Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Cl:15][C:16]1[C:17](I)=[N:18][CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[C:17]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Clc1cccnc1I
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncccc1Cl
Yield: 78 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (64 mg, 0.35 mmol) was converted [using 3-chloro-2-iodopyridine (prepared according to Eur. J. Org. Chem. (24), 4181, 2002) instead of 2-chloro-4-iodopyridine] to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 81 mg, 78%) which was obtained as a light yellow solid. MS: m/e=295.2/297.3 [M+H]+.
Reaction SMILES: [SiH](CC)(CC)CC.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:25])=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=O)[CH:14]=1>C(O)(C(F)(F)F)=O.C(S(O)(=O)=O)(F)(F)F>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:25])=[C:13]([CH2:15][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH3:24])=[CH:21][CH:22]=2)[CH:14]=1
Reactant: CCc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a stirred solution of Et3SiH (400 g, 3.45 mol) and (5-bromo-2-chlorophenyl)(4-ethylphenyl)methanone (534 g, 1.65 mol) containing ˜7% of the isomeric ketone in 300 mL of the TFA at 30° C. was added CF3SO3H (1.5 g, 0.01 mol). Within minutes the temperature increased causing the solution to reflux violently. Caution: this moderate exotherm requires cooling with an external ice bath. After 1 hr, HPLC revealed the reaction to be 90% complete. After addition of an additional Et3SiH (20 g) and heating overnight at 70° C., the reaction was >95% complete by HPLC analysis. Upon cooling, the volatiles were removed by bulb to bulb distillation at reduced pressure. The resultant ˜1 L of the light gray oil was poured into 1 L of H2O. The mixture was extracted three times with hexane, the combined organic layers were washed three times with H2O, twice with aq Na2CO3 and twice with brine before drying over Na2SO4. After concentration using a rotary evaporator, ˜1 L of clear light amber oil remained. This material was further concentrated, the (Et3Si)2O (450 mL) was removed by distillation until the distillation head temperature reached 75° C., and the residue was allowed to cool. 1HNMR analysis of the residue revealed it to contain an ˜8:1 mixture of diarylmethane to (Et3Si)2O. Crystallization of this mixture was achieved by pouring the product into vigorously stirred cold (10° C.) mixture of 85% EtOH:H2O (1.2 L). After stirring for several hours, the crystals were collected by filtration, washed with cold 1:1 EtOH/H2O and dried under vacuum. The 4-bromo-1-chloro-2-(4-ethylbenzyl)benzene (500 g), was obtained as a low melting solid containing ˜1% (Et3Si)2O, and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:23]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Cl)c1
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-chlorophenyl isocyanate (0.60 ml, 5.01 mmol) in THF (20 ml) was added Et3N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-chlorophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-[N′-(2-chlorophenyl)ureido]phenylacetate (1.35 g, 76%) as a colorless powder. 1H-NMR (CDCl3) δ3.58 (s, 3H), 3.71 (s, 2H), 7.04 (m, 3H), 7.18 (dd, J=8.5, 2.0 Hz, 1H), 7.27-7.39 (m, 3H), 8.07 (m, 2H); MS (ESI) m/z 353 (M++1), 355 (M++3), 357 (M++5).
Reaction SMILES: ClC1C=CC([N+]([O-])=O)=C(C)C=1C.[Cl:13][C:14]1[C:15]([CH3:29])=[C:16]([CH2:23][C:24](=O)[C:25]([OH:27])=[O:26])[C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:29])=[C:16]2[C:17](=[CH:18][CH:19]=1)[NH:20][C:24]([C:25]([OH:27])=[O:26])=[CH:23]2
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1CC(=O)C(=O)O
Agent: Cc1c(Cl)ccc([N+](=O)[O-])c1C
Product: Cc1c(Cl)ccc2[nH]c(C(=O)O)cc12

Procedure:
The compound was prepared via 4-chloro-2,3-dimethylnitrobenzene (m.p. 57°-58° C) and 3-(3-chloro-2-methyl-6-nitrophenyl)-pyruvic acid (oil).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:25][C:26]1([F:34])[CH2:31][CH2:30][CH:29]([CH:32]=O)[CH2:28][CH2:27]1>C1COCC1>[F:25][C:26]1([F:34])[CH2:31][CH2:30][CH:29]([CH:32]=[CH:4][C:3]([O:2][CH3:1])=[O:24])[CH2:28][CH2:27]1
Reactant: O=CC1CCC(F)(F)CC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C=CC1CCC(F)(F)CC1
Reaction time: 6 h
Yield: 82.6 %

Procedure:
Methyl(triphenylphosphoranylidene)acetate (8.827 g, 26 mmol, 1.1 eq) is added at room temperature to a solution of 4,4-difluorocyclohexanecarbaldehyde (3.55 g, 24 mmol, 1 eq) in dry THF (60 ml). The mixture is stirred for 6 h and the solvent is evaporated. Hexane (50 ml) is added to the crude, the mixture is put a few minutes in an ultrasonic bath, stirred for 1 h and filtered. The filtrate is concentrated under reduced pressure to afford 4.05 g of methyl 3-(4,4-difluorocyclohexyl)prop-2-enoate a1-16.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[F:27][CH:28]([F:31])[CH2:29][NH2:30].CCOC(C)=O>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:30][CH2:29][CH:28]([F:31])[F:27])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: NCC(F)F
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCC(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.5 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.64 g, 1.63 mmol) in CH3CN, was added neat 2,2-difluoroethylamine (0.23 g, 1.97 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3.5 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of EtOAc and hexanes (1:1, 2:1. then pure EtOAc, respectively), providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(2,2-difluoroethyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.433 g, 56% yield) 1H NMR (500 MHz, CDCl3) δ 1.99 (s, 3H), 2.00 (s, 3H), 2.03 (s, 3H), 2.06 (s, 3H), 3.83-3.86 (m, 2H), 3.95 (s, 1H), 4.02-4.09 (m, 2H), 4.18-4.23 (m, 1H), 5.05-5.11 (m, 1H), 5.21-5.30 (m, 1H), 5.72 (d, 1H, J=8.6 Hz), 5.94 (t, 1H, J=56.1 Hz), 6.63-6.73 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:17]([CH3:19])[CH3:18].O>CN(C=O)C>[CH:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cccc(C=O)c1
Temperature: 50 °C

Procedure:
50 g of 3-hydroxybenzaldehyde are dissolved, under nitrogen, in 250 ml of DMF. 60 g of K2CO3 and then 60 ml of 2-iodopropane are added and the reaction mixture is heated for 18 hours at 50° C. and poured into 2.5 liters of water. Extraction is carried out with ethyl ether and the ether phase is washed with a dilute solution of NaOH, dried over MgSO4 and concentrated under vacuum to give 53.5 g of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:25])=[C:11]([CH3:26])[N:10]=1.[N:27]([CH2:30][CH3:31])=[C:28]=[O:29]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([C:28]([NH:27][CH2:30][CH3:31])=[O:29])[C:17]=23)[C:12]([CH3:25])=[C:11]([CH3:26])[N:10]=1
Reactant: Cc1nc(-c2cc(F)ccc2F)nc(Nc2ccnc3cn[nH]c23)c1C
Reactant: CCN=C=O
Solvent: CC#N
Product: CCNC(=O)n1ncc2nccc(Nc3nc(-c4cc(F)ccc4F)nc(C)c3C)c21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N-(2-(2,5-Difluorophenyl)-5,6-dimethylpyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (0.081 g, 0.230 mmol) was suspended in acetonitrile (2.3 mL), isocyanatoethane (0.018 mL, 0.230 mmol) was added and the mixture was stirred at 70° C. for 2 hours. The reaction was filtered and purified on silica column chromatography using a step gradient of 0 to 5% MeOH in DCM to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.27 (3H, m) 2.40 (3H, s) 2.54 (3H, s) 3.37-3.48 (2H, m) 7.35-7.47 (2H, m) 7.76-7.87 (1H, m) 8.51 (1H, d, J=5.56 Hz) 8.64 (1H, s) 8.97 (1H, d, J=5.31 Hz) 9.11-9.19 (1H, m) 11.94 (1H, s). MS [M+H] found 424.4.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8](OC(C)C)=[O:9])[C:5]2[C:14]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:16]=[C:17]([Cl:18])[C:4]=2[N:3]=1.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[C:5]2[C:14]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:16]=[C:17]([Cl:18])[C:4]=2[N:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CCO)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (2.06 g, 5.773 mmol) in tetrahydrofuran (15.0 mL) was added lithium tetrahydroborate (377.2 mg, 17.318 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was quenched with water at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-35% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (883.0 mg, 2.932 mmol, 51%).
Reaction SMILES: [C:1]1([C:7](=[CH:10][CH3:11])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:14]([Cl:17])(Cl)[Cl:15]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:15][C:14]1([Cl:17])[CH:10]([CH3:11])[C:7]1([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: ClC(Cl)Cl
Reactant: CC=C(C#N)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: CC1C(Cl)(Cl)C1(C#N)c1ccccc1
Temperature: 0 °C
Yield: 32.9 %

Procedure:
A three-neck flask was charged with a mixture of 20 g (0.14 mol) of 2-phenyl-2-butenonitrile, 200 g of chloroform and 2 g of triethylbenzylammonium chloride, and the mixture was stirred. To the mixture were dropwise added 100 g of a 50% sodium hydroxide solution under cooling with ice. The reaction mixture was further stirred at room temperature for 15 hours, then poured into ice water, and the organic phase was separated. The aqueous phase was extracted with hexane. The organic phase fractions were combined together, and dried over anhydrous sodium sulfate. The inorganic substances were filtered off, and the organic solvent was distilled off under a reduced pressure. The resultant oily residue was distilled under a pressure of 0.1 mmHg (116°-120° C.) to obtain 10.4 g of 2,2-dichloro-3-methyl-1-phenylcyclopropanecarbonitrile. Yield: 33%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[CH:17]([O:20][C:21](Cl)=[O:22])([CH3:19])[CH3:18].C1(C)C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[O:22])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (2.5 g, 8.87 mmol) taken up in DCM. Isopropylchloroformate 1M in toluene (13.3 mL, 13.3 mmol), and triethylamine (2.47 mL, 17.7 mmol) added and stirred at room temperature 30 minutes. Reaction washed with water, DCM layer dried over magnesium sulfate filtered reduced in vacuo. Run on an Isco silica column with DCM:MeOH 0-5%. Product fractions were combined and reduced in vacuo to obtain 2.86 g crude product for further reaction as is. LRMS (ESI) m/z 368/370 [(M+H)]+, calc'd for C14H18BrN5O: 368.24.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.Cl.[CH3:46][O:47][C:48]1[CH:54]=[C:53]([CH3:55])[CH:52]=[C:51]([O:56][CH3:57])[C:49]=1[NH2:50]>C(OC(C)C)(C)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:4]([O:3][C:1]([NH:8][CH2:9][C:10](=[O:12])[NH:50][C:49]1[C:51]([O:56][CH3:57])=[CH:52][C:53]([CH3:55])=[CH:54][C:48]=1[O:47][CH3:46])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: COc1cc(C)cc(OC)c1N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(OC)c1NC(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
6.6 g of N-Boc-glycine and 15.6 g of BOP are successively added to 100 ml of dimethylformamide and then, at 0° C., 14 ml of triethylamine are added dropwise. The mixture is left for 20 minutes at 0° C. and 6.7 g of 2,6-dimethoxy-4-methylaniline hydrochloride are then added portionwise. The reaction mixture is left at room temperature for 15 hours. 400 ml of ethyl acetate are added to the reaction mixture and the organic phase is successively washed with 3×200 ml of water, with a 1N aqueous sodium hydroxide solution and then with water. The organic phase is dried over anhydrous sodium sulphate. Evaporation of the solvent leaves a semi-crystalline residue which is solidified in diisopropyl ether to provide N-tert-butyloxycarbonyl-[(2,6-dimethoxy-4-methylphenyl)carbamoyl]methylamine, in the form of white crystals; M.p.=146° C.; Yield: 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]3[C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=1)[N:6]=[C:5]2[CH3:36].FC(F)(F)C(O)=O>ClCCl>[OH:25][CH2:24][C:23]([NH:22][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)[C:5]([CH3:36])=[N:6]3)[N:12]=2)[NH:17][CH:18]=1)=[O:21])([CH3:27])[CH3:26]
Reactant: Cc1nn(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2ccc(Cl)cc12
Reaction time: 15 h
Yield: 77.7 %

Procedure:
2-(5-Chloro-3-methyl-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 151 μmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) added. After stirring for 15 h the mixture was concentrated in vacuo, a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane (25 mL) added, and the mixture stirred for 1 h then concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(5-chloro-3-methyl-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2hydroxy-1,1-dimethyl-ethyl)-amide (46.8 mg 77%) as a solid. MS (M−H)−=397; 1H NMR (DMSO-d6) δ: 8.99 (s, 1H), 8.65 (d, J=9.0 Hz, 1H), 8.39 (d, J=2.6 Hz, 1H), 8.05 (d, J=1.5 Hz, 1H), 7.59-7.62 (m, 1H), 7.58 (d, J=2.1 Hz, 1H), 3.59 (d, J=5.7 Hz, 2H), 2.64 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2.N1C2C(=C[CH:28]=[C:29]([C:32]([O:34]C)=[O:33])C=2)C=C1.BrCCC(O)=O>CN(C=O)C>[Br:3][C:4]1[N:5]([CH2:28][CH2:29][C:32]([OH:34])=[O:33])[C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: O=C(O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 eq of NaH (60% dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in published International patent application WO 2004/087714, from commercially available methyl indole-6-carboxylate) in DMF (0.2 M) and the solution allowed to stir at RT for 1 h. Then 1.1 eq of 3-bromopropanoic acid were added and the mixture stirred at RT for 2 h. DMF was concentrated in vacuo and the residue taken up in EtOAc. The organic phase was washed with 1 N HCl and then brine before being dried over Na2SO4, filtered and the solvent evaporated in vacuo. The title compound was used crude in the next step; MS (ES+) m/z 408 (M+H)+, m/z 410 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH2:8])=[CH:2]1.[CH3:9][O:10][CH2:11][C:12](Cl)=[O:13].C(N(CC)CC)C.Cl>C1COCC1>[CH3:9][O:10][CH2:11][C:12]([NH:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:13]
Reactant: COCC(=O)Cl
Reactant: NCCc1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)NCCc1ccsc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.0 g (78.6 mmol) 2-thiophen-3-yl-ethylamine are dissolved in 120 ml THF and at −10° C. combined successively with 7.9 ml (86.5 mmol) methoxyacetic acid chloride and a solution of 21.9 ml (157.2 mmol) triethylamine in 30 ml THF. The mixture is heated to RT and stirred for one hour. Then it is acidified with 2N hydrochloric acid and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[C:9]=1[OH:18])=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]([Cu])#[N:20]>[C-]#N.C([N+](CC)(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:19]#[N:20])[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[C:9]=1[OH:18])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccsc2c1O
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(C#N)c2ccsc2c1O
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 151.3 %

Procedure:
A mixture of 4-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester (example 44a, 165 mg, 0.5 mmol), CuCN (181 mg, 2 mmol), tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol), 1,1′-bis(diphenylphosphino)ferrocene (114 mg, 0.2 mmol), tetraethylammonium cyanide (83 mg, 0.5 mmol), and anhydrous 1,4-dioxane (3 ml) was heated in a microwave oven at 140° C. with stirring for 15 min. Then silica gel was added and the mixture concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with ethyl acetate:hexanes=1:1 and in vacuo concentration gave a tan solid (209 mg). Purification by flash column chromatography on silica gel using ethyl acetate:hexanes=3:7 and then 1:1 gave the title compound as a tan solid (63 mg); MS-(+)-ion: MS-(−)-ion: M−1=275.1.
Reaction SMILES: [OH-].[K+].C(O)C.[SH:6][C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][CH:13]([CH3:15])[CH2:12][C:11]=2[CH:16]=1.[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>O>[CH:20]1([CH2:23][S:6][C:7]2[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]3[O:14][CH:13]([CH3:15])[CH2:12][C:11]=3[CH:16]=2)[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CC1Cc2cc(S)cc(C(=O)O)c2O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1Cc2cc(SCC3CC3)cc(C(=O)O)c2O1

Procedure:
73 g of potassium hydroxide were dissolved in 84 ml of water in a 2-liter round-bottomed flask and 387 ml of absolute ethanol and 130.5 g of 5-mercapto-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were then added. 86 g of cyclopropylmethyl bromide were then quickly poured in and the contents were heated under reflux for 1 hour. After adding water, the contents were filtered and the solution was acidified by adding concentrated hydrochloric acid until a color change of Congo red was observed. The precipitate formed was drained, washed with water and dried at 40° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]=4[CH3:30])[N:23]([CH3:31])[CH2:22]3)[C:12]2=[O:32])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>O1CCOCC1.O>[CH3:31][N:23]1[C:24]2[C:29](=[C:28]([CH3:30])[CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]([C:5]3([CH2:4][C:3]([OH:33])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:12]2=[O:32])=[CH:22]1
Reactant: COC(=O)CC1(n2c(=O)n(CC3CN(C)c4cccc(C)c43)c3ccccc32)CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2c1c(Cn1c(=O)n(C3(CC(=O)O)CCCCC3)c3ccccc31)cn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
To a solution of {1-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclohexyl}-acetic acid methyl ester (131 mg, 0.29 mmol) in dioxane (2.5 ml) was added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (2.5 mL). The solution was stirred at room temperature for 4 hours. The reaction mixture was quenched with 4M HCl in dioxane (500 □L) and concentrated. The resulting residue was purified by CombiFlash with 3% MeOH in dichloromethane as the eluent to afford the desired {1-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclohexyl}-acetic acid (85 mg, 68%). LCMS (ESMS): 432.32 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH2:11][CH3:12])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCN1CCNCC1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(C=O)c(Cl)c2)CC1
Temperature: 100 °C

Procedure:
In a 250 mL round bottom flask, 2-chloro-4-fluorobenzaldehyde (3.15 g, 20 mmol), 1-ethylpiperazine (2.8 mL, 22 mmol), and potassium carbonate (2.76 g, 20 mmol) were dissolved in anhydrous DMF (20 mL). The mixture was heated at 100° C. for 4 hours. DMF was evaporated under vacuum. The crude product was partitioned between water (100 mL) and DCM (150 mL). The organic phase was separated, washed with water, dried over Na2SO4, and evaporated to provide nearly pure 2-chloro-4-(4-ethylpiperazin-1-yl)benzaldehyde.