Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)c1cc(Br)ccc1CBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cc(Br)ccc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
3.0 g of 4-bromo-1-bromomethyl-2-methanesulfonylbenzene and 2.0 g of potassium phthalimide are stirred at 100° C. for 1 h in 30 ml of anhydrous DMF. The mixture is allowed to cool, diluted with 200 ml of water and the suspension is stirred at RT for 30 minutes. The product is then filtered off and 1.8 g of a colorless solid are obtained, mp 188-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccc1C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), methyl-o-tolyl-amine (44 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 L, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-o-tolyl-amide: MS m/z: (M+H) 518.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:13])[N:3]=1.[NH2:15][NH2:16]>>[NH:15]([C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:13])[N:3]=1)[NH2:16]
Reactant: Cc1ccc(C)c2c(C)cc(Cl)nc12
Reactant: NN
Product: Cc1ccc(C)c2c(C)cc(NN)nc12
Yield: 38 %

Procedure:
A solution of 2-chloro-4,5,8-trimethylquinoline (2.2 g, 10.7 mmoles) in NH2NH2 was reacted as outlined in Scheme 1 above to give the desired title compound (830 mg, 38%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.62 (s, 3 H) 2.78 (s, 6 H) 4.13 (br. s., 2 H) 5.74 (br. s., 1 H) 6.52 (s, 1 H) 6.95 (d, J=7.03 Hz, 1 H) 7.28 (d, 1 H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])[N:37]=[CH:38][C:31]=12>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:30]1[C:31]2[CH:38]=[N:37][N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])[C:32]=2[N:33]=[CH:34][N:35]=1)[C:24]([O:26][CH3:27])=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ccccc1Cl

Procedure:
Prepared according to the method for Intermediate AE2 from (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) and 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1). 1H NMR (400 MHz, DMSO) δ 0.94 (9H, s), 3.56-3.75 (4H, m), 3.68 (3H, s), 3.90-4.09 (2H, m), 5.80-5.85 (1H, m), 7.29-7.43 (6H, m), 7.50-7.67 (7H, m), 7.67-7.74 (1H, m), 8.43 (1H, s), 8.52 (1H, s); m/z (ESI+) (M+H)+=631; HPLC tR=3.38 min.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:15][CH:16]([NH2:24])[CH2:17][CH2:18][CH2:19][C:20](O)([CH3:22])[CH3:21].Cl>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]([NH2:24])[CH3:15])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccccc1
Reactant: CC(N)CCCC(C)(C)O
Agent: Cl
Product: CCCCCCCCc1ccc(C(C)(C)CCCC(C)N)cc1

Procedure:
6-(4-n-Octylphenyl)-6-methyl-2-heptylamine b0.26 162°-6° was prepared following the procedure of Example 3 from n-octylbenzene and heptaminol hydrochloride.
Reaction SMILES: C([O:8][C:9](=[O:17])[CH2:10][NH:11][C:12](=[O:16])[C:13]([CH3:15])=[O:14])C1C=CC=CC=1>O>[C:12]([NH:11][CH2:10][C:9]([OH:17])=[O:8])(=[O:16])[C:13]([CH3:15])=[O:14]
Reactant: CC(=O)C(=O)NCC(=O)OCc1ccccc1
Solvent: O
Product: CC(=O)C(=O)NCC(=O)O

Procedure:
Preferably in this method of synthesis, the thionyl chloride or oxalyl chloride is added to a suspension of sodium pyruvate to yield the pyruvyl chloride to which is added the of glycine benzyl ester hydrochloride. The resulting slurry is cooled during the addition of N-methylmorpholine solution to yield a pyruvyl-glycine benzyl ester. The yielding of the pyruvyl-glycine benzyl ester occurs after warming, the addition of water, separation, washing, drying, evaporation, precipitation, filtering, and drying again. The pyruvyl-glycine benzyl ester is then charged in a hydrogen pressure vessel in a solvent and a palladium on carbon catalyst, with the hydrogen pressure being approximately 60 psi such that hydrogen is digested whereby following filtering, concentration, precipitation, filtering, and drying there is yielded pyruvyl-glycine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:15]>C(OCC)(=O)C.ClCCl.[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]12[CH2:19][CH:20]3[CH2:21][CH:22]([CH2:23][CH:24]([CH2:26]3)[CH2:25]1)[CH2:27]2)=[O:15]
Reactant: COC(=O)/C=C/c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: [Rh]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 24 h
Yield: 104 %

Procedure:
5% Rhodium on carbon (0.40 g) was added to a solution of (2E)-3-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-2-propenoic acid, methyl ester (Example 6a, 2.2 g) in ethyl acetate/dichloromethane (4:1) (160 ml) and the mixture hydrogenated at 3 bar for 24 h. The catalyst was removed by filtration and the filtrate concentrated to give the subtitled compound as an oil (2.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15][Cl:20])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CO)=NC=C1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C1CC(CCl)=NC=C1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 5-benzyloxy-2-hydroxymethyl-4-pyridone (33 g) in benzene (500 ml) was added thionyl chloride (28.4 ml) at ambient temperature under stirring. After being stirred at the same temperature for 30 minutes, the mixture was refluxed for 4 hours. The resulting mixture was cooled to ambient temperature. The precipitate was collected by filtration, washed with benzene and dried under reduced pressure to give 5-benzyloxy-2-chloromethyl-4-pyridone (41.5 g).
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([CH:20]2[CH2:22][CH2:21]2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)[CH3:3].[CH2:23]([O:25][C:26](=[O:37])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[CH3:36])[CH3:24].[H-].[Na+]>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:37])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:2]([C:4]2[C:5]([CH:20]3[CH2:22][CH2:21]3)=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:8][CH:9]=2)[CH3:3])=[CH:31][C:30]=1[CH3:36])[CH3:24]
Reactant: CC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Yield: 56.9 %

Procedure:
180 mg (0.551 mmol) of [rac]-5-(1-chloro-ethyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 28H), 116 mg (0.551 mmol) of (4-hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (WO02092590) and 31 mg (0.71 mmol) sodium hydride (55% in oil) were stirred in 3 ml DMF over night. The reaction mixture was partitioned between ether and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 to give 157 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic acid ethyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+](=[CH2:15])=[N-]>CCOCC>[CH3:15][O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc2[nH]ccc2c1
Yield: 86 %

Procedure:
To a solution of 4.8 g (29.8 mmol) of indole-5-carboxylic acid in ether (200 ml) was added dropwise etheral diazomethane until the yellow color of diazomethane did not disappear. The mixture was concentrated and the obtained residue was chromatographed on silica gel (ethyl acetate as an eluant) to give 4.5 g of indole-5-carboxylic acid methyl ester. Yield: 86%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:6]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:29](=O)[CH2:30][CH:31]([CH3:33])[CH3:32].C(O)(=O)C>ClCCCl>[CH3:32][CH:31]([CH3:33])[CH2:30][CH2:29][NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[N:6]=1
Reactant: CC(C)CC=O
Reactant: N#Cc1ccc(-c2csc(N)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CCNc1nc(-c2ccc(C#N)cc2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
Slurry 4-(2-amino-thiazol-4-yl)-benzonitrile (2.0 g, 9.9 mmol), sodium triacetoxyborohydride (6.3 g, 29.7 mmol), isovaleraldehyde (1.7 g, 19.8 mmol) and acetic acid (3.6 mL) in 1,2-dichloroethane (100 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 16 h at room temperature. Quench the reaction with saturated aqueous NaHCO3 (75 mL, pH to 7.0-7.5). Extract the mixture twice with DCM (100 mL) and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g) eluting with hexane/EtOAc (20:1 to 3:2 gradient) to obtain the desired intermediate (1.8 g, 67%). MS (ES+) m/z: 272 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=3)[NH:29][N:28]=2)=[CH:23][CH:22]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([NH:36][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:34]=3)[NH:29][N:28]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, 3-(4-Fluoro-phenyl)-1H-indazole-5-ylamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=478 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[NH:21][N:20]=2)COCC[Si](C)(C)C)(=[O:9])=[O:8])=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:41][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:21]2[C:22]3[C:27](=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][CH:23]=3)[C:19]([NH:10][S:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:8])=[N:20]2)=[CH:33][CH:34]=1)(=[O:39])=[O:40]
Reactant: COc1cccc2[nH]nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c12
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(S(N)(=O)=O)cc1
Reaction time: 18 h
Yield: 10 %

Procedure:
5-Chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) (1.734 g, 3.66 mmol) was dissolved in DMF (2.4 mL) and an aliquot (0.1 mL, 0.15 mmol) added to 4-(bromomethyl)benzenesulfonamide (APAC Pharm) (0.15 mmol) and potassium carbonate (0.15 mmol) added last. The tubes were capped and shaken. Stood at room temperature for 18 h, more potassium carbonate (excess) added and reshaken the tubes. Filtered through alltech tube to remove inorganic solids, and washed tubes with MeOH (1 mL) and blown to dryness under a stream of nitrogen in a Radley's blow down unit. Redissolved in DCM (0.5 mL) and applied to a 10 g silica cartridge, and purified by chromatography on Flashmaster using a gradient of 0-100% DCM-(DCM with 20% EtOAc) over 20 min. The appropriate fractions were combined and evaporated in vacuo using the Genevac. The residue was dissolved in TBAF (1M, 0.5 mL) and heated in a microwave oven (50 Watts, 10 min, at approx 110° C. The sample was purified by MDAP on Atlantis column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo using the Genevac to give the title compound (7.9 mg, 10%) LCMS (System A) RT=0.92 min, ES+ve m/z 513/515 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.[NH4+:21].[Cl-].[NH4+].[OH-]>O>[NH2:21][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1
Reactant: [NH4+]
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Product: Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To 2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (1.1 g, 3.77 mmol) was added NH4Cl (100 mL) and NH4OH (100 mL). The resulting solution was heated to 90° C. and stirred for 16 hrs until complete. The reaction was cooled to ambient temperature and diluted with H2O (500 mL) until a precipitate formed. The solid precipitate was collected and dried to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11]Cl)(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH2:13]([C:15]([CH2:17][CH3:18])=[CH2:16])[CH3:14].[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(#N)C>[CH2:13]([C:15]1([CH2:17][CH3:18])[CH2:16][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Reactant: C=C(CC)CC
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: CCC1(CC)CN1S(=O)(=O)c1ccc(C)cc1
Yield: 40.5 %

Procedure:
Chloramine-T (10 g, 43.9 mmol) was suspended in acetonitrile (146 mL) at room temperature under nitrogen. To this suspension was added 2-ethylbut-1-ene (5.55 g, 65.9 mmol) followed by phenyltrimethylammonium tribromide (1.65 g, 4.39 mmol) in two roughly equal portions. After three days the reaction mixture was concentrated to half volume and then filtered through a sintered glass funnel. The filtrate was concentrated to half volume again which caused further precipitation. This mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The organic phase was dried with MgSO4, filtered and concentrated. The crude material was purified by column chromatography using a Biotage 65i column eluting with (0-100% EtOAc/hexane) to give 2,2-diethyl-1-[(4-methylphenyl)sulfonyl]-aziridine as a colorless solid (4.5 g).
Reaction SMILES: [CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([OH:10])[CH2:6][O:5]2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=1[CH3:22]>CN(C)C=O>[CH2:3]1[C:4]2([O:9][CH2:8][CH:7]([O:10][C:14]3[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=3[CH3:22])[CH2:6][O:5]2)[CH2:1][CH2:2]1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: OC1COC2(CCC2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OC2COC3(CCC3)OC2)cc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 64.4 %

Procedure:
To a dimethyl formamide (30 ml) solution of the 5,9-dioxaspiro[3.5]nonan-7-ol (1.68 g, 11.7 mmol) obtained in the step (9e), sodium hydride, in oil (587 mg, 13.5 mmol as the content was regarded as 55%) was added at room temperature. The mixture was stirred at room temperature for 50 minutes. After 4-chloro-2,3-dimethylpyridine 1-oxide (1.84 g, 11.7 mmol) was added thereto, the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated and dimethylsulfoxide (30 ml) was added thereto and stirred at 80° C. After 12 hours, sodium hydride, in oil (587 mg, 13.5 mmol as the content was regarded as 55%) was added to the reaction mixture and stirred at 80° C. After one hour, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate, ethyl acetate/methanol=9/1) to obtain the title compound (2.00 g, yield: 64.4%) as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH2:11][O:12]C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)CCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: OCCCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-phenyl-5-tetrahydropyranyloxypent-1-yne (0.2 g), absolute ethanol (4 ml) and p-toluenesulphonic acid (20 mg) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (40 ml) and extracted with ether (2×20 ml). The ether extracts were washed with saturated NaHCO3 solution, dried over MgSO4 and purified by chromatography on silica (20 g), eluting with 10% ether in hexane grading to 100% ether, followed by 10% ethyl acetate in ether. The solvent was removed to give 5-phenylpent-4-yn-1-ol as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=2)[N:13]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[N:13]=1
Reactant: CCOC(=O)c1cn2nc(OCc3cc(OC)c(OC)c(OC)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(COc2ccc3nc(C(=O)O)cn3n2)cc(OC)c1OC
Yield: 83.5 %

Procedure:
The product of stage (a) (1.94 g, 5 mmol) was heated under reflux with stirring with sodium hydroxide solution (1 ml, 10M, 10 mmol), water (9 ml) and methanol (5 ml) for 20 min. The mixture was cooled and acidified with dilute hydrochloric acid and filtered to give a solid which was dried at 60° in vacuo to give the title compound as a powder (1.5 g), m.p. 224°-226° (decomp), Nmr δH (d6 -DMSO) 8.56 (1H,s,3H), 8.07 (1H,JAB 8.8 Hz, 8H), 7.05 (1H, JAB 8.8 Hz, 7H), 6.88 (2H,s,ArH), 5.29 (2H,s,CH2Ar), 3.82 (6H, s, OCH3)3.68 (3H, s, OCH3) and 3.32 (1H, br.s, CO2H).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:12])=[O:21]
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: Cc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 66.1 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2 mmol) and 2-methyl phenyl isocyanate (2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (0.38 g, 53%). EI-MS m/z 288 (M+H)+
Reaction SMILES: CO[C:3]([C:5]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=1[OH:27])=[O:4].[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[N:15]3[C:7](=[CH:8][C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([OH:27])=[C:5]([C:3]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])[C:17]2=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)c1c(O)c2cc3ccccc3n2n(Cc2ccc(F)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc3ccccc3n2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 4-(4-fluoro-benzyl)-1-hydroxy-3-oxo-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH:14]([N:21]=[C:22]=S)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>C(OCC)(=O)C>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:22]([NH:21][CH:14]([CH3:13])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[NH:2][C:3]=2[CH:7]=1
Reactant: CC(C)CCCC(C)N=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CCCC(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 1,5-dimethylhexyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 197°-199° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.85 (d, 6H), 1.12 (d, 3H), 1.1-1.6 (m, 7H), 3.77 (m, 1H), 7.07 (s, 1H), 7.12 (br. s, 1H), 10.72 (br. s, 1H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[C:16]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH:14]=[CH:13][N:12]4[C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=3)[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: COC(=O)c1ccc(I)cc1
Product: COC(=O)c1ccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)cc1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using methyl 4-iodobenzoate and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 510.3 (M+H)+.