Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2.[CH3:34][N:35]=[C:36]=[O:37]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:36]([NH:35][CH3:34])=[O:37])[C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2
Reactant: Cc1c(N2CCN[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CN=C=O
Product: CNC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)C[C@@H]1C

Procedure:
Prepared according to Procedure N using (S)-5,7-difluoro-3-methyl-2-(3-methylpiperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and methylisocyanate to give (S)-4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-N,2-dimethylpiperazine-1-carboxamide. 1H NMR (CDCl3) δ ppm 7.94 (1H, d, J=2.5 Hz), 7.69 (1H, d, J=2.2 Hz), 7.30 (1H, ddd, J=10.0, 2.5, 1.2 Hz), 6.90 (1H, d, J=13.3 Hz), 6.81 (1H, ddd, J=13.8, 8.7, 2.5 Hz), 6.59 (1H, t, J=2.3 Hz), 4.49 (1H, q, J=4.9 Hz), 4.18-4.31 (1H, m), 3.78-3.91 (5H, m), 3.69-3.78 (1H, m), 3.60 (1H, dt, J=12.8, 1.7 Hz), 3.37 (1H, td, J=12.4, 3.1 Hz), 3.09-3.23 (5H, m), 2.96 (1H, td, J=12.4, 3.5 Hz), 2.87 (3H, d, J=4.7 Hz), 2.10 (3H, s), 1.31 (3H, d). Mass Spectrum (ESI) m/e=512.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=1[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2F)c(C)c1
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a solution of 5-bromo-2-fluorobenzoic acid (3.50 g, 15.9 mmol) in CH2Cl2 (50 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (2.86 g, 15.9 mmol, see preparation 12) and N,N-diisopropylethylamine (8.35 ml, 47.9 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 20.5 ml, 31.9 mmol) is added via syringe and stirred at ambient temperature. After 36 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 10% ethyl acetate in hexane to give the title compound as a white solid (4.20 g, 69%). Mass spectrum (m/z): 380.2 (M+1).
Reaction SMILES: [CH:1]([O:3][CH:4]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:19])=[C:12]([C:15](=[O:17])[CH3:16])[CH2:13][S:14][C@H:9]12)=[O:6])=[O:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.CCCCCCC>CC(C)=O>[CH:1]([O:3][CH:4]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([OH:20])=[O:19])=[C:12]([C:15](=[O:17])[CH3:16])[CH2:13][S:14][C@H:9]12)=[O:6])=[O:2]
Reactant: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2SC1
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Product: CC(=O)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2SC1
Temperature: 5 °C
Yield: 99.3 %

Procedure:
To a cooled (5° C.), stirred slurry of 0.194 g. of benzhydryl 7-(2-formyloxy-2-phenylacetamido)-3-acetyl-3-cephem-4-carboxylate in 10 ml. of anisole was added 1 ml. of cold trifluoroacetic acid. After allowing the reaction mixture to stir with cooling for 15 minutes, 30 ml. of n-heptane was added and the resulting solution was evaporated in vacuo to a low volume. An additional 30 ml. of n-heptane was added, and the resulting solution was stirred with cooling in an ice bath for 5 minutes. The solid obtained by filtration of the n-heptane solution was dissolved in acetone, the acetone solution was filtered, and the filtrate was evaporated in vacuo to a low volume. The residue was transferred with the aid of cold ethyl acetate to a separatory funnel where the resulting ethyl acetate solution was extracted twice with cold aqueous sodium bicarbonate solution. The aqueous extracts were combined, layered with cold ethyl acetate, and acidified with cold 1N.HCl. The organic layer was separated, washed twice with brine, and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided 0.136 g. (99.3 percent) of the title product as a white froth which failed to crystallize from aceonte/hexane or chloroform/hexane:
Reaction SMILES: [OH:1][C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]1[N:7]=[CH:6][N:5]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11][CH2:10]2)[N:4]=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[C:31]1([C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:3]2[N:7]=[CH:6][N:5]([CH2:8][CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[N:4]=2)[OH:1])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Cn2cnc(C(O)(c3ccccc3)c3ccccc3)n2)CC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: OC(c1ccccc1)(c1ccccc1)c1ncn(CC2CCNCC2)n1
Temperature: 25 °C
Yield: 51 %

Procedure:
Benzyl 4-({3-[hydroxy(diphenyl)methyl]-1H-1,2,4-triazol-1-yl}methyl)piperidine-1-carboxylate (Preparation 25, 5.2 g, 16.78 mmol) was dissolved in ethanol (300 ml) and ammonium formate (6 g) and palladium hydroxide [20 wt. % (dry basis) on carbon (wet)] (1 g) added. After stirring at reflux for 1 hour the reaction mixture was cooled to room temperature and filtered through Arbocel®. The solvent was removed in vacuo and the residue partitioned between dichloromethane (500 ml) and water (500 mL). The aqueous layer was separated and then basified with aqueous sodium hydroxide solution (2N, 200 ml) and extracted with dichloromethane (500 ml). This organic layer was then dried over magnesium sulphate, filtered and the solvent removed in vacuo. The crude material was recrystallised from acetonitrile to furnish the title compound as a white solid, in 51% yield, 1.9 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH3:26][NH:27][CH2:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([N:32]3[CH2:33][CH2:34][O:35][CH:30]([CH2:29][CH2:28][NH:27][CH3:26])[CH2:31]3)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: CNCCC1CNCCO1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Product: CNCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
By the use of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2 -methylaminoethyl)morpholine, the reaction is similarly carried but as Example 26 to give 1-(2,4-difluorophenyl)-6,8-difluoro-1,4-dihydro-7-[2-(2-methylaminoethyl)morpholino]-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[NH2:42][C:43]1[C:47](C#N)=[C:46]([C:50]#[N:51])[NH:45][N:44]=1>>[C:43]([C:47]1[C:46]([C:50]#[N:51])=[N:45][N:44]2[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:17]=12)#[N:42]
Reactant: N#Cc1[nH]nc(N)c1C#N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: N#Cc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 4.86 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 50 ml. of glacial acetic and 2.66 g. of 3-aminopyrazole-4,5-dicarbonitrile is refluxed for 10 hours and the solvent removed under reduced pressure. The residue is reacted with trifluoroacetic anhydride to give the product of the example.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH:5](O)[CH2:4][CH:3]1[CH3:10].S(Cl)([Cl:13])=O>C1C=CC=CC=1.O>[CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH:5]([Cl:13])[CH2:4][CH:3]1[CH3:10]
Reactant: CC1CC(O)CC(C)N1C
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CC1CC(Cl)CC(C)N1C
Temperature: 70 °C

Procedure:
The starting material, 1,2,6-trimethyl-4-piperidinol, may be prepared by the method disclosed in Archi Kem, Volume 27, pages 189-192 (1955). To a cooled (ice-bath) solution of 1,2,6-trimethyl-4-piperidinol (12.2 g, 85.3 mmol) in 120 mL of dry benzene is slowly add thionylchloride (17 mL, 233 mmole). The dark reaction mixture is warmed to 70° C. for 20 min. The reaction is cooled and then suspended in water followed by filtration. The filtrate is extracted once with diethylether. The aqueous layer is separated and the basified with 30% NaOH solution. The product is then extracted twice with CH2Cl2, washed once with brine, dried (Na2SO4), filtered and the solvent removed to produce a crude brown liquid which is distilled (2-4 mmHg, 62°-64° C.) to give the title compound (8.0 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])#[N:21]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cccc(C#N)c2)c(=O)[nH]c1=O
Yield: 47.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (185 mg, yield: 47.3%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:16])[CH:13](Br)[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>C(O)CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:16])[CH:13]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Br)C(C)Cc1ccc(C(C)(C)C)cc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: OCCO
Product: CC(Cc1ccc(C(C)(C)C)cc1)C(C)N1CCCCC1

Procedure:
21.2 g of 3-(p-tert.butyl-phenyl)-1,2-dimethyl-propyl bromide, 17 g of piperidine and 7.5 g of ethyleneglycol are heated to 110° C. for 60 hours. After cooling, the mixture is treated with 2-N hydrochloric acid and the neutral constituent is extracted with ether. Subsequently, the hydrochloric acid solution is made alkaline with 5-N sodium hydroxide solution and extracted with ether. The combined ether extracts are washed neutral with water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 1-[3-(p-tert.butyl-phenyl)-1,2-dimethyl-propyl]-piperidine (boiling point 125° C./0.005 Torr) in the form of a colourless oil.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]([NH2:24])[C:17](=[CH:21][C:22]=1[F:23])[C:18]([OH:20])=O.Cl.[CH2:26]([O:29][NH2:30])[CH:27]=[CH2:28].C(N(CC)CC)C>C1COCC1>[NH2:24][C:16]1[CH:15]=[C:14]([F:13])[C:22]([F:23])=[CH:21][C:17]=1[C:18]([NH:30][O:29][CH2:26][CH:27]=[CH2:28])=[O:20]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: C=CCON
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCONC(=O)c1cc(F)c(F)cc1N
Yield: 53.6 %

Procedure:
Carbonyldiimidazole (3.37 g, 20 mmol) was added to a suspension of 4,5-difluoroanthranilic acid (3.0 g, 17 mmol) in 80 mL of THF, and the mixture was heated to reflux for 2 hours. The solution was cooled and O-allylhydroxylamine hydrochloride (1.89 g, 17 mmol) and triethylamine (2.8 mL, 20 mmol) were added, and the mixture was heated to reflux for 17 hours. The reaction mixture was concentrated and washed with 1N HCl, saturated NaHCO3, and brine and dried over magnesium sulfate. The solution was concentrated and purified by column chromatography (silica gel, CHCl3/MeOH, 98:2) to give 2.08 g of the title compound as a solid.
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=4[F:40])=[O:28])=[CH:22][CH:21]=3)[C:14]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=4[F:40])=[O:28])=[CH:22][CH:21]=3)[C:14]([CH2:16][CH2:17][CH:18]=[O:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: Nc1ncnn2cc(CCCO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(CCC=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Yield: 99.1 %

Procedure:
To a solution of THF (5 mL) was added N-{4-[4-amino-6-(3-hydroxypropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (55 mg, 0.11 mmol) followed by Dess-Martin Periodinane reagent (0.29 mL, 0.14 mmol, 15% wt in CH2Cl2). The reaction was stirred until HPLC indicated completion of reaction (2 h). The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3/Na2S2O3 1:1 (3×). The aqueous layer was back extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4), filtered, and evaporated to give a crude yellow solid (53 mg, 96%) that was used without further purification. 1H-NMR (DMSO-d6) δ 9.35 (s, 1H), 8.98 (s, 1H), 8.62 (d, J=7.2 Hz, 1H), 7.80 (s, 1H), 7.62 to 7.28 (m, 6H), 2.71 (t, J=7.5 Hz, 2H), 2.41 (t, J=7.4 Hz, 2H); MS [M+H]+=487; LCMS RT=2.62 min.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[N:7]([CH3:27])[C:8]([C:17]([C:19]2[N:20]([CH3:26])[C:21]([S:24][CH3:25])=[CH:22][CH:23]=2)=[O:18])=[C:9]([CH3:16])[C:10]=1C(OCC)=O)C.CN1C(C2N(C)C(SC)=CC=2)=C(C)C=C1CC(O)=O>>[CH3:27][N:7]1[C:8]([C:17]([C:19]2[N:20]([CH3:26])[C:21]([S:24][CH3:25])=[CH:22][CH:23]=2)=[O:18])=[C:9]([CH3:16])[CH:10]=[C:6]1[CH2:5][C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2ccc(SC)n2C)n1C
Agent: CSc1ccc(-c2c(C)cc(CC(=O)O)n2C)n1C
Product: CSc1ccc(C(=O)c2c(C)cc(CC(=O)O)n2C)n1C

Procedure:
Following substantially the same procedures as described in Example 7, steps B, C and D, 10 g of ethyl-1,4-dimethyl-5-(1-methyl-5-methylthiopyrrol-2-oyl)-3-ethoxycarbonylpyrrole-2-acetate was converted in three steps to 6.3 g of 1,4-dimethyl-5-(1-methyl-5-methylthiopyrrol-2-yl)pyrrole-2-acetic acid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9]>>[CH:5]1[CH:4]=[CH:3][C:2]([S:8]([OH:11])(=[O:10])=[O:9])=[C:1]([OH:7])[CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Product: O=S(=O)(O)c1ccccc1O

Procedure:
100 g of phenolsulphonic acid (produced by a four-hour sulphonation of 250 parts of phenol with 270 parts of 98% sulphuric acid) are slowly reacted with a solution of 61.5 g of dimethylolurea in 75 g of water at 40° C. and the mixture is stirred for a few hours until a clear solution forms. The solution is then neutralised with 30% aqueous sodium hydroxide and then concentrated. About 150 g of a light coloured salt are produced.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:26][O:27][C@@H:28]3[O:37][CH:36]4[C@@H:31]([O:32][CH:33]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[O:34][CH2:35]4)[C@H:30]([O:44][C:45](=[O:67])[CH2:46][S:47][C:48]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C@@H:29]3[NH:68][C:69](=[O:71])[CH3:70])[C:20]([O:22]CC=C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CNC1C=CC=CC=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:26][O:27][C@@H:28]3[O:37][CH:36]4[C@@H:31]([O:32][CH:33]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[O:34][CH2:35]4)[C@H:30]([O:44][C:45](=[O:67])[CH2:46][S:47][C:48]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[C@@H:29]3[NH:68][C:69](=[O:71])[CH3:70])[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C=CCOC(=O)[C@@H](CO[C@@H]1OC2COC(c3ccccc3)O[C@H]2[C@H](OC(=O)CSC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1NC(C)=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CNc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1[C@H](OC[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)OC2COC(c3ccccc3)O[C@H]2[C@@H]1OC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
Allyl protected glycosyl amino acid 34 (135 mg, 0.14 mmol) was suspended in THF (6 ml). N-methylaniline (0.15 ml, 1.38 mmol) and Pd(PPh3)4 (16 mg, 0.01 mmol) were added and the reaction stirred at rt for 20 min. The solvent was removed in vacuo and the product purified by column chromatography (eluent: 95:5 v/v dichloromethane/methanol—9:1 v/v dichloromethane/methanol) to give the desired acid 35 as a pale yellow solid (123 mg, 95%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@@H:29]1[CH2:33][C@@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:31]([F:42])[CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:33][C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C@@H:31]([F:42])[CH2:30]4)=[O:27])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](N)C[C@H]1F
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1C[C@H](NC(=O)OC(C)(C)C)[C@@H](F)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1R*,2R*,4R*)-4-amino-2-fluorocyclopentyl]carbamate (example C44) the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([N:29]3[CH2:28][CH2:27][N:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:31][CH2:30]3)=[O:18])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(C(=O)O)o2)c(C)[nH]c1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCc1cc(-c2ccc(C(=O)N3CCN(c4ccc(F)cc4)CC3)o2)c(C)[nH]c1=O
Yield: 98 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-carboxylic acid and (4-fluoro-phenyl)-piperazine to afford the title compound (98% yield). LC/MS: RT 2.9 min; m/e 410 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:16])([CH3:15])[C:10](=[O:14])[NH:11]2)=[CH:7][C:6]=1[N+:17]([O-])=O)(=O)[CH3:2].[H][H]>[Pt](=O)=O.C(O)(=O)C>[CH3:2][C:1]1[NH:4][C:5]2[CH:13]=[C:12]3[NH:11][C:10](=[O:14])[C:9]([CH3:16])([CH3:15])[C:8]3=[CH:7][C:6]=2[N:17]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(C)(C)C(=O)N2
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C

Procedure:
Analogously to Example 5, 5.00 g. (0.019 mole) 6-acetamido-5-nitro-3,3-dimethylindolin-2-one are suspended in 900 ml. glacial acetic acid and hydrogenated in the presence of 0.5 g. platinum dioxide at normal pressure and ambient temperature. After 1.4 liters of hydrogen have been taken up, the reaction mixture is filtered and the filtrate is evaporated to dryness in a vacuum. The residue is taken up in water and neutralised with a 2N aqueous ammonia solution. The precipitate obtained is filtered off with suction and recrystallised from ethyl acetate. There are obtained 2.75 g. (67% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1[O:32][C:33]([CH2:36]Br)=[CH:34][CH:35]=1)=[O:30])[CH3:27]>>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:36][C:33]4[O:32][C:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])=[CH:35][CH:34]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1ccc(CBr)o1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of example 8 step (i) (2.3 g) and 5-bromomethyl-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807) (2.3 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 25% ethyl acetate in toluene. Yield 1.8 g. Used directly in the next step.
Reaction SMILES: S(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(C)(=O)=O.[Na+].[I-:26]>C(#N)C>[I:26][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1CCOS(C)(=O)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1CCI
Yield: 118.1 %

Procedure:
Ethyl 1-(2-mesyloxyethyl)-3-carboethoxy-4-methylpyrrole-2-acetate (11.6 g) and 27 g of NaI was heated to reflux with 150 ml of acetonitrile for 1 hour. Solvent was removed by distillation and the residue triturated with water. The insoluble product was separated by filtration, air dried and crystallized from methylenechloride/hexane to yield 14.9 g of ethyl 1-(2-iodoethyl)-3-carboethoxy-4-methylpyrrole-2-acetate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Brc1cncnc1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cncnc2)n1

Procedure:
The title compound, light brown solid, MS (ISP): m/e=327.0 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-bromo-pyridine.