Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](C2C=CC=CC=2S([O-])(=O)=O)=[C:4]([CH3:21])[CH:3]=1.[OH-:22].[Na+].Cl>O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:22])=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1-c1ccccc1S(=O)(=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1O
Reaction time: 2 h

Procedure:
84.2 (0.26 mol) of the ester from step 2 are suspended in 1 l of water and mixed with 30.8 g (0.77 mol) of sodium hydroxide platelets. After 2 hours cooking under reflux the starting material is cooled and the solution is adjusted to a pH value of 2.1 with 2 N hydrochloric acid. The precipitated material is filtered by suction, washed with water and dried in vacuum at 50° C. The yield amounts to about 45.6 g 95.4% of the theoretical yield).
Reaction SMILES: BrC[CH2:3][C:4]1([CH3:17])[CH2:8][C:7]2[C:9]([CH3:16])=[C:10]([NH2:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[CH2:18]([N:25]([CH2:32][CH2:33][CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]2[O:5][C:4]([CH2:3][N:29]3[CH2:30][CH2:31][CH:26]([N:25]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:32][CH2:33][CH:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:27][CH2:28]3)([CH3:17])[CH2:8][C:7]=2[C:9]=1[CH3:16]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CCBr)O2
Reactant: c1ccc(CN(CCC(c2ccccc2)c2ccccc2)C2CCNCC2)cc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(N(CCC(c3ccccc3)c3ccccc3)Cc3ccccc3)CC1)O2
Yield: 60 %

Procedure:
Using 2-bromoethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and N-benzyl-N-(3,3-diphenylpropyl)-4-piperidinamine, the procedure of Example 1 was otherwise repeated to provide 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-benzyl-N-(3,3-diphenylpropyl)-4-piperidinamine. Yield 60%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[N:4][CH:3]=1.C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O1CCCC1.C(Cl)(Cl)Cl>[Cl:8][C:7]1[C:2]([NH:1][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:3][N:4]=[N:5][C:6]=1[Cl:9]
Reactant: Nc1cnnc(Cl)c1Cl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Nc1cnnc(Cl)c1Cl)Oc1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 26.4 %

Procedure:
A stirred suspension of 2.0 grams (0.012 mole) of 4-amino-5,6-dichloropyridazine in 75 ml of tetrahydrofuran is cooled to 0° C. and 1.5 grams (0.015 mole) of triethylamine is added in one portion. A solution of 2.3 grams (0.015 mole) of phenyl chloroformate in tetrahydrofuran is added dropwise during a 30 minute period. Upon completion of addition the reaction mixture is allowed to warm to ambient temperature where it is stirred for three days. The reaction mixture is taken up in 500 ml of chloroform and filtered to collect 0.98 gram of phenyl N-(5,6-dichloro-4-pyridazinyl)carbamate. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel to yield an additional 0.9 gram of phenyl N-(5,6-dichloro-4-pyridazinyl)carbamate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[I:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1.Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C>[I:16][C:17]1[CH:21]=[CH:20][N:19]([C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:18]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: Ic1cc[nH]n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)n1ccc(I)n1
Temperature: 40 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
A stirred solution of NaHMDS in THF (1.0 M, 3.1 mL, 3.1 mmol) was cooled in an ice water bath under Ar. 3-iodo-1H-pyrazole (500 mg, 2.6 mmol) was added as a solution in DMF (1 mL), washing with additional DMF (2×1 mL). tert-butyl 2-bromo-2-methylpropanoate (0.58 mL, 3.1 mmol) was added and the reaction mixture was removed from the cold bath and heated to 40° C. After 16 h, the reaction mixture was cooled and diluted with water and EtOAc. The phases were separated, and the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to afford tert-butyl 2-(3-iodo-1H-pyrazol-1-yl)-2-methylpropanoate 7.03 (649 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.36 (d, J=2.4 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 1.79 (s, 6H), 1.38 (s, 9H).
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](I)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:27]([CH:35]1[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)=O.CC(C)=O.O>O1CCCC1.C(OCC)(=O)C>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:27]([OH:34])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:35]3[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]3)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2ccnc2)cc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccccc3)C3CCN(C(C)=O)CC3)cc2c(Cl)c1Cc1ccc(-n2ccnc2)cc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (1.3 M, 0.70 mL, 0.92 mmol) was added dropwise to a stirring mixture containing 3-(4-(1H-imidazol-1-yl)benzyl)-4-chloro-6-iodo-2-methoxyquinoline (350 mg, 0.736 mmol, Intermediate 17: step c) and 1-(4-benzoylpiperidin-1-yl)ethanone (170 mg, 0.736 mmol, Intermediate 18) in tetrahydrofuran (7.4 mL) at −35° C. (dry ice-acetone cooling bath). The cooling bath was allowed to slowly warm to 23° C. After 16 hours, water (30 mL) and ethyl acetate (30 mL) were added. The layers were separated. The aqueous layer was extracted with ethyl acetate (30 mL) and the organic layers were combined. The combined solution was dried with sodium sulfate and the dried solution was filtered. Silica gel (2 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with ethyl acetate initially, grading to 10% methanol-ethyl acetate provided the title compound as an impure off-white solid. The impure solid was further purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the twice purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. MS (ESI): 581.1 [M+H]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[CH2:33][CH:32]([C:34]#[N:35])[CH2:31][C:29]=3[N:30]=2)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O[C:43]1[CH:48]=[CH:47][C:46]([C:49]2(C(OCC)=O)N(C([O-])=O)C=CS2)=[CH:45][CH:44]=1)CCCCC.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C(OCC)(=O)CC(OCC)=O.BrCCCCCCC.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[CH2:33][C:32]([C:34]#[N:35])([CH2:47][CH2:48][CH2:43][CH2:44][CH2:45][CH2:46][CH3:49])[CH2:31][C:29]=3[N:30]=2)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCOc1ccc(-c2nc3c(s2)CC(C#N)C3)cc1
Reactant: CCCCCCOc1ccc(C2(C(=O)OCC)SC=CN2C(=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCCCBr
Solvent: CCOC(=O)CC(=O)OCC
Solvent: C1CCOC1
Product: CCCCCCCC1(C#N)Cc2nc(-c3ccc(OCCCCCC)cc3)sc2C1
Reaction time: 0.25 h

Procedure:
6.1 ml of a 15% solution of butyllithium in hexane are added to a mixture of 1.4 ml of diisopropylamine in 10 ml of THF at -20°. 3.3 of g of 2-(4-n-hexyloxyphenyl)-5-cyano-5,6-dihydro-4-H-cyclopenta[d]thiazole (which can be prepared from ethyl 2-(4-n-hexyloxyphenyl)-thiazole-2,3-dicarboxylate by (a) reduction of the carbonyl groups, (b) conversion into the tosylate, (c) cyclization by reaction with diethyl malonate, (d) saponification and decarboxylation and (e) introduction of the nitrile group) in 10 ml of THF are then added at -60°, the mixture is stirred for 15 minutes, 1.8 g of 1-bromoheptane are then added and the mixture is stirred at -60° for a further 30 minutes and stirred overnight at room temperature. 10% ammonium chloride solution is added and the mixture is then worked up in the customary manner to give 2-(4-n-hexyloxyphenyl)-5-cyano-5-n-heptyl-5,6-dihydro-4-H-cyclopenta[d]thiazole.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(C2C=C([N+:33]([O-])=O)C=CC=2Cl)=O)C=CC=CC=1>>[C:1]1([S:7]([C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=2[NH2:33])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)c2ccccc2)c1
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccccc2)ccc1Cl
Product: Nc1ccc([N+](=O)[O-])cc1S(=O)c1ccccc1
Reaction time: 20 h

Procedure:
The procedure described in Example 20 is followed, except that as a starting material instead of phenyl-(4-chloro-3-nitrophenyl) sulfoxide a corresponding amount of phenyl-(2-chloro-5-nitrophenyl) sulfoxide is employed, and the reaction is carried out at 140° C. for 20 hours.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](N)[S:7][CH:8]=1)([CH3:3])[CH3:2].[Cl-:10].C([N+]([O-])=O)(C)(C)C>C(#N)C>[Cl:10][C:6]1[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: [Cl-]
Reactant: CC(C)c1csc(N)n1
Agent: CC(C)(C)[N+](=O)[O-]
Solvent: CC#N
Product: CC(C)c1csc(Cl)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
500 mg of 4-isopropyl-thiazol-2-yl amine obtained in step 93-2 was dissolved in 10 ml of acetonitrile and 900 mg of cupper(II) chloride dehydrate was added to the mixture, followed by adding 630 μl of t-BuNO2 thereto dropwise. The resulting mixture was heated to 65° C. and stirred for 2 hr. The resulting solution was cooled to room temperature and the reaction was terminated by adding water. The resulting mixture was extracted twice with ethyl acetate and washed with water and saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure to obtain 500 mg of the title compound as a light brown oil.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].P(Br)(Br)[Br:20]>N1C=CC=CC=1.CCOCC>[Br:20][CH2:1][C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC#CCC#CCC#CCC#CCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC#CCC#CCC#CCC#CCBr
Temperature: 0 °C

Procedure:
A mixture of 5 g of 2,5,8,11-heptadecatetrayn-1-ol, 1.25 cm3 of phosphorus tribromide and one drop of pyridine in 15 cm3 of anhydrous ether, stirred in the absence of light, is heated under reflux for 2 hours. The solution is then poured into 100 cm3 of ice water and extracted twice with ethyl ether. The ether phases are washed initially with a solution of sodium bicarbonate and then with water, and finally dried over sodium sulphate.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C@H:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:4].C=O.[CH:15]([OH:17])=O>>[CH3:4][CH2:3][N:2]([C:15]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C@@H:3]([N:2]([CH3:1])[CH3:12])[CH3:4])[CH:6]=1)=[O:17])[CH3:1]
Reactant: O=CO
Reactant: C[C@@H](c1cccc(O)c1)N(C)C
Agent: C=O
Product: CCN(C)C(=O)Oc1cccc([C@H](C)N(C)C)c1

Procedure:
Patent publication WO2006/068386 describes a process for preparation of 3-(1-dimethylamino)phenol by subjecting (S)-3-(1-dimethylaminoethyl)phenol to N-methylation using formaldehyde/formic acid. The 3-(1-dimethylamino)phenol it is subjected to O-carbamoylation to form rivastigmine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2sccc2n(Cc2cccc(F)c2)c1=O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: CCOC(=O)c1c(N2CCNCC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
7-Chloro-4-(3-fluoro-benzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (17) (10 g, 27.39 mmol) was added slowly to a solution of piperazine (9.42 g, 109 mmol) in dichloromethane. The solution was stirred at room temperature for 3 h. The solvent was evaporated under vacuum. The residue was suspended in water, stirred vigorously at room temperature, and filtered. The solids were again dissolved in dichloromethane and washed by water. The organic phase was dried over MgSO4 and concentrated to yield 9.63 g (84%) of 4-(3-fluoro-benzyl)-5-oxo-7-piperazin-1-yl-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.29 (m, 3H), 2.81 (m, 4H), 3.21 (m, 4H), 4.25 (m, 2H), 5.35 (s, 2H), 7.12 (m, 3H), 7.30 (m, 2H), 7.97 (m, 1H); EIMS m/z 416 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5]([CH3:13])=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>C(=O)(O)[O-].[Na+]>[OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5]([CH3:13])=[N:6][C:7]=1[C:8]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:9]
Reactant: CCOC(=O)c1nc(C)c2c(-c3ccc(OC)cc3)noc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(-c2noc3c(O)c(C(=O)NCC(=O)O)nc(C)c23)cc1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
Ethyl 7-hydroxy-3-(4-methoxyphenyl)-4-methylisoxazolo[4,5-c]pyridine-6-carboxylate (35 mg, 0.11 mmol) and glycine (320 mg, 4.27 mmol) were added to sodium methoxide solution (6.4 mL, 3.20 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in minimum amount of water and 0.25 M hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 22 mg of crude solid. The solid was dissolved in 10 mL of saturated sodium bicarbonate solution and washed with hexanes and EtOAc. The aqueous layer was acidified to pH 3 with concentrated hydrochloric acid and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 19 mg of the title compound. MS: (+) m/z 358.37 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]3[NH:11][C:12]([CH:17]=O)=[C:13]([O:15][CH3:16])[CH:14]=3)[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:4]=2[CH:3]=1.[CH3:26][C:27]1[NH:28][CH:29]=[C:30]([CH3:32])[CH:31]=1.Cl>CO.CCOCC>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]3[CH:14]=[C:13]([O:15][CH3:16])/[C:12](=[CH:17]/[C:29]4[NH:28][C:27]([CH3:26])=[CH:31][C:30]=4[CH3:32])/[N:11]=3)[N:5]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:4]=2[CH:3]=1
Reactant: Cc1c[nH]c(C)c1
Reactant: COc1cc(-c2cc3sc(Cl)cc3n2C(=O)OC(C)(C)C)[nH]c1C=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC1=CC(c2cc3sc(Cl)cc3n2C(=O)OC(C)(C)C)=N/C1=C\c1[nH]c(C)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a solution of tert-butyl 2-chloro-5-(5-formyl-4-methoxy-1H-pyrrol-2-yl)-4H-thieno[3,2-b]pyrrole-4-carboxylate (11 mg) and 2,4-dimethyl-1H-pyrrole (3.5 mg) in 1 mL of MeOH was added 2 small drops of a solution of 2 N HCl in ether. The dark-red reaction solution was stirred at r.t. for 10 min and then quenched with 3 mL of pH 7 sodium phosphate buffer solution. The product was extracted with 2×5 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 60% EtOAc/hexanes to give 10 mg of the title compound as a dark solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:28]([OH:30])=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I-].[Na+].[C:40]([O:46][CH2:47]Cl)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]>C(Cl)(Cl)Cl.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[C:40]([O:46][CH2:47][O:29][C:28](=[O:30])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[CH:16][CH:15]=1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Oc1ccc(CC(NC(=O)OCc2ccccc2)C(=O)OCOC(=O)C(C)(C)C)cc1

Procedure:
To a solution of 2.5 mmol of the compound of Step A above in 15 ml of chloroform there are added (nBu)4NHSO4 (0.5 of an equivalent), triethylamine (2 equivalents), sodium iodide (1 equivalent) and chloromethyl pivalate (2 equivalents). The reaction mixture is refluxed for 18 hours and then concentrated. The residue is dissolved in diethyl ether and is extracted with water, twice with 0.5M HCl, twice with 5% NaHCO3, and with water. The organic phase is concentrated and chromatography (dichloromethane/methanol: 9.9/0.1 to 9.5/0.5) allows the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)[CH2:14][CH2:13]1)=[O:10].[NH2:25][OH:26]>CCO.CCOC(C)=O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]2[CH:22]=[CH:21][C:20](/[CH:23]=[N:25]/[OH:26])=[CH:19]2)[CH2:14][CH2:13]1)=[O:10]
Reactant: NO
Reactant: Cc1[nH]c(C(=O)NC2CCN(n3ccc(C=O)c3)CC2)c(Cl)c1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(n3ccc(/C=N/O)c3)CC2)c(Cl)c1Cl

Procedure:
A solution of 3,4-dichloro-N-[1-(3-formyl-1H-pyrrol-1-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 259, 151 mg, 0.41 mmol) and 50% aqueous hydroxylamine (55 μl, 0.83 mmol) in 5 ml EtOH was heated at 80° C. for 30 min. The mixture was diluted with EtOAc and washed with brine. Drying (MgSO4) and removal of solvent gave a solid that was purified by reverse phase HPLC (30-55% gradient CH3CN in water with 0.1% TFA) to give product as a mixture of geometrical isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Cc1cc(Cl)cc(C(=O)O)n1
Reactant: Nc1nnn[nH]1
Product: Cc1cc(Cl)cc(C(=O)Nc2nnn[nH]2)n1
Yield: 68.7 %

Procedure:
0.68 g of 4-chloro-6-methyl-2-pyridinecarboxylic acid, 0.67 g of N,N'-carbonyldiimidazole and 0.37 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.65 g of N-(5-tetrazolyl)-4-chloro-6-methyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.[NH3:28]>CO>[NH2:28][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(C(=O)Nc2ccc(OCCBr)c(-c3ccnn3C)c2)c1
Reactant: N
Solvent: CO
Product: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Temperature: 150 °C
Yield: 53 %

Procedure:
A mixture of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-metho xy-benzamide (0.5000 g, 1.161 mmol) and ammonia (0.2515 g, 11.62 mmol) in 20 mL of methanol were heated to 150° C. for 30 minutes under microwave irradiation in a heavy walled sealed tube. The reaction mixture was concentrated to produce the crude product that was subjected to purification on HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid (TFA salt) in 53% yield. LCMS m/z (%)=367 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.83 (dd, J, =2.53 and J2=8.89 Hz, 1H), 7.68 (d,
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[N:19][C:20]=1[CH3:21]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:22][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[C:20]([CH3:21])[N:19]=2)[CH:7]=1
Reactant: Cc1nc(N)ccc1F
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(F)c(C)n1
Temperature: 140 °C
Yield: 16.3 %

Procedure:
A pressure tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol), 5-fluoro-6-methylpyridin-2-amine (257 mg, 2.04 mmol), and acetonitrile (8 mL) and then heated at 140° C. for 3 d. After cooling to room temperature the reaction mixture was concentrated in vacuo and the residue purified by chromatography (silica, 50 μm, 80 g, Analogix, 0 to 10% acetone in dichloromethane, 25 min) to afford ethyl 6-chloro-4-(5-fluoro-6-methylpyridin-2-ylamino)pyridazine-3-carboxylate (69 mg, 16%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.72 (br. s., 1H) 9.06 (s, 1H) 7.38 (s, 1H) 6.74-6.85 (m, 1H) 4.58 (q, J=7.07 Hz, 2H) 2.56 (d, J=3.03 Hz, 3H) 1.53 (t, J=7.07 Hz, 3H) 1.27 (s, 1H). LCMS (EI/CI) m/z: 311 [M+H].
Reaction SMILES: I[CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:4].CCN(C(C)C)C(C)C.[SH:33][C:34]([CH3:52])([CH3:51])[CH2:35][N:36]([CH3:50])[CH2:37][CH2:38][O:39][C:40]1[CH:45]=[C:44]([CH2:46][OH:47])[N:43]=[C:42]([CH2:48][OH:49])[CH:41]=1>CN(C=O)C>[OH:47][CH2:46][C:44]1[CH:45]=[C:40]([O:39][CH2:38][CH2:37][N:36]([CH3:50])[CH2:35][C:34]([S:33][CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:4])([CH3:52])[CH3:51])[CH:41]=[C:42]([CH2:48][OH:49])[N:43]=1
Reactant: CN(CCOc1cc(CO)nc(CO)c1)CC(C)(C)S
Reactant: COC(=O)CCOCCOCCOCCOCCNC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOCCNC(=O)CSC(C)(C)CN(C)CCOc1cc(CO)nc(CO)c1
Reaction time: 24 h
Yield: 57.1 %

Procedure:
73.7 mg of methyl 3-[2-(2-{2-[2-(2-iodoacetylamino)ethoxy]ethoxy}ethoxy)ethoxy]propanoate in solution in 1 ml of DMF and 39 μl of DIPEA are added to 45 mg of 4-{2-[(2-mercapto-2-methylpropyl)(methyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine in solution in 1 ml of DMF. After 24 h at AT, the mixture is concentrated under RP and purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-8 g), using a gradient from 0 to 10% of methanol in DCM. 53 mg of methyl 3-{2-[2-(2-{2-[2-(2-{[2-(2,6-bis(hydroxymethyl)pyridin-4-yloxy)ethyl](methyl)amino}-1,1-dimethylethylsulphanyl)acetylamino]ethoxy}ethoxy)ethoxy]ethoxy}propanoate are thus obtained.