fluoro-pyridin-2-ylamine (43, 1.50 g, 13.4 mmol) in 52.9 mL of acetonitrile, 5-fluoro-6-methoxy-pyridine-3-carbaldehyde (57, 2.00 g, 12.9 mmol), triethylsilane (10.6 mL, 66.3 mmol), and trifluoroacetic acid (5.3 mL, 69.0 mmol) were added. The reaction was stirred at 80° C. overnight, then concentrated under vacuum, combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as white solid (58, 3.21 g).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])[NH2:3].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C=O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([NH:3][N:2]([CH3:1])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])=[O:23])([OH:18])=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(N)C(=S)Nc1ccccc1
Solvent: CN(C)C=O
Product: CN(NC(=O)c1ccccc1C(=O)O)C(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-4-phenyl-3-thiosemicarbazide (0.2 mole) was dissolved in 75 ml of dimethylformamide and placed in a 3-necked round-bottomed flask equipped with magnetic stirrer, condenser, additional powder funnel and thermometer. Phthalic anhydride (0.2 mole) was added in portions at 20°. The contents were stirred overnight at room temperature, then poured into ice water. The resulting solid product was recrystallized from a mixture of hexane and ethanol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][S:7][C:8]1[N:13]=[C:12](O)[C:11]([CH2:15][C:16]([O:18]CC)=O)=[CH:10][N:9]=1.C(O)C.[CH3:24][NH2:25]>CO>[CH3:6][S:7][C:8]1[N:9]=[CH:10][C:11]2[CH2:15][C:16](=[O:18])[N:25]([CH3:24])[C:12]=2[N:13]=1
Reactant: CN
Reactant: CCOC(=O)Cc1cnc(SC)nc1O
Solvent: CO
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1ncc2c(n1)N(C)C(=O)C2
Yield: 36 %

Procedure:
Phosphorus oxychloride (59.0 g) was added to 4.84 g (21.2 mmoles) of ethyl 2-methylthio-4-hydroxy-pyrimidine-5-acetate, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and after adding chloroform, neutralized with an aqueous solution of sodium hydrogen carbonate. The chloroform layer was concentrated under reduced pressure. To the concentrate were added 20 ml of ethanol and 3.48 g (44.9 mmoles) of a 40 methanol solution of methylamine, and the mixture was reacted at 100 ° C. for 5 hours in an autoclave. The solvent was evaporated under reduced pressure, and after adding water, the mixture was extracted with chloroform. The chloroform layer was concentrated under reduced pressure, treated with activated carbon in ethanol, and recrystallized to give 1.50 g (yield 36%) of the desired compound.
Reaction SMILES: [C:1]([C:3]1[C:20]([C:21]#[N:22])=[CH:19][C:6]2[N:7](CCC)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2].[CH2:23]([C:26](C1C=CC(C=O)=CC=1)([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:23]([C:26]([C:13]1[CH:14]=[CH:15][C:10]([C:8]2[NH:7][C:6]3[CH:19]=[C:20]([C:21]#[N:22])[C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[CH:11][CH:12]=1)([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]
Reactant: CCCn1c(-c2ccccc2)nc2cc(C#N)c(C#N)cc21
Reactant: C=CCC(CC=C)(CC=C)c1ccc(C=O)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCC(CC=C)(CC=C)c1ccc(-c2nc3cc(C#N)c(C#N)cc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A solution of 1 (198 mg, 1.25 mmol) in NMP (2.5 mL) and a solution of 2 (300 mg, 1.25 mmol) in NMP (3.5 mL) were combined in a flask fitted with a Hickman still. The mixture was heated at 120° C. and stirred for 2 h. Then FeCl3.6H2O (17 mg, 63 μmol) was added and oxygen was bubbled through the mixture with continued heating and stirring for 20 h. The cooled reaction mixture was diluted with ethyl acetate. The organic solution was washed with water and brine. The organic layer was dried (Na2SO4), filtered, concentrated, and chromatographed (silica, CH2Cl2 w/ethyl acetate gradient of 0-5%). Fractions containing the desired compound were concentrated to give a reddish solid, which was chromatographed over a short plug of alumina (CH2Cl2 w/ethyl acetate gradient of 10-100%) yielding a colorless solid (268 mg, 57%): mp 264-266° C.; 1H NMR (do-acetone) δ 2.57 (d, J=7.2 Hz, 6H), 4.88-5.11 (m, 6H), 5.56-5.69 (m, 3H), 7.65 (d, J=8.8 Hz, 2H), 8.26 (d, J=8.8 Hz, 2H), 12.89 (brs, 1H); 13C NMR (d6-acetone) δ 41.6, 44.0, 108.2, 116.9, 117.7, 126.4, 127.3, 128.0, 134.4, 150.2; FABMS obsd 379.1909, calcd 379.1923 (C25H22N4).