Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=O.S(O)(O)(=O)=O.[NH2:17][OH:18].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=[N:17][OH:18]
Reactant: Cc1c(Cl)ccc(Cl)c1C=O
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1c(Cl)ccc(Cl)c1C=NO
Temperature: 80 °C
Reaction time: 2 h

Procedure:
198 g (0.975 mol) of 93% pure 3,6-dichloro-2-methylbenzaldehyde and 416.2 g (0.634 mol) of a 25% strength aqueous solution of hydroxylamine sulfate are mixed in 1.5 l of toluene and heated at 80° C. Over a period of 2 h, 109.2 g (1.36 mol) of 50% strength NaOH are then added dropwise such that the pH is between 3 and 5. Stirring at 80° C. is continued for 1 h, and the phases are then separated at 80° C. The organic phase is washed once with 250 ml of water. The organic phase is concentrated and the residue is recrystallized from cyclohexane. This gives 165.4 g of the aldoxime (83.3% of theory). 1H-NMR: (DMSO-D6): 2.4 ppm (s, 3H, Me), 7.4 ppm (d, 1H, arom-H), 7.5 ppm (d, 1H, arom-H), 8.3 ppm (s, 1H, NH), 11.7 ppm (s, 1H, OH).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[C:11]([C:13]([O:15]C)=O)[S:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[NH3:17]>CO>[Br:1][C:2]1[C:3]2[CH:12]=[C:11]([C:13]([NH2:17])=[O:15])[S:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: N
Reactant: COC(=O)c1cc2c(Br)cn(C)c(=O)c2s1
Solvent: CO
Product: Cn1cc(Br)c2cc(C(N)=O)sc2c1=O
Temperature: 45 °C
Yield: 95 %

Procedure:
Using a sealed tube, a solution of methyl 4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxylate (250 mg, 65 mmol) in MeOH (6 mL) stirred at rt was treated with 2N NH3 in methanol (8 ml). The sealed tube was heated to 45° C. for 60 h. After cooling to 0° C., the resulting suspension was filtered; the filter cake was washed with cooled (0° C.) MeOH (3 mL) and isopropyl ether (3 mL) to afford the title compound (215 mg, 95%) as a white solid. LCMS (M+H)+=288.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O>CC(C)=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(C)cn(CCCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
A stirred solution of methyl 3-methyl-1 H-indole-6-carboxylate (0.5 g, Reference Example 30) in acetone (35 ml) was treated with 1-bromo-3-phenylpropane (0.577 g) and sodium hydroxide (0.116 g). The mixture was stirred at room temperature for 12 hours then poured into water (35 ml) and then extracted three times with ethyl acetate (50 ml). The combined extracts were washed with dilute hydrochloric acid (50 ml, 1N) then with saturated sodium bicarbonate solution (50 ml), then dried over magnesium sulphate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (50:1, v/v) to yield the title compound (0.58 g).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].O.[C:31]([OH:35])(=[O:34])[CH:32]=O>CCO>[C:18]([C:15]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:20][C:21]3[C:22]([NH:27][CH2:32][C:31]([OH:35])=[O:34])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH2:28][C@@H:7]([NH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:29])[CH2:8][C:9]=3[C:17]=2[CH:16]=1)#[N:19]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N)c3ccc(C#N)cc23)C1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3NCC(=O)O)c3ccc(C#N)cc23)C1
Temperature: 75 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
Dissolve [(S)-4-(2-amino-pyridin-3-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (253 mg, 0.650 mmol) in EtOH (25 mL). Add 3 Å molecular sieves and glyoxylic acid monohydrate (239 mg, 2.60 mmol), then stir at 40-110° C. for 18 h under hydrogen (60 psi, 4.08 bar). Filter the reaction through a pad of diatomaceous earth and wash the catalyst/sieves with THF (50 mL). Combine the filtrate and concentrate in vacuo to a yellow oil. Triturate with water (30 mL) and sonicate the resulting aqueous slurry for 5 min. Filter off a tan solid and dry in vacuo. Triturate the solid with Et2O (5 mL) and sonicate the slurry for 30 min. Filter to obtain 190 mg (65%) of the product as a tan solid. LCMS 100% @ 3.99 min m/z 448 (M+H), 446 (M−H).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[NH:5][C:6]=1[I:7].[H-].[Na+].[C:13]([NH:20][CH2:21][CH2:22]Br)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][N:3]1[C:2]([I:1])=[C:6]([I:7])[N:5]=[C:4]1[CH:8]([CH3:10])[CH3:9])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CC(C)c1nc(I)c(I)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a yellow solution of 4,5-diiodo-2-isopropyl-1H-imidazole (10.000 g; 27.629 mmol) in anhydrous DMF (140 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (1.326 g; 33.154 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (6.810 g; 30.391 mmol) in anhydrous DMF (100 ml) was added dropwise, over 1 h, with an addition funnel. After completion of the addition, the resulting mixture was further heated at 100° C. for 1 h30. The reaction mixture was cooled to 0° C., and water (300 ml) was added slowly. This mixture was extracted with ether (5×150 ml). The combined organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give an orange oil. The crude was purified by FC (DCM/MeOH=30/1) to give the pure product [2-(4,5-diiodo-2-isopropyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow solid which was further dried under HV (9.720 g; 70%). LC-MS: tR=0.82 min.; [M+H]+=506.32 g/mol.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:25][CH3:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:25][CH3:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Oc1ccc(F)cc1
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2Cl)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
(1R,2R,4R) and (1S,2S,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (25 mg, 0.062 mmol, example 56) was dissolved in DMF (1.5 ml) and 4-fluorophenol (14 mg, 0.125 mmol) and Cs2CO3 (61 mg, 0.187 mmol) were added. The reaction mixture was stirred for 4 h at 50° C. Then water was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel chromatography (DCM/EtOAc 9:1) to obtain the title compound (21 mg, 63%) as white solid. MS (EI): 491.1 (M−H)−.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17](OCC)=[O:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Li+]>CO>[O:1]([CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN1CC(COc2ccccc2)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1OC(COc2ccccc2)CN1CCCO
Yield: 100.4 %

Procedure:
A procedure similar to that described in Preparation 5(a) was repeated, except that 1.64 g of ethyl 3-(5-phenoxymethyl-2-oxooxazolidin-3-yl)propionate (prepared as described in Preparation 113), 15 ml of anhydrous tetrahydrofuran, 244 mg of lithium borohydride and 179 mg of anhydrous methanol were used, to give 1.41 g of the title compound having an Rf value of 0.28 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[CH2:37]([O:40][C:41]([NH:43][C@@H:44]([CH:48]([CH3:50])[CH3:49])[C:45](O)=[O:46])=[O:42])[CH:38]=[CH2:39]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:45](=[O:46])[C@@H:44]([NH:43][C:41]([O:40][CH2:37][CH:38]=[CH2:39])=[O:42])[CH:48]([CH3:50])[CH3:49])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: C=CCOC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Product: C=CCOC(=O)N[C@H](C(=O)OC(C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1)C(C)C
Yield: 91 %

Procedure:
In analogy to Example 5, 400 mg (0.78 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (S)-2-allyloxycarbonylamino-3-methylbutyric acid and, after workup and purification, 495 mg (91%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>O1CCCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:5]2[C:4]([CH3:3])=[C:8]([CH3:9])[N:7]=[CH:6]2)=[CH:17][CH:16]=1
Reactant: Clc1cccc(Oc2ccc(CBr)cc2)c1
Reactant: Cc1nc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncn(Cc2ccc(Oc3cccc(Cl)c3)cc2)c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
While stirring thoroughly, 1.91 g of 80% strength sodium hydride is introduced into a solution of 6.04 g of 4,5-dimethylimidazole in 80 ml of tetrahydrofuran. Upon completion of the exothermic reaction, the mixture is kept for 3 hours at 60° C., ad then cooled. A solution of 17.85 g of p-(3-chlorophenoxy)-benzyl bromide in 20 ml of tetrahydrofuran is then added. The reaction batch is stirred for 12 hours at 20° C., then poured into about 750 ml of ice water and extracted by shaking with methyl tertbutyl ether. The extract is washed twice with 5% strength aqueous sodium hydroxide solution and twice with water. After the extract has been dried over sodium sulfate, the solvent is removed under reduced pressure and the residue is chromatographed over silica gel 60 with acetone/ethyl acetate (2:1). There is obtained 12.1 g (65%) of N-[p-(3-chlorophenoxy)-benzyl]-4,5-dimethylimidazole as a resin-like liquid which slowly crystallizes on standing.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[CH:5][CH:4]=1.N>[Ni].C(O)C>[F:11][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:8]=1[CH2:9][NH2:10]
Reactant: N#Cc1cnccc1C(F)(F)F
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cnccc1C(F)(F)F
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Add Raney nickel (0.5 g) to a solution of 4-trifluoromethyl-nicotinonitrile (1.0 g, 5.8 mmol) in ethanol saturated with ammonia (20.0 mL) and shake under hydrogen at 500 psi for 1 hour. Filter reaction, concentrate the filtrate, and dry the solid obtained to give the title compound (1.0 g, 98%). MS (ES) 177.0 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[O:24][CH3:23])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: COc1ccccc1CN
Solvent: C1COCCO1
Product: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-(t-butoxycarbonyl)tryptophan (46.4 g, 152.6 mmoles) in 500 ml of dioxane was added carbonyl diumidazole (25.4 g, 156 mmoles) in a portionwise manner. The resulting mixture was stirred for about 2.5 hours at room temperature and then stirred at 450° C. for 30 minutes. Next, 2-methoxybenzylamine (20.7 ml, 158.7 mmoles) was added and the reaction mixture was then stirred for 16 hours at room temperature.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]([CH2:12][CH3:13])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:16](N)[CH2:17][NH2:18]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]([C:10]2[NH:18][CH2:17][CH2:16][N:11]=2)[CH2:12][CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC(C#N)c1cccc(C(F)(F)F)c1
Reactant: NCCN
Product: CCC(C1=NCCN1)c1cccc(C(F)(F)F)c1

Procedure:
rac-2-[1-(3-Trifluoromethyl-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(3-trifluoromethyl-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 257.0 ((M+H)+.).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1([CH3:44])[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:37]2[CH:36]=[C:35]([CH3:44])[CH:40]=[CH:39][CH:38]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 118.8 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (3.0 g, 6.04 mmol), m-tolylboronic acid (2.05 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.5 g, 0.71 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated in a microwave at ˜90° C. for 2 h. The reaction mixture was cooled to 25° C., diluted with ethyl acetate (300 mL), washed with a saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 9% ethyl acetate/petroleum ether) afforded 1-benzenesulfonyl-2-(3-methyl-1-m-tolyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (2.99 g, crude) as a white solid, which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (dd, 1H, J1=4.8 Hz, J2=0.9 Hz), 7.89 (dd, 1H, J1=7.8 Hz, J2=1.5 Hz), 7.61 (dd, 2H, J1=8.4 Hz, J2=1.5 Hz), 7.43-7.01 (m, 7H), 6.89 (s, 1H), 6.52 (s, 1H), 6.11 (d, 1H, J=10.2 Hz), 2.73-2.60 (m, 1H), 2.17 (s, 3H), 1.12 (dd, 6H, J1=9.3 Hz, J2=6.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.[C:26](O)([CH3:29])([CH3:28])[CH3:27]>CN(C)C1C=CN=CC=1.CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:5]
Reactant: O=C(O)c1ccccc1Br
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccccc1Br
Yield: 77710.2 %

Procedure:
A solution of o-bromobenzoic acid (1 g), N, N'-dicyclohexyl carbodiimide (1.129 g), t-butanol (405 mg) and 4-dimethylaminopyridine (61 mg) in dry ether (20 ml) was stirred at room temperature for 18 h. The resulting precipitate was filtered off and the filtrate evaporated to give a colourless solid which was triturated under petroleum ether (40°-600°) (20 ml) and filtered. The filtrate was evaporated to give a pale yellow oil (0,994 g). b.p. 80°-84°/0.35 mmHg.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[C:26]2[N:29]2[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=O)[CH2:36][C:37]3[N:38]=[CH:39][N:40]([C:42]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:41]=3)[C:30]2=[O:62])=[CH:21][CH:20]=1)([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.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:72])=CC=1>C1COCC1>[Si:1]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[C:26]2[N:29]2[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[S:72])[CH2:36][C:37]3[N:38]=[CH:39][N:40]([C:42]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:41]=3)[C:30]2=[O:62])=[CH:21][CH:20]=1)([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
Reactant: CC(C)(C)[Si](Oc1ccc2cccc(N3CC[C@H](NC(=O)Cc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3=O)c2c1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1ccc2cccc(N3CC[C@H](NC(=S)Cc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3=O)c2c1)(c1ccccc1)c1ccccc1
Temperature: 45 °C

Procedure:
A mixture of (S)-N-{1-[7-(tert-butyldiphenylsilyloxy)naphthalen-1-yl]-2-oxopyrrolidin-3-yl}-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]acetamide, as described above in Step D, (3.00 g, 3.61 mmol) and Lawesson's Reagent (728 mg, 1.80 mmol) in dry THF (45 mL), under argon, was heated to 45° C. for 90 min. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous Na2CO3 (125 mL) and CH2Cl2 (300 mL). The aqueous layer was extracted further with CH2Cl2 (150 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—40% EtOAc—1% MeOH—0.1% NH4OH to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[C:20](=O)[CH2:19]1)=[O:17].[CH3:34][NH2:35]>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[CH:20]([NH:35][CH3:34])[CH2:19]1)=[O:17]
Reactant: CN
Reactant: O=C(NCC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Product: CNC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1CNC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 25 5-chloro-thiophene-2-carboxylic acid {(1RS,4SR)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentylmethyl}-amide (example 32A) was reacted with methylamine (solution in THF) to give 5-chloro-thiophene-2-carboxylic acid {4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methylamino-cyclopentylmethyl}-amide. Light yellow solid. 503.3 ([M+H]+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[I:22]N1C(=O)CCC1=O.[NH4+].[OH-]>CC(O)=O>[CH2:1]([C:8]1[CH:9]=[C:10]([I:22])[C:11]([OH:14])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cn1
Reactant: O=C1CCC(=O)N1I
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Oc1ncc(Cc2ccccc2)cc1I
Reaction time: 8 h

Procedure:
To a yellow solution of 5-benzylpyridin-2-ol (1.10 g, 5.94 mmol) in 22 mL AcOH under Ar was added 1.5 mL TFA, followed by N-iodosuccinimide (1.34 g, 5.94 mmol). The red homogeneous solution was allowed to stir overnight, poured onto ice and neutralized with conc. NH4OH. The solids were collected by filtration, rinsed with water, treated with MeOH/DCM, dried over sodium sulfate, and evaporated. The resulting brown solid was purified by silica gel chromatography (ISCO, 80 g, 0-70% 90/10 DCM/MeOH in DCM) to give 5-benzyl-3-iodopyridin-2-ol as a yellow/brown solid. MS (ESI) m/z: Calculated: 311.0; Observed: 311.9 (M++1).
Reaction SMILES: CN(C=O)C.[CH3:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:20]1[CH:25]=[CH:24][C:23]2=[N:26][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:42]([F:45])([F:44])[F:43])=[C:33]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=3)=[CH:28][N:22]2[N:21]=1>O>[CH3:38][C:37]([CH3:40])([CH3:39])[C:36]([NH:35][C:33]1[CH:34]=[C:29]([C:27]2[N:26]=[C:23]3[N:22]([CH:28]=2)[N:21]=[C:20]([N:10]2[CH2:11][CH2:12][CH:7]([CH3:6])[CH2:8][CH2:9]2)[CH:25]=[CH:24]3)[CH:30]=[CH:31][C:32]=1[C:42]([F:44])([F:43])[F:45])=[O:41]
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCN(c2ccc3nc(-c4ccc(C(F)(F)F)c(NC(=O)C(C)(C)C)c4)cn3n2)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
An 8 mL vial is charged with DMF (1 mL), 4-methylpiperidine (0.030 g), Cs2CO3 (0.130 g), and N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0396 g, 0.1 mmol). The mixture is stirred at 120° C. for 16 hr, then diluted with H2O (5 mL) and extracted with Et2O (3 mL×2). Organics are dried and concentrated onto celite, purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.020 g, 43% yield). LCMS m/z=460.6 [M+H]+, tR=3.14 min. (compound same as Example 233)