Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[N:19][NH2:20])[S:15][CH:16]=2)[CH:7]=1.[ClH:22]>C(O)C>[ClH:22].[NH2:20][N:19]=[CH:18][NH:17][C:14]1[S:15][CH:16]=[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([NH:1][NH2:2])=[O:4])[N:13]=1
Reactant: NN
Reactant: COC(=O)c1cccc(-c2csc(NC=NN)n2)c1
Agent: Cl
Solvent: CCO
Product: NN=CNc1nc(-c2cccc(C(=O)NN)c2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 10 ml. of 95% hydrazine is added 3-[2-[(aminoiminomethyl)amino]-4-thiazolyl]benzoic acid methyl ester (1.1 g., 0.004 mole). This is stirred for 1 hour at room temperature. The product precipitates out and is filtered off and rinsed with ethanol. The filtrate is reduced to dryness and ethanol is added to the residue, and the insoluble material is filtered off and combined with previously filtered solid to give a crude yield of about 1 g. of the carboxhydrazide. This crude solid is added to 40 ml. ethanol and to this is added 10 ml. of ethanolic HCl solution and the mixture is heated briefly at reflux temperature. The suspension that forms is filtered off and recrystallized from 90% aqueous ethanol to give 0.65 g. of the desired product, m.p. 275° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:16](=[O:18])[CH3:17])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)cc1F
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
A solution of 4-bromo-2-fluorophenylamine (10.9 g, 57.4 mmol) and pyridine (9.4 mL, 115 mmol) in 50 mL of anhydrous dichloromethane was treated with acetyl chloride (3.33 mL, 63.1 mmol) at 0° C. After 10 minutes at 0° C. and 10 minutes at room temperature, the mixture was concentrated in vacuo and the residue was treated with 300 mL of 1 N aqueous sulfuric acid. The organic layer was concentrated in vacuo to give 12.9 g of N-(4-bromo-2-fluorophenyl)acetamide as a light greyish solid (97% yield).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:6]N(C)C)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH2:21][CH2:22][CH3:23]>>[C:11]1([C:10]2[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:25]=[C:20]([CH2:21][CH2:22][CH3:23])[N:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC(=N)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Agent: Cl
Product: CCCc1ncc(C(=O)O)c(-c2ccccc2)n1

Procedure:
In an analogous manner to that described in example 3b) starting from 2-benzoyl-3-dimethylamino-acrylic acid ethyl ester and butyramidine hydrochloride, followed by saponification as described in example 3c) there was obtained 4-phenyl-2-propyl-pyrimidine-5-carboxylic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([OH:14])=[CH:12][CH:13]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[CH:9]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(O)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium carbonate (5.04 g, 36.5 mmol) was added at room temperature to a solution of 4-amino-o-cresol (3.00 g, 24.4 mmol) and ethyl bromoacetate (2.70 mL, 24.4 mmol) in DMF (30 mL). The resulting solution was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 5.10 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]#[N:20])[N:4]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:25][NH:24][C:19]([C:5]1[N:4]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)[N:6]=1)=[NH:20]
Reactant: N#Cc1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A stirred mixture of 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (example B.2) (1.0 g, 3.15 mmol), hydroxylamine hydrochloride (0.81 g, 11.7 mol) and sodium carbonate (0.67 g, 6.32 mol) in water (15 mL) and ethanol (15 mL) was heated under reflux conditions for 2 h. The ethanol was removed partly and the mixture stirred at room temperature for 0.5 h. The precipitate was collected by filtration, washed with water and dried to yield the title compound (1.08 g, 98%) as a light brown solid. MS (ISP) 351.1 [(M+H)+]; mp 224° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23]([OH:25])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@@H:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[NH:22][CH:21]=2)=[O:25])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1CCN2C(=NCCC2)CC1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>[OH-].[Na+]>[CH:19]1([NH:25][C:26](=[O:27])[NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NCCCC(=O)O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CCCNC(=O)NC1CCCCC1
Yield: 76 %

Procedure:
To a cold solution of 4-aminobutyric acid (2.16 g, 21 mmol) and catalytic amount of DBU in 22 mL of 1.0 N NaOH, 2.5 g (20 mmol) of cyclohexyl isocyanate were added in one time. The mixture was strongly mixed at room temperature overnight. The reaction was then acidified with concentrated HCl. The formed white solid was collected by filtration. The mixture was purified by chromatography on a silica column (8×3 cm). Elution with a mixture 50:50:1 of hexane:ethyl acetate: acetic acid gave the pure targeted product. The resulting white crystal (3.46 g; yield: 76%) had a mp of 153.0-154.0° C. [M+H]+ 281.18.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[O:11]=[CH:12][C:13](OCC)=O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[NH:9][C:12](=[O:11])[CH:13]=[N:10]2
Reactant: CCOC(=O)C=O
Reactant: Nc1cc(F)c(F)cc1N
Solvent: CCO
Product: O=c1cnc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a stirred solution of 4,5-difluorobenzene-1,2-diamine (4.7 g, 32.6 mmol) in ethanol (75 mL) was added ethyl oxoacetate (50 wt % in toluene, 13.3 mL, 65.3 mmol). The reaction was stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give 4.3 g (73%) of the product as a colorless solid.
Reaction SMILES: [O:1]([C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:24]([O:26][C:27](=[O:31])[C:28]([OH:30])=O)[CH3:25]>C(Cl)CCl>[CH2:24]([O:26][C:27](=[O:31])[C:28]([N:17]([CH2:18][CH3:19])[C:16]([O:15][CH2:14][CH2:13][O:12][C:11]1[CH:21]=[CH:22][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)=[O:20])=[O:30])[CH3:25]
Reactant: CCNC(=O)OCCOc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)C(=O)N(CC)C(=O)OCCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C

Procedure:
9.0 g of N-ethyl-carbamic acid-2-(4-phenoxyphenoxy)ethyl ester are dissolved in 90 ml of ethylene chloride. To this solution are added 9.6 g of oxalic acid monoethyl ester chloride, and stirring is maintained for 10 hours under mild refluxing conditions. The cooled reaction mixture is then poured into 200 ml of ice-water, and the organic phase is separated. This is washed with cold water, dried over sodium sulfate, concentrated by evaporation and taken up in dichloromethane. Chromatography on silica gel with dichloromethane as the eluant thus yields the compound of the formula ##STR6## in the form of white crystals having a m.p. of 56°-58° C.
Reaction SMILES: [C:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20](O)[CH3:21])=[CH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:25])=O>C(Cl)Cl>[C:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]([Cl:25])[CH3:21])=[CH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(O)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(N-carbobenzoxy indol-3-yl)ethanol (1.02 g, 3.45 mmol) in CH2Cl2 (20 ml) at -78° C. under nitrogen was added thionyl chloride (0.63 ml, 8.62 mmol). After warming to room temperature and stirring for 2 hrs, the mixture was evaporated to a brown oil. This was dissolved in CHCl3, treated with activated carbon and filtered through a pad of Super Cel; the filtrate was evaporated to give 1.03 g (95%) of light brown oil: NMR (CDCl3) δ1.90 (3, d, CH3), 5.26 (1, q, CHCl), 5.33 (2, s, PhCH2), 7.20-7.85 (9, m, aromatic H's) 8.04 ppm (1, m, H-7). This material was relatively unstable, and therefore was used immediately without further purification (e.g. as in Example 13).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:52]([NH:59][CH2:60][CH:61]=O)([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>C(Cl)(Cl)Cl>[C:55]([O:54][C:52]([NH:59][CH2:60][CH2:61][N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:11]3[N:10]=[CH:9][C:8]([CH2:26][C:27]([NH2:29])=[O:28])=[C:7]([NH:6][CH2:5][C:4]4[CH:3]=[C:2]([F:1])[CH:32]=[C:31]([F:33])[CH:30]=4)[CH:12]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
20 mg of 4-[(3,5-difluorobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 221) was dissolved in 0.5 mL of chloroform, to which 1.4 mg of acetic acid, 15 mg of sodium triacetoxyborohydride and 8.7 mg of N-Boc-2-aminoacetaldehyde were added, and stirred overnight at room temperature. The reaction mixture was washed with water and saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 19 mg (71%) of the title compound as a light yellow solid.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[S:3])[NH:1]2)[CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17]
Reactant: O=C1CNC(=S)N1
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=S)NC1=Cc1cc(O)c(O)c(Cl)c1
Temperature: 100 °C

Procedure:
A solution containing 1.16 g of thiohydantoin, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 0.2 ml of piperidine in 20 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with ether. Yield 1.0 g, mp 303-304° C.
Reaction SMILES: [N:1]1[C:11]2[C@@H:10]3[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C@H:9]3[CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[Cl:36].[OH-].[Na+]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([S:37]([N:7]2[CH2:8][C@@H:9]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][C@H:10]3[C:11]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)(=[O:38])=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNCc3cccnc3[C@@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H]2CN(S(=O)(=O)c3ccc(Cl)c(Cl)c3)Cc3cccnc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Example 334B (100 mg, 0.34 mmol) and triethylamine (0.097 mL, 0.69 mmol) in dichloromethane (2 mL) was stirred at ambient temperature for 10 minutes. 3,4-Dichlorobenzene-1-sulfonyl chloride (0.52 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred at room temperature overnight. A 10% NaOH solution (2 mL) was added; the dichloromethane layer was separated, treated with water (2 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([C:4]#[CH:5])[CH3:3].[CH:7]1([C:10](O)=[O:11])[CH2:9][CH2:8]1>>[CH3:1][C:2]([NH:6][C:10]([CH:7]1[CH2:9][CH2:8]1)=[O:11])([C:4]#[CH:5])[CH3:3]
Reactant: O=C(O)C1CC1
Reactant: C#CC(C)(C)N
Product: C#CC(C)(C)NC(=O)C1CC1

Procedure:
The title compound was prepared from 2-methylbut-3-yn-2-amine and cyclopropanecarboxylic acid following the procedure described in Preparation 4.
Reaction SMILES: [H-].[Na+].F[C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([P:33](=[O:36])([OH:35])[OH:34])([OH:32])[PH2:30]=[O:31])=[CH:25][CH:24]=2)[N:5]=1.[CH2:37]([OH:39])[CH3:38]>>[CH2:37]([O:39][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([P:33](=[O:36])([OH:35])[OH:34])([OH:32])[PH2:30]=[O:31])=[CH:25][CH:24]=2)[N:5]=1)[CH3:38]
Reactant: O=[PH2]C(O)(c1ccc(Nc2nc(F)nc3c2ncn3CCc2cccc(O)c2)cc1)P(=O)(O)O
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(Nc2ccc(C(O)([PH2]=O)P(=O)(O)O)cc2)c2ncn(CCc3cccc(O)c3)c2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled flask (0° C.) under an atmosphere of N2 containing 0.096 g (4.02 mmol) of sodium hydride was added 2.0 mL of absolute ethanol. After the effervescence had ceased, the solution was transferred via pipette to a cooled (0° C.) pressure flask, under an atmosphere of N2, containing a mixture of [(4-{2-Fluoro-9-[2-(3-hydroxy-phenyl)-ethyl]-9H -purin-6-ylamino}-phenyl)-hydroxy-phosphinoylmethyl]-phosphonic acid (0.199 g, 0.39 mmol) in 2.0 mL of absolute ethanol. Upon sealing the reaction vessel, the resulting mixture was stirred at ambient temperature for ˜10 min, then heated at 80° C. overnight. Ethanol was removed via N2 flow (slight heat) and the resulting thick suspension was dissolved in 25 mL of H2O (adjusted to pH ˜8 with 10% NaOH), filtered (0.2 μm, PTFE filter), and purified by RP-HPLC (CH3CN/H2O). Lyophilization provided a white solid (0.105 g): m/z 532 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29]>N1CCCCC1.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=[C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20][C:21]2=[O:29])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)OC)c1C
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)c(CCC(=O)OC)c1C
Temperature: 10 °C
Yield: 75.1 %

Procedure:
5-Formyl-4-(2-methoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (80.2 g), 2-oxindole (37.9 g) and ethanol (300 mL) were warmed to 70° C. in a 500 mL, 3-neck round bottom flask equipped with mechanical stirring and a reflux condenser. Piperidine (1.3 g) was added and the mixture was refluxed for 4 hours. The mixture was cooled to 10° C. and the orange precipitate collected by vacuum filtration and washed with 30 mL of ethanol. The solid was slurry-washed in 150 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 81.7 g (75%) of 4-(2-Methoxycarbonylethyl)-3-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as an orange solid.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:25][CH:22]1[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NC3CC3)c2)N1C

Procedure:
6.6 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of cyclopropyl amine and 4 g of triethyl amine in 50 ml of ethanol and worked up. Fair yellow crystals, melting point: 180° C. (decomposition).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[O:24])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Product: CCN(CC)C(=O)CN(c1ccc(C)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid with diethylamine
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][CH:36]([CH3:42])[CH2:37][CH2:38][C:39](O)=[O:40].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][CH2:37][CH:36]([CH3:42])[CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CC(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CCC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 4-methylpentanoic acid (37 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(4-methyl-pentanoylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (114 mg) as a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([OH:14])=O)[CH:5]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([Cl:24])=[O:14])[CH:5]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 75 °C
Reaction time: 7 h
Yield: 117.4 %

Procedure:
A 500 mL three neck round bottom flask with thermowell was fitted with a condenser which vented to a trap and then an aqueous 10% NaOH scrubber, magnetic stir bar, two stoppers and a thermometer. To the vessel was added 4,5,6-trichloropicolinic acid (86 g which contained 8.6 g water, 77.4 g active, 0.32 mol), toluene (160 mL), thionyl chloride (85 mL, 1.12 mol) and DMF (0.3 mL). The slurry was heated to 70-80° C., held there for 7 h and then cooled to room temperature and allowed to stir overnight. Approximately 0.2 mL of the pale yellow solution was placed in a vial and concentrated to a solid under a stream of N2. The solid was treated with a mixture of triethylamine/methanol (0.3 mL/2 mL) and then warmed with a heat gun for ca. 1 min. HPLC analysis indicated that less than 1% of the carboxylic acid remained as compared to the methyl ester derivative. The solution was concentrated on a rotary evaporator leaving a pale yellow solid. The solid was dried (40° C./20 mmHg) for about 1 h providing the title compound (92 g): mp 68-70° C.; 1H NMR (CDCl3, 400 MHz) δ 8.12 (s), the solid contained about 4 wt % toluene as determined by integration of the proton signals; 13C NMR (CDCl3, 101 MHz) δ 167.3, 151.0, 145.82, 145.8, 135.7, 125.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7]2.Br[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:23]=1[CH3:33]>>[CH3:28][C:27]1[CH:26]=[C:25]([Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:24]=[C:23]([CH3:33])[C:22]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[O:11]
Reactant: CC1(C)OB(c2ccc(F)c3c2CCC3=O)OC1(C)C
Reactant: Cc1cc([Si](C)(C)C)cc(C)c1Br
Product: Cc1cc([Si](C)(C)C)cc(C)c1-c1ccc(F)c2c1CCC2=O

Procedure:
The title compound is prepared from 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one and (4-bromo-3,5-dimethylphenyl)trimethylsilane following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.89 min; Mass spectrum (ESI+): m/z=327 [M+H]+.