Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17](OCC)=O)[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1>O.C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([CH3:17])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Cc1ccc(Br)cc1)C(=O)O
Temperature: 200 °C
Yield: 82.2 %

Procedure:
A solution of sodium hydroxide (175 g) in water (800 ml) was added to a solution of diethyl (4-bromophenyl)methylmalonate (150 g) in ethanol (850 ml) and the mixture was heated under reflux for 9 hours. Volatile material was removed by evaporation and the residue was dissolved in a solution of sodium hydroxide (130 g) in water (250 ml). The solution was heated under reflux for 2.5 hours, filtered through a bed of diatomaceous earth and the filtrate was acidified with 6M sulphuric acid. The mixture was extracted with ether (4×500 ml) and the extracts were dried (MgSO4). The solution was concentrated and the residue was heated at 200° C. until evolution of carbon dioxide ceased. The residue was dissolved in 1M sodium hydroxide solution (500 ml) and the solution was acidified with 6M sulphuric acid. The mixture was extracted with ether (4×500 ml) and the extracts were dried (MgSO4). The solvent material was removed by evaporation to give 3-(4-bromophenyl)-2-methylpropionic acid (91 g), m.p. 72-73 ° C.; 1H NMR (d6-DMSO): 1.0 (d, 3H), 2.05-2.15 (m, 2H), 2.85-2.9 (m, 1H), 7.1 (d, 2H), 7.4 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[CH2:26][OH:27])/[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[C:20](\[CH2:26][O:27][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])/[CH2:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)C/C(=C/c1ccc(Cl)cc1)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC/C(=C\c2ccc(Cl)cc2)CC(C)(C)C)cc1
Reaction time: 24 h
Yield: 97 %

Procedure:
42 g of 4-methylbenzenesulfonyl chloride are added to a solution of 45.8 g of Z-1-(4-chlorophenyl)-2-hydroxymethyl-4,4-dimethylpent-1-ene in 200 ml of methylene chloride and 59 g of triethylamine at room temperature. After 24 hours, the reaction mixture is washed with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. The residue gives 73.1 g (98%) of Z-1-(4-chlorophenyl)-2-(4-methylphenylsulfonyloxymethyl)-4,4-dimethylpent-1-ene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1>C(O)(=O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:6]2[CH:15]=[CH:16][CH:3]=[CH:4][CH:5]=2)[OH:8])([C:9]2[CH:14]=[CH:13][C:12]([O:2][CH3:1])=[CH:11][CH:10]=2)[OH:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C(O)(c2ccccc2)c2ccccc2)cc1
Reaction time: 140 h

Procedure:
To a one neck, one liter round bottom glass flask equipped with a stirrer and condenser was charged 10 g of 4-methoxybenzophenone, 300 cc of isopropanol, and 1 drop of glacial acetic acid. The solution was exposed to radiation through the flask wall for 140 hours from a 275 watt U.V. sunlamp situated 4 inches from the side of the flask. The solvent was stripped off under vacuum and the residue crystallized from ethyl alcohol to give 4,4'-dimethoxybenzopinacol with, after drying, a melting point of 163°-165° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH:16]=[C:15]([Cl:18])[CH:14]=[CH:13][C:12]=2[C:11](=[O:19])[C:10]2=[CH:20][CH:21]=[CH:22][N:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:41]N1C(=O)CCC1=O.[Al]>C1COCC1>[CH2:1]([N:8]1[C:17]2[CH:16]=[C:15]([Cl:18])[CH:14]=[CH:13][C:12]=2[C:11](=[O:19])[C:10]2=[CH:20][CH:21]=[C:22]([Cl:41])[N:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2cccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Al]
Solvent: C1CCOC1
Product: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2c(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
5-Benzyl-7-chloropyrrolo[1,2-b]cinnolin-10(5H)-one (4.5 g) was taken up in 50 ml of THF and a catalytic amount of dibenzoyl peroxide was added. N-chlorosuccinimide (1.95 g) was added portionwise over a period of 10 min. The flask was covered with aluminum foil and the mixture stirred at room temperature overnight under N2. The reaction mixture was concentrated and the residue taken up in chloroform and extracted with H2O and brine. The organic layer was then dried (MgSO4), charcoaled, filtered and concentrated to a green semisolid. This was purified by HPLC (silica, dichloromethane) to give a light green powder which was recrystallized from ethanol to yield 2.3 g of green crystals, mp 134°-136°.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=3)[N:8]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(-c2csc(N)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2nc(-c3ccc(C)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-p-Tolyl-thiazol-2-ylamine (38.1 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (13.5 mg, 0.0438, 21.9%). ESI-MS m/z calc. 308.1. found 309.0 (M+1)+ Retention time 3.72 minutes.
Reaction SMILES: [C:1]([N:9]([C:18]1[N:22]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH3:32])[CH:27]=[CH:26]3)[C:21]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:35][C:34]=2[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:20][N:19]=1)C(=O)C1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:51]([O:50][C:34]1[CH:35]=[C:36]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:37]([CH:39]([CH3:41])[CH3:40])=[CH:38][C:33]=1[C:21]1[N:22]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH3:32])[CH:27]=[CH:26]3)[C:18]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:19][N:20]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(C)c1cc(-c2nnc(N(C(=O)c3ccccc3)C(=O)c3ccccc3)n2-c2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(-c2nnc(NC(=O)c3ccccc3)n2-c2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 16 h

Procedure:
A flask was charged with [5-(5-Isopropyl-2,4-dibenzyloxy-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-phenyl-amine (0.33 mmol, 183 mg.), dichloromethane (10 mL), diisopropylethylamine (3 eq., 0.2 mmol), and benzoyl chloride (2 eq., 70 mg.), and the reaction was stirred for 16 hours. The organic solution was washed with saturated ammonium chloride (2×5 mL), dried and the product was purified by column chromatography to give N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide and also N-benzoyl-N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide. The N-benzoyl-N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide was dissolved in methanol (5 mL), and 10% aqueous potassium carbonate (1 mL) was added, and the reaction was stirred for 16 hours. The solvent was then evaporated, and the solid was dissolved in ethyl acetate (10 mL), washed with water (2×5 mL), dried and evaporated to give more N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide. The N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide was hydrogenolyzed in a fashion analgous to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide (Compound 4) to give N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide. MS: expected ion=467.2; observed ion=467.3.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH2:33][CH3:34])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:38]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31]([OH:38])=[O:32])[C:20]([CH2:33][CH3:34])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@@H]1C=C(CC)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(CC)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-ethyl-2-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 210, 2.35 g, 4.72 mmol) following the procedure described for Intermediate 19. The title compound was obtained as a tan foam (1.89 g, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9]2)[CH3:2].O1CCCC1.CO.[OH-].[K+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9]2)[CH3:2]
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
To a mixture of methyl 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (0.65 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added a solution of potassium hydroxide (85%, 0.33 g) in water (5 mL). The mixture was stirred at room temperature for 15 h and then partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (548 mg, 88%) as pale yellow crystals. MS 377 (MH+).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]CC(O)=O)=[CH:10][CH:9]=1>ClCCl>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(CCC(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(CCC(=O)Cl)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of oxalyl chloride (5 ml) in dichloromethane (5 ml) was added dropwise to a solution of 3-(4-methylphenyl)propionic acid (1.5 g) in dichloromethane (20 ml). The mixture was stirred at 20° C. for 16 hours and then evaporated to give 3-(4-methylphenyl)propionyl chloride as an oil.
Reaction SMILES: Cl.C(OC([N:9]1[C:13]2=[C:14]([NH:29][S:30]([C:33]3([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[CH2:35][CH2:34]3)(=[O:32])=[O:31])[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[C:16]([CH3:19])[C:17](=[O:18])[N:12]2[CH2:11][CH2:10]1)=O)(C)(C)C.CO>C1COCC1.C(Cl)(Cl)Cl>[F:28][C:22]1[CH:23]=[C:24]([I:27])[CH:25]=[CH:26][C:21]=1[NH:20][C:15]1[C:14]([NH:29][S:30]([C:33]2([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[CH2:34][CH2:35]2)(=[O:31])=[O:32])=[C:13]2[NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[C:16]=1[CH3:19]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)c2n(c1=O)CCN2
Temperature: 40 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
Concentrated HCl (3 mL) was added to a stirred solution of 8-[1-(2,3-dihydroxy-propyl)-cyclopropanesulfonylamino]-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (80 mg) in THF (5 mL). The resulting mixture was stirred at 40° C. for 2 hours. The reaction was monitored by TLC (15% MeOH in CHCl3). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was washed with saturated NaHCO3 solution and concentrated to afford the crude product. Purification by column chromatography on silica gel (5% methanol in CHCl3), followed by preparative HPLC afforded 10 mg of the product (14.7% yield)
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][CH:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.O>ClCCl>[CH3:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4]
Reactant: CC1CCCN1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: ClCCl
Solvent: O
Product: CC1CCCN1c1ccc([N+](=O)[O-])cc1N
Temperature: 100 °C

Procedure:
5 g (32.03 mmol) of 2-fluoro-5-nitroaniline and 4.9 ml (48.04 mmol) of 2-methylpyrrolidine (racemic) are placed in a screw reactor. The reactor is closed and the mixture is heated at 100° C. for 5 h. After cooling, the mixture is taken up with 100 ml of water and 100 ml of dichloromethane. The organic phase is separated, washed with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The resulting product is used as it is in the subsequent reaction.
Reaction SMILES: CC([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:5]1=[O:18])=C.Cl>CC(O)C>[O:17]=[C:15]([CH3:16])[CH2:14][CH2:13][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:4][C:5]1=[O:18]
Reactant: C=C(C)n1c(=O)n(CCC(C)=O)c2ccccc21
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)CCn1c(=O)[nH]c2ccccc21
Yield: 73.4 %

Procedure:
A mixture of 48.8 parts of 1,3-dihydro-1-(1-methylethenyl)-3-(3-oxobutyl)-2-H-benzimidazol-2-one, 12 parts of 2-propanol, saturated with gaseous hydrogen chloride and 240 parts of 2-propanol is stirred for 3 hours at room temperature. The precipitated product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 30 parts (73.4%) of 1,3-dihydro-1-(3-oxobutyl)-2H-benzimidazol-2-one.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:7]2[C:8](=[O:11])[C:9]=1[Br:10])[CH3:3].C(N(CC)CC)C.[CH:24]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH2:25]>CO>[Br:10][C:9]1[C:8](=[O:11])[N:7]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:6]2=[N:5][C:4]=1[CH:2]([NH:1][CH2:25][CH2:24][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH3:3]
Reactant: C=CS(=O)(=O)CC
Reactant: CC(N)c1nc2ccc(F)cn2c(=O)c1Br
Solvent: CCN(CC)CC
Solvent: CO
Product: CCS(=O)(=O)CCNC(C)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 50 °C
Yield: 100.3 %

Procedure:
E3 (222 mg, 0.78 mmol) was dissolved in 5 mL methanol. Triethylamine (0.11 mL, 0.78 mmol) was added followed by ethyl vinyl sulfone (0.082 mL, 0.78 mmol). The reaction was heated at 50° C. overnight. After removal of methanol, the mixture was purified by chromatography with 1:1 dichloromethane:ethyl acetate then gradient methanol in dichloromethane (2% to 4% to 6%) to give 318 mg E4 as an oil.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].C([O-])(=O)C.[NH4+:19]>CO>[NH2:19][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [NH4+]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: CC(=O)[O-]
Solvent: CO
Product: Nc1c([N+](=O)[O-])ccc(F)c1C(=O)O

Procedure:
2.0 g (9.9 mmol) of 2,6-difluoro-3-nitro-benzoic acid in methanol and 3.0 g (30.0 mmol) of ammonium acetate was stirred at room temperature for 12 h. The solvent was evaporated and dilute HCl solution was added. The precipitated solid was collected by filtration and washed with water to produce 2-amino-6-fluoro-3-nitro-benzoic acid. LCMS: 201 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:28])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH3:28]
Reactant: O=C(O)c1ccc(N2CC(O)C2)c(OCC2CC2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(N2CC(O)C2)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=389.1 [M+H]+.
Reaction SMILES: Br[Si](C)(C)C.C([N:9](C(C)C)[C:10]1[N:15]=[CH:14][N:13]([CH2:16][C@H:17]([O:20][CH2:21][P:22]([OH:25])([OH:24])=[O:23])[CH2:18][OH:19])[C:12](=[O:26])[N:11]=1)(C)C>C(#N)C>[OH:19][CH2:18][C@@H:17]([O:20][CH2:21][P:22]([OH:24])([OH:25])=[O:23])[CH2:16][N:13]1[CH:14]=[N:15][C:10]([NH2:9])=[N:11][C:12]1=[O:26]
Reactant: CC(C)N(c1ncn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1)C(C)C
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: Nc1ncn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Reaction time: 20 h

Procedure:
Bromotrimethylsilane (4.7 ml, 35 mmol) was added to a solution of 9 (1.34 g, 3.13 mmol) in acetonitrile (30 ml) and the mixture was set aside at ambient temperature for 20 h. The mixture was evaporated at 30° C., the residue coevaporated with acetonitrile (2×30 ml) and 90% aqueous methanol (50 ml) was added. The solution was neutralized with 1 M triethylammonium hydrogencarbonate to pH 7 and evaporated. The residue was partitioned between water (100 ml) and ether (100 ml), an aqueous layer evaporated to a volume 5 ml and applied onto a column of Dowex 1 (AcO− form, 100 ml). Elution was performed with water (500 ml), then with a linear gradient of acetic acid (0.1-1 M, 1.5 l) and finally, the product was eluted with 1 M formic acid. UV absorbing fractions were taken down in vacuo and the residue coevaporated with water (4×20 ml). The residue was crystallized from water. Yield 350 mg (37%) of compound 3, identical with the product described in Example 1. M.p. 175-178° C.,
Reaction SMILES: Cl[CH:2]([O:8][CH3:9])[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([CH:19]([F:21])[F:20])[NH:16][C:15]=2[CH:22]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([CH:19]([F:20])[F:21])[N:16]([CH2:9][O:8][CH2:2][CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[C:15]=2[CH:22]=1
Reactant: COC(Cl)C[Si](C)(C)C
Reactant: FC(F)c1nc2ccc(Br)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(C(F)F)nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2-Chloro-methoxy-ethyl)-trimethyl-silane (1.1 ml, 6.4 mmol, 1.5 eq.) was added to an anhydrous dichloromethane solution (22 ml) of 6-bromo-2-difluoromethyl-1H-benzimidazol (1.0 g, 4.27 mmol) and N,N-diisopropyl ethyl amine (1.9 ml, 10.6 mmol, 2.5 eq.). This was stirred at room temperature for 18 hours. The reaction mixture was concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 6-bromo-2-difluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole was obtained as a yellow solid (1.37 g, 85%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:31])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:19]=2)=[CH:12][C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[C:10]([N:39]([CH3:41])[CH3:40])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][N:39]([CH3:41])[C:10]1[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[CH:12][C:13]2[NH:14][C:15](=[O:31])[CH2:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:19]=3)=[N:7][C:8]=2[CH:9]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1-c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1-c1ccccc1F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {2-dimethylamino-2′-fluoro-5-(3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M35) (302 mg, 0.531 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (208 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.Cl.Cl[CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[N:10]=[CH:11][C:3]=12
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2ncc3c(Cl)nc(N)nc32)c1C
Temperature: 80 °C
Yield: 17.2 %

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (1.76 g), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride (3.70 g), K2CO3 (5.17 g), and DMF (20 ml) was heated to 80° C. for 30 min, diluted with EtOAc, washed with water and brine, concentrated, and purified by flash chromatography to give the title compound as a white solid (0.57 g). R.t. 4.46 min. 1H-NMR (CDCl3) δ 8.10 (s, 1H), 7.89 (s, 1H), 5.53 (2H), 5.24 (br. s, 2H), 3.74 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:12][C:11](=[O:21])[C:10]=1[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH:33]1[CH2:35][CH2:34]1.CC(C)([O-])C.[K+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:13]2([CH2:14][CH2:15][N:16]([O:19][CH3:20])[CH2:17][CH2:18]2)[N:12]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:11](=[O:21])[C:10]=1[C:22]1[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CON1CCC2(CC1)C(OCc1ccccc1)=C(c1c(C)cc(C)cc1C)C(=O)N2CC1CC1
Temperature: 100 °C
Reaction time: 120 h
Yield: 30.9 %

Procedure:
To a solution of 4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.4) (1.0 g, 2.46 mmol) in dioxane (40 ml) was added bromomethyl-cyclopropane (1.257 ml, 1.78 g, 13.16 mmol) and potassium tert-butoxide (1.50 g, 13.37 mmol). The reaction mixture was stirred at 100° C. for 5 days, then poured on water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate/heptane 1:5, stirred overnight, filtered and dried to afford a first crop of product as a white solid (350 mg). The mother liquor was concentrated, and the residue purified by chromatography on silica gel (dichloromethane/acetone 10:1) to further deliver 205 mg of product. Yield: 555 mg of 4-benzyloxy-1-cyclopropylmethyl-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.8) as a solid, mp 119-121° C.