Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH2:23][Br:24])[CH:14]=1.C(OCC)(=O)C>CN(C=O)C>[BrH:24].[C:4]([C:3]1[C:2](=[NH:1])[N:10]([CH2:23][C:15]2[CH:14]=[C:13]([Cl:12])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH:9]=[C:8]([Cl:11])[CH:7]=1)(=[O:5])[NH2:6]
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: COC(=O)c1ccc(Cl)cc1CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: COC(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 25 °C
Yield: 15.2 %

Procedure:
(Step 3) A solution of 2-amino-5-chloronicotinamide (202 mg) and methyl 4-chloro-2-bromomethylbenzoate obtained in Step 2 (470 mg) in DMF (5 ml) was stirred overnight at 90° C. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol and ethyl acetate to give the title compound (78 mg).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](N)=[CH:37][CH:36]=1)=[O:34]>CN(C=O)C>[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])[CH3:32].[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: CC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The D-biotin (1 g, 4.1 mmol) is solubilized in 45 ml of anhydrous DMF in the hot state. The mixture is cooled to 0° C. under argon, and then N-methylmorpholine (590 μl, 5.33 mmol) and isobutyl chloroformate (840 μl, 6.60 mmol) are successively added. The mixture is kept stirred for 30 min, and then 4-aminoacetophenone (824 mg, 6.10 mmol) is added. The solution is maintained stirred at 0° C. for 2 h, and then evaporated to dryness. The residue is taken up in 50 ml of water. The precipitate obtained is filtered, washed with water and then with 50 ml of MeOH in the hot state. The white precipitate is dissolved in DMF while heating and then the solution obtained is filtered and washed with MeOH. The filtrate is recovered and evaporated to dryness to give 888 mg of 1b (2.46 mmol, 60%).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH2:13]([N:15](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[C:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:15]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
In dichloromethane (20 ml), methyl 4-hydroxymethylbenzoate (1.00 g) was dissolved, followed by the addition of triethylamine (0.9 ml). Under ice cooling, a solution of methanesulfonyl chloride (0.70 g) in dichloromethane (dichloromethane: 5 ml) was added to the resulting solution. The resulting mixture was stirred at room temperature for 15 hours. After dilution with dichloromethane, the reaction mixture was washed with water and was then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in acetonitrile (12 ml). To the resulting solution, potassium cyanide (0.80 g) and 18-Crown-6 (0.16 g) were added, followed by stirring at room temperature for 40 hours. After concentration under reduced pressure, the concentrate was diluted with dichloromethane, washed with water and then, dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane), whereby colorless crystals (0.91 g, 86%) was obtained. A portion of the resulting crystals was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained.
Reaction SMILES: S([O-])(O)=O.[Na+].[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[C-:21]#[N:22].[Na+].[OH-].[Na+]>O>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:21]#[N:22])=[CH:9][CH:8]=1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(Br)cc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CC(c1ccc(Br)cc1)N1CCOCC1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A solution of 78.1 parts of sodium hydrogen sulfite in 400 parts of water was stirred for 15 min at 20° C. under a nitrogen atmosphere. After cooling to -5° C., there were added portionwise 100 parts of 4-bromobenzaldehyde and stirring was continued for 20 min at 10° C. Next there were added portionwise 65.3 parts of morpholine and, after stirring for 15 min, a solution of 26.9 parts of sodium cyanide in 90 parts of water. The mixture was stirred for 22 hours at 50° C. and was then treated with 8.7 parts of a sodium hydroxide solution 50%. The product was filtered off, washed with water and dried in vacuo at 50° C., yielding 138.5 parts (98.5%) of α-(4-bromophenyl)-4-morpholineacetonitrile (interm. 44).
Reaction SMILES: [CH2:1]([C:3]1[C:15]([CH2:16][CH2:17][NH2:18])=[C:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:15]([CH2:16][CH2:17][NH:18][C:26](=[O:28])[CH3:27])=[C:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccc3oc(C)cc3c2c1CCN
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nn2ccc3oc(C)cc3c2c1CCNC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a solution of 2-(2-ethyl-8-methylfuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanamine (100 mg, 0.411 mmol) and triethylamine (85.9 μL, 0.616 mmol) in tetrahydrofuran (4 mL) was added acetyl chloride (58.3 μL, 0.617 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. A saturated aqueous sodium hydrogen carbonate solution (100 μL) was added and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallization (ethyl acetate/hexane) to give the title compound (59.7 mg, yield 51%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH2:19][C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([F:28])[C:21]=2[F:29])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[N+:39]([O-])=O.Cl>CN(C)C=O>[NH2:39][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:33]=1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1[CH:10]=[C:11]([O:18][CH2:19][C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([F:28])[C:21]=2[F:29])[C:12]([O:16][CH3:17])=[CH:13][C:14]=1[Cl:15]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: COc1cc(Cl)c(NC(=O)OC(C)(C)C)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(N(C(=O)OC(C)(C)C)c2ccncc2N)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.8 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)-5-chloro-2-(2,3-difluoro-6-methoxy-benzyloxy)anisole (0.2 g) in N,N-dimethylformamide (2 mL) was added sodium hydride (55%, 21 mg), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 4-chloro-3-nitropyridine (78 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL)—methanol (5 mL). To the solution were added nickel(II) bromide (5 mg) and sodium borohydride (53 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give 3-amino-4-{N-(tert-butoxycarbonyl)-N-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]amino}pyridine (53 mg). This material was dissolved in diglyme (1 mL), and the solution was stirred at 150° C. for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/methanol=10/1). The obtained product was dissolved in ethyl acetate. To the solution were added diethyl ether and n-hexane, and the precipitated crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give the title compound (6 mg).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=O)C.[N:17]#[C:18][NH2:19].[OH-].[Na+].Cl>O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]([S:13]([NH:19][C:18]#[N:17])(=[O:15])=[O:14])=[CH:6][C:5]=1[NH2:4]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1NC(C)=O
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(S(=O)(=O)NC#N)cc1N
Temperature: 10 °C

Procedure:
132 parts of 3-acetylamino-4-methoxybenzenesulfonyl chloride and 25 parts of cyanamide are suspended in 400 parts of water at 0° C. and reacted with one another at a temperature of about 20° C. while a pH between 9 and 11 is maintained. Then 130 parts by volume of 33% strength aqueous sodium hydroxide solution are added and the acetylamino group is hydrolyzed at 100° C. in the course of an hour. The batch is then cooled down to 10° C. and brought to pH 2 with hydrochloric acid and the precipitated 2-methoxy-5-cyanamidosulfonylaniline is isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)[CH:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH:31]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:29])C.[CH2:44]([N:46](CC)[CH2:47][CH3:48])[CH3:45]>CC(CC)=O>[ClH:13].[CH2:44]([N:46]([CH2:29][CH2:28][N:30]1[CH2:35][CH2:34][N:33]([CH2:12][C:11]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH2:32][CH:31]1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:47][CH3:48])[CH3:45]
Reactant: CCN(CC)CC
Reactant: CCN(CC)C(C)N1CCNCC1c1ccccc1
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: CCC(C)=O
Product: CCN(CC)CCN1CCN(Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1c1ccccc1
Product: Cl

Procedure:
30 g. of 3,4-dibenzyloxy benzylchloride, 23 g. of 1-diethylamino ethyl-2-phenyl piperazine, 20 ml. of triethylamine, and 200 ml. of methylethylketone are boiled under reflux for 12 hours. The precipitated triethylamine hydrochloride is filtered off by suction. The solvent is distilled off and the residue is dissolved in benzene. The benzene solution is extracted with dilute hydrochloric acid (1 : 8). The hydrochloric acid extract is rendered alkaline by the addition of ammonia and is extracted with benzene. The benzene is removed from the benzene extract by distillation. Water-free alcoholic hydrochloric acid is added to the residue, and the hydrochloride of the resulting base is precipitated by the addition of a mixture of petroleum ether and acetone (1 : 1). The hydrochloride is redissolved in alcohol and is again precipitated by the addition of petroleum ether and acetone. Melting point of the hydrochloride: It starts to sublimate at 203° C. and melts at 235°-239° C. with decomposition. White crystals.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4]C=1.C(C1C=C2C(=CC=1)[NH:33]C(=O)/C/2=C\C1NC=CC=1)#C.BrC1C=NC=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[N:33]1[CH:2]=[CH:7][CH:6]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Brc1cccnc1
Product: O=C1Nc2ccc(C#Cc3cccnc3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (47 mg, 0.21 mmol) (Example 82) was coupled with 3-bromopyridine (33 mg, 0.30 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (15 mg, 0.021 mmol) (Aldrich) as catalyst in 1 mL DMF and I mL triethylamine at 70° C. for 15 hours to give (Z)-1,3-dihydro-5-(3-pyridinyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 30 mg, 47%).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH2:8][CH2:9][CH3:10])C(O)=O)[CH3:3].S(Cl)(Cl)=O.[CH3:15][NH:16][C:17]1[C:22]([C:23]([NH2:25])=[O:24])=[C:21]([O:26][CH3:27])[C:20]([O:28][CH3:29])=[CH:19][CH:18]=1.Cl[CH:31](Cl)Cl>>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:8][CH2:9][CH2:10][C:15]1[N:16]([CH3:31])[C:17]2[C:22]([C:23](=[O:24])[N:25]=1)=[C:21]([O:26][CH3:27])[C:20]([O:28][CH3:29])=[CH:19][CH:18]=2
Reactant: ClC(Cl)Cl
Reactant: CCCC(C(=O)O)N(C)C
Reactant: CNc1ccc(OC)c(OC)c1C(N)=O
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1OC)c(=O)nc(CCCCN(C)C)n2C
Temperature: 57.5 °C
Reaction time: 1.5 h

Procedure:
3.80 g (20.9 mmol) Dimethylamino-pentanoic acid were added to 25 ml thionyl chloride and stirred for 90 min. at 55-60° C. The remaining thionyl chloride was distilled in vacuum and the residue was added to a solution of 2.00 g (11.1 mmol) 6-methylamino-2,3-dimethoxybenzamide dissolved in 30 ml trichloromethane at 0° C. The mixture was boiled for 2 h and stirred overnight at room temperature. After filtration the residue was dissolved in trichloromethane and saturated sodium bicarbonate solution. The organic solution was dried over magnesium sulfate and evaporated under vacuum.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.N(C(C(C)C)C#N)=NC(C(C)C)C#N.[CH:23]1([PH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH:23]1([P:28]2[CH:5]3[CH2:6][CH2:7][CH2:8][CH:1]2[CH2:2][CH2:3][CH2:4]3)[CH2:27][CH2:26][CH2:25][CH2:24]1.[CH:23]1([P:28]2[CH:6]3[CH2:7][CH2:8][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1=CCCC=CCC1
Reactant: PC1CCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)C(C#N)N=NC(C#N)C(C)C
Solvent: Cc1ccccc1
Product: C1CCC(P2C3CCCC2CCC3)C1
Product: C1CCC(P2C3CCCCC2CC3)C1
Temperature: 80 °C

Procedure:
A 25 ml stirred vessel was charged at room temperature under nitrogen with 2.0 g (18.5 mmol) of 1,5-cyclooctadiene (Aldrich, 82018 Taufkirchen, DE), 71 mg of azo-bis-isovaleronitrile (VAZO 67, Aldrich, 82018 Taufkirchen, DE) and 3.8 g of a 50% strength solution of monocyclopentylphosphine in toluene (Cytec). This initial charge was subsequently heated to a bath temperature of 80° C. with stirring. After 24 h it was cooled to room temperature, treated with a further 71 mg of AIBN and heated with stirring at a bath temperature of 80° C. for a further 24 h. Subsequently it was worked up by vacuum distillation, giving 2.3 g of cyclopentylphobane isomer mixture (60% of theory; b.p.: 95° C. at 0.05 mbar).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:17])[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:16])[CH:8]=[CH:7][CH:6]=2.[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[CH:24][N:25]2[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1C=CC=CC=1.C(OCC)(=O)C>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][CH2:2][C:3]3[N:4]([CH3:17])[C:5]4[C:10]([C:11]=3[C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:16])[CH:8]=[CH:7][CH:6]=4)[CH:27]=2)[CH:23]=[CH:24]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1c(CBr)n(C)c2cccc(Cl)c12
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(N)cc21
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(CNc2ccc3ccn(CC(=O)OC(C)(C)C)c3c2)n(C)c2cccc(Cl)c12
Temperature: 25 °C
Yield: 55 %

Procedure:
Methyl 2-(bromo-methyl)-4-chloro-1-methyl-1H-indole-3-carboxylate (1.10 mmol, 1.0 equiv.) and tert-butyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate A) (1.10 mmol, 1.0 equiv.) were dissolved in benzene (5 ml) and triethylamine (1.3 mmol, 1.2 equiv.) and refluxed for 16 h. The reaction mixture was cooled to 25° C., diluted with ethyl acetate and washed with water and sat. NaCl solution. Drying over Na2SO4 was then carried out, followed by concentration under reduced pressure. The crude product was purified by column chromatography (40% ethyl acetate in hexane). Yield: 55%
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([O:18]C)=[O:17])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:22].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:22]
Reactant: COC(=O)c1cc(C(=O)NCc2ccc(F)c(C)c2)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CNC(=O)c2cc(C(=O)O)ncn2)ccc1F
Reaction time: 3 h

Procedure:
8.75 g (0.02 mol) of methyl 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylate (70%) were taken up in 150 ml of ethanol, after which 1.89 g (0.022 mol) of NaOH in 6 ml of water were added. After 3 hours (h) at room temperature, the solvent was removed under reduced pressure and water was added to the residue; the solution was then brought to pH <2 with conc. HCl. The precipitate was filtered off with suction and dried. This resulted in 5.5 g (94%) of 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid. MS (ES+): m/e=289.09.
Reaction SMILES: [Li][CH2:2]CCC.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH2:27][C:28]3[N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[CH:31](I)[NH:30][C:29]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=3)=[CH:14][C:9]=2[O:8][CH2:7]1.C(S([C:54]#[N:55])(=O)=O)C1C=CC=CC=1>C1COCC1>[CH2:33]([N:32]1[C:28]([CH2:27][N:16]([CH2:15][C:13]2[CH:12]=[CH:11][C:10]3[O:6][CH2:2][CH2:7][O:8][C:9]=3[CH:14]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=2)=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:30]=[C:31]1[C:54]#[N:55])[CH2:34][CH2:35][CH3:36]
Reactant: N#CS(=O)(=O)Cc1ccccc1
Reactant: [Li]CCCC
Reactant: CCCCN1C(CN(Cc2cccc(OCC)c2)Cc2ccc3c(c2)OCO3)=C(c2ccccc2)NC1I
Solvent: C1CCOC1
Product: CCCCn1c(C#N)nc(-c2ccccc2)c1CN(Cc1cccc(OCC)c1)Cc1ccc2c(c1)OCCO2
Temperature: -78 °C

Procedure:
n-BuLi (1.6 M in 0.2 mL hexane) is added dropwise to a solution of 200 mg of benzo[1,3]dioxol-5-ylmethyl-(1-butyl-2-iodo-4-phenyl-3H-imidazol-5-ylmethyl)-(3ethoxy-benzyl)-amine (prepared by the procedure set forth in the preceding example) at −78° C. under N2. The resulting mixture is stirred at −78° C. A solution of benzylsulfonyl cyanide (63 mg) in 5 mL THF is added and the resulting mixture is stirred at −78° C. for 2 hours, then warmed to room temperature and stirred overnight. The reaction is quenched with 5.0 mL water, extracted with ethyl acetate, and dried over Na2SO4. Concentration and purification via flash chromatography provides the desired product (Compound 5).
Reaction SMILES: [CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:27]([O:29]C)=[O:28])=[C:23]([CH2:25][CH3:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:27]([OH:29])=[O:28])=[C:23]([CH2:25][CH3:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCc1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)sc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)sc1C(=O)O
Temperature: 65 °C
Reaction time: 18 h
Yield: 125.8 %

Procedure:
To a stirred solution of methyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylthiazole-5-carboxylate (example 71A, 103 mg, 0.203 mmol) in MeOH (2 mL) was added NaOH (1.420 mL, 1.420 mmol). The solution was then stirred at 65° C. for 18 hrs. The reaction mixture was then cooled to room temperature and concentrated in vacuo to afford yellow slurry. The mixture was then diluted with water, brought to pH 4 with 1N HCl, and the precipitate collected by vacuum filtration. The filtrate was then extracted with CH2Cl2; the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude residue was then purified by silica-gel flash chromatography using an Isco 40 g column eluting from 0-8% MeOH/CH2Cl2. Desired fractions were combined with the collected precipitate and concentrated to afford 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylthiazole-5-carboxylic acid (126 mg, 126% yield) as an orange/yellow solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[NH3:15].Cl[S:17]([OH:20])(=O)=[O:18]>>[NH2:13][C:11]1[N:10]=[C:9]([NH2:14])[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[C:6]([S:17](=[O:20])(=[O:18])[NH2:15])[CH:5]=2)[N:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: N
Reactant: Nc1nc(N)nc(-c2ccccc2)n1
Product: Nc1nc(N)nc(-c2cccc(S(N)(=O)=O)c2)n1
Reaction time: 1 h

Procedure:
6.0 g of benzoguanamine is heated in 30 g of chlorosulfonic acid at 130° to 140° C. for 4 hours. After cooling, the mixture is added dropwise into 300 ml of 28% aqueous ammonia with stirring and after 1 hour, the insoluble matter is filtered out and recrystallized from aqueous dimethylsulfoxide. Melting point: over 290° C.; yield: 2.0 g.
Reaction SMILES: [P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].P([CH2:15]N[C@H](C(O)=O)C)(O)(O)=O>>[CH3:15][N:6]([CH2:5][P:1]([OH:4])([OH:3])=[O:2])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CNCP(=O)(O)O
Reactant: C[C@H](NCP(=O)(O)O)C(=O)O
Product: CN(CC(=O)O)CP(=O)(O)O

Procedure:
Liquid chromatography analysis of the recrystallized product showed that N-phosphonomethylglycine was present along with a sister compound whose peak on the chromatogram was of an intensity equal to that exhibited by glyphosate. The sister compound was understood to be N-phosphonomethylalanine. No N-methylglyphosate was formed, but a measurable trace of N-formylglyphosate was observed.