Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH2:7][NH:6][C:5]2[CH2:8][C@@:9]3([CH2:27][C:4]=2[CH:3]=1)[C:17]1[C:12](=[N:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]3=[O:26].Br[C:29]([F:36])([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CS(C)=O.[Cu]>[F:35][C:29]([F:36])([C:2]1[CH:3]=[C:4]2[CH2:27][C@@:9]3([C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[C:10]3=[O:26])[CH2:8][C:5]2=[N:6][CH:7]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(CC3=C(C2)NCC(I)=C3)c2cccnc21
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Copper bronze (0.522 g, 8.22 mmol) was added to a solution of (S)-3-iodo-1′-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1H)-one (described in Intermediate 7) (0.811 g, 1.644 mmol) and ethyl bromodifluoroacetate (1.056 mL, 8.22 mmol) in DMSO (10 mL) at ambient temperature. The resulting mixture was heated to 100° C. and stirred for 4 h. The reaction was cooled, partitioned between water (40 mL) and EtOAc (200 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (30 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—85:15 to 0:100, to give the title compound. MS: m/z=489.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[O:53][CH:54]=[C:55]([Sn](CCCC)(CCCC)CCCC)[CH:56]=2)[CH2:47][CH2:46]1.BrC1C=C(CN2CCN(C)CC2)OC=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.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>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([C:55]3[CH:56]=[C:52]([CH2:51][N:48]4[CH2:47][CH2:46][N:45]([CH3:44])[CH2:50][CH2:49]4)[O:53][CH:54]=3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1coc(CN2CCN(C)CC2)c1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1oc(CN2CCN(C)CC2)cc1Br
Solvent: C1COCCO1
Product: COc1ccc(Cn2nc(-c3coc(CN4CCN(C)CC4)c3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 90 °C

Procedure:
A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (35 mg, 0.0503 mmol) and a 14:86 mixture of 1-methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine and 1-((4-bromo-5-(tributylstannyl)furan-2-yl)methyl)-4-methylpiperazine (26.0 mg, 0.0554 mmol, prepared in Example 66, Step B) in dioxane (0.5 mL) was sparged with N2 for 2 minutes. PdCl2(PPh3)2 (2 mg, 0.003 mmol) was added, and the reaction was heated to 90° C. for 18 hours in a sealed vessel. After cooling to ambient temperature, the crude reaction mixture was loaded directly on to a preparative TLC plate (0.5 mm thickness, Rf=0.60) eluting with 90:10 CHCl3/MeOH (containing 7N NH3). Isolated product as an off-white solid (27 mg, 83:17 mixture of N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide by 1H-NMR). The mixture of products were carried forward without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2CC(C)(C)C(C)(C)C2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: COc1cc(B2CC(C)(C)C(C)(C)C2)cc(Cl)c1O
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN(C)C)CC4)c3c2)cc(Cl)c1O
Yield: 70.1 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (35 mg, 0.084 mmol) was reacted with 2-chloro-6-methoxy-4-(3,3,4,4-tetramethylborolan-1-yl)phenol (42 mg, 0.150 mmol) to afford the desired product (29.1 mg, 70%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 8.30 (s, 1H), 8.07-7.99 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 7.25 (d, J=1.9 Hz, 1H), 4.00 (s, 3H), 3.54 (d, J=12.4 Hz, 2H), 3.22 (t, J=12.2 Hz, 2H), 2.59-2.50 (m, 1H), 2.43 (d, J=6.2 Hz, 2H), 2.35 (s, 6H), 2.01-1.83 (m, 3H), 1.67-1.53 (m, 2H), 1.35-1.27 (m, 2H), 1.27-1.19 (m, 2H); ESI MS m/z 494 [C28H32ClN3O3+H]+; HPLC 98.9% (AUC), tR=10.51 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:32])[N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=[C:21]([NH2:23])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:40]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[N:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:32])[N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:20]=[C:21]([NH:23][C:45]([C:43]2[CH:42]=[N:41][N:40]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:44]=2)=[O:46])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cnn(Cc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cc(NC(=O)c3cnn(Cc4ccccc4)c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (6c), 2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (0.3 g, 0.659 mmol) in acetonitrile (10 mL) was added 1-benzyl-1H-pyrazole-4-carboxylic acid (0.111 g, 0.549 mmol) and triethylamine (0.133 g, 0.184 mL, 1.32 mmol). O-benzotriazole-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.312 g, 0.823 mmol) was added last and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (25 mL) and aqueous saturated sodium hydrogen carbonate solution (20 mL). The organic layer was separated and the aqueous was extracted with a further portion of ethyl acetate (25 mL). The combined ethyl acetate layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—35% ethyl acetate/hexane—50% ethyl acetate/hexane (gradient) to afford the desired title compound as a light brown solid, 0.246 g, 70%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.CI.[CH3:21]C(C)=O.C(=O)=O.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Reactant: CC(C)=O
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (318 mg, 0.0012 mol) and MeI (88 μl, 0.0014 mol, 1.18 eq) were added to DMF (5 ml) and the solution cooled to −10° C. using acetone/dry ice before the addition of NaH (30 mg, 0.0013 mol, 1.07 eq). The RM was then stirred at 0° C. for 30 min and rt for 30 min. The RM was concentrated and the product extracted using EtOAc/H2O. The organic extracts were combined, washed with sat NaCl, dried using MgSO4, filtered and the filtrate evaporated under reduced pressure and further dried in vacuo to give the product as a purple oily residue (252 mg, 75%); Rt=13 min (Vydac 1); MS+ve: 281.2.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[NH3:14]>>[NH2:14][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: N
Product: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 154a from 6-chloro-5-nitro-nicotinic acid and conc. ammonia (aq).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:18]2[C:19]3[C:15](=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)n2ccc3c(N4CCN(Cc5ccccc5)CC4)cccc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)n2ccc3c(N4CCNCC4)cccc32)cc1

Procedure:
A mixture of 250 mg(0.54 mmole) 4-(4-benzyl-piperazin-1-yl)-1-(4-methoxybenzenesulfonyl)-1H-indole, 500 mg (8 mmole) ammonium formate and 50 mg 10% Pd-C in 20 mL ethanol was heated under reflux for 2 hours. The mixture was filtered through Whatman GF/B and the filtrate was concentrated under reduced pressure. The residue was partitioned between 10 mL 10% sodium carbonate and 25 mL ethyl acetate. The organic phase was washed with 5 ml water, 5 mL saturated sodium chloride, dried (magnesium sulfate) and concentrated under reduced pressure. The 1-(4-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-indole (3) was isolated as the hydrochloride salt from methanol-ethyl acetate-ether, 128 mg, m.p. 209-210° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>C(Cl)Cl.N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:2]1
Reactant: OCC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of tetrahydro-3-furanmethanol (Aldrich, 1.0 mL, 10.4 mmol) in 5 mL CH2Cl2 and 5 mL pyridine was added para-toluenesulfonyl chloride (3.0 g, 15.6 mmol) portion-wise over 15 minutes. This mixture stirred at ambient temperature for 3 hours then 5 mL H2O was added. The layers were separated and the aqueous layer was extracted 2×5 mL CH2Cl2. The combined organics were dried over Na2SO4, filtered, concentrated under reduced pressure and dried under vacuum (˜1 mm Hg) to afford the title compound (2.62 g, 10.2 mmol, 98% yield). 1H NMR (300 Mhz, CDCl3) δ ppm 1.49-1.63 (m, 1H) 1.94-2.08 (m, 1H) 2.46 (s, 3H) 2.52-2.68 (m, 1H) 3.49 (dd, J=9.16, 5.09 Hz, 1H) 3.64-3.84 (m, 3H) 3.88-4.03 (m, 2H) 7.36 (d, J=8.14 Hz, 2H) 7.76-7.82 (m, 2H); MS (DCI/NH3) m/z 257 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[N:15]=[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C>[ClH:32].[C:24]1(/[C:16](=[N:15]/[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCC/C(=N\OCCN1CCC[C@@H](C(=O)OCC)C1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC/C(=N\OCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of E-(R)-1-(2-(((1-phenyl-1-octanylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (0.3 g, 0.75 mmol, prepared as described in example 3), ethanol (5 ml) and 12N sodium hydroxide (0.27 ml) was stirred at ambient temperature for 2 h, then neutralised with 4N hydrochloric acid and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (70 ml) and washed with water (20 ml). The aqueous phase was extracted with ethyl acetate (50 ml), the combined organic phases were washed with brine and dried (Na2SO4). The solvent was evaporated in vacuo and the residue dissolved in toluene (3 ml). The mixture was heated to 40° C. and then added to a freshly prepared solution of chloro trimethylsilane (40 μl) and methanol (4 μl) in toluene (0.14 ml). The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. This afforded 0.13 g of the title compound as an oil. 1H-NMR (DMSO-d6) δ 4.32 (m,2H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1.C([O-])(O)=O.[Na+]>C(#N)C>[Br:25][C:11]1[C:12]([NH2:15])=[N:13][CH:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)[CH:10]=1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1Br
Temperature: 23 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine (example C.25 step 1) (3.9 g, 16 mmol) in acetonitrile (65 mL) at 0° C. was added NBS (2.914 g, 16 mmol) and the mixture was stirred at 23° C. for 2 h. Poured on ice with sat. NaHCO3-sol., extracted thrice with AcOEt, dried the combined organic layers over Na2SO4, filtered off and evaporated. The residue was purified by silica gel column chromatography with AcOEt followed by trituration with heptane and very little ether to give the title compound as a light brown solid (3.7 g, 71%). MS (ISP) 317 [(M+H)+], 319 [(M+2+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[CH2:10]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:12](=O)[CH2:11]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[C:10]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:12]=[C:11]3[N:8]=2)[CH:3]=1
Reactant: O=C1CCC(C(=O)O)C1
Reactant: Cc1ccc(NN)cc1
Product: Cc1ccc2c(c1)=C1C(=CC=C1C(=O)O)N=2

Procedure:
Utilizing the procedure of Example 1, paramethylphenylhydrazine was reacted with cyclopentanone-3-carboxylic acid to give 7-methyl-cyclopenta[b]indole carboxylic acid, m.p. 250° (decomp.).
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:29]([CH2:30]C(O)=O)[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=1>C1C=CC=CC=1>[CH3:14][C:11]([O:10][C:6](=[O:5])[CH2:30][N:29]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=[C:21]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)([CH3:12])[CH3:13]
Reactant: O=C(O)Cn1c(-c2ccccn2)nc2cccnc21
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Temperature: 25 °C
Yield: 45.1 %

Procedure:
Under a nitrogen atmosphere, N,N-dimethylformamide-di-tert-butyl acetal (8.12 g, 0.040 mole) was added dropwise over a 20-minute period to a stirred, refluxing suspension of 2-(2-pyridyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.54 g, 0.010 mole) in anhydrous benzene (50 ml). The resulting solution was refluxed for 1 hour and allowed to cool to room temperature. The reaction mixture was washed with 10% potassium carbonate solution (2×25 ml), water (25 ml), dried over sodium sulfate and concentrated in vacuo. The residue (3.5 g) was dissolved in tetrahydrofuran and treated with excess ethereal hydrogen chloride. The crystalline solid was recrystallized from tetrahydrofuran, giving 1.5 g (43%). Drying in vacuo at 65° C. for 8 hours and then at 78° C. overnight gave 1.4 g of the compound as the free base, mp 124°-125.5° C.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:14]([CH2:16][C:17]([N:20]([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:15]=2)=[CH:7][C:6]=1[C:29]([F:32])([F:31])[F:30].[Cl:33][C:34]1[C:35]2[CH2:42][C:41](=[O:43])[NH:40][C:36]=2[N:37]=[CH:38][N:39]=1>CN(C=O)C>[ClH:33].[CH3:22][N:20]([CH3:21])[C:17]([CH3:19])([CH3:18])[CH2:16][N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[C:6]([C:29]([F:30])([F:31])[F:32])[CH:7]=2)[N:12]=[C:13]1[CH:23]1[CH2:28][CH2:27][N:26]([C:34]2[C:35]3[CH2:42][C:41](=[O:43])[NH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH2:25][CH2:24]1
Reactant: CN(C)C(C)(C)Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C(C)(C)Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3c2CC(=O)N3)CC1

Procedure:
Combine {2-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-1,1-dimethyl-ethyl}-dimethylamine tris hydrochloride (247 μmol; 200 mg); 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1.5 equiv; 575 μmol; 97.5 mg); TEA (1.92 mmol; 267 μL); DMF (2 mL) and heat in microwave reactor at 160° C. for 30 min. Evaporate and purify on 40 g silica gel with 2-7.5% MeOH/DCM to provide 137.3 mg (0.25 mmol; 66%) of the title compound as the free base. Dissolve in DCM/MeOH, add 1 equiv 1M HCl in ether and evaporate to provide 162.4 mg of the title compound. MS (ES+): m/z=546 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].[CH2:12]([O:14][C:15](=[O:26])[CH:16]=[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18])[CH3:13].[H-].[Na+]>C(#N)C>[CH2:12]([O:14][C:15]([C:16]1[C:2]2[C:3](=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:17]=1[CH3:18])=[O:26])[CH3:13]
Reactant: CCOC(=O)C=C(C)Nc1ccccc1
Reactant: Cc1cccc(Br)c1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c(=O)c2c(C)cccc12
Temperature: 0 °C
Yield: 22.3 %

Procedure:
To a cold (ice/water bath) solution of 2-bromo-6-methyl-benzoic acid (650 mg, 3.023 mmol) and 3-phenylamino-but-2-enoic acid ethyl ester (750 mg, 3.65 mmol) in acetonitrile (10 ml), sodium hydride (267 mg, 6.67 mmol, 60% dispersion in mineral oil) was added in portions. The cold bath was removed and the mixture was sonicated at ambient temperature until gas evolution ceased (10 min). Copper (I) bromide was added (957 mg, 6.67 mmol) and the obtained suspension was flushed with argon, sealed and heated under microwave irradiation at +80° C. for 30 min. LC-MS indicated a full conversion to 2-(1-ethoxycarbonyl-2-phenylamino-propenyl)-6-methyl-benzoic acid (LC-MS (m/z) 340.4 (MH+); tR=1.59. The obtained suspension was heated at +160° C. under microwave irradiation for 30 min. It was diluted with ethyl acetate (50 ml) and filtered. The obtained organic solution was washed with 1M HCl (3×50 ml), water (2×10 ml) and sat. aq. NaHCO3 solution (30 ml), absorbed on SiO2 (3 g) and flash chromatographed on SiO2 (50 g, gradient heptane-30% ethyl acetate in heptane) to give 217 mg of yellow oil. Yield 22%. LC-MS (m/z) 322.2 (MH+); tR=1.62. 1H NMR (500 MHz, DMSO-d6): 1.32 (t, 3H), 1.91 (s, 3H), 2.74 (s, 3H), 4.39 (q, 2H), 7.3 (d, 1H), 7.36 (overlapping m, 3H), 7.49 (m, 1H), 7.55 (t, 2H), 7.61 (t, 1H).
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].IC[CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25]>>[F:28][C:23]([F:29])([C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:21][CH2:14][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: FC(F)(F)C(F)(F)CCCI
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Product: C=CCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(6-heptenyl)malonate prepared in Example 9 and the 1-iodo-4,4,5,5,5-pentafluoro-pentane prepared in Example 1, the same procedure as shown in Example 5 was repeated to give ethyl 2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate.
Reaction SMILES: [CH2:1]([Al](CC)CC)[CH3:2].C1(C)C=CC=CC=1.C([Li])C.C1CCCCC1.C1C=CC=CC=1.[CH3:30][O:31][C:32]1[C:37]2[CH2:38][O:39][C:40](=[O:41])[C:36]=2[CH:35]=[CH:34][N:33]=1.CO>C1COCC1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>[CH2:1]([C:40]1([OH:41])[C:36]2[CH:35]=[CH:34][N:33]=[C:32]([O:31][CH3:30])[C:37]=2[CH2:38][O:39]1)[CH3:2]
Reactant: CC[Al](CC)CC
Reactant: COc1nccc2c1COC2=O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Li]CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC1(O)OCc2c1ccnc2OC
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To 10.52 mL triethylaluminum in toluene (1.9 M, 19.99 mmol, 1.1 eq) were added dropwise 39.97 mL ethyllithium in cyclohexane/benzene (0.5 M, 19.99 mmol, 1.1 eq) at 0° C. After 15 min at 0° C., 50.5 mL THF (precooled to −40° C.), were added rapidly via a canula. A solution of 3.0 g 4-methoxy-3H-furo[3,4-c]pyridin-1-one (18.17 mmol), as obtainable from example 15, in 75 mL THF was subsequently added rapidly at 40° C. After 10 min at −40° C., additional 39.97 mL ethyllithium in cyclohexane/benzene (0.5 M, 19.99 mmol, 1.1 eq) were added slowly. The mixture was allowed to warm up to −15° C. within 3 h and the reaction was afterwards quenched by addition of 3.68 mL methanol (100 mmol, 5 eq). After 30 min, the mixture was poured in 1.5 L saturated aqueous potassium sodium tartrate and was extracted three times with 500 mL, in total with 1.5 L dichloromethane. The combined organic phases were dried over 100 g Na2SO4 (30 min) and filtered. The solid was washed with 200 mL dichloromethane. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the crude product (3.77 g, 106% w/w) was obtained as a brown oil (HPLC purity 51.5% area), which was purified by column chromatography with heptane/ethyl acetate (7:3) yielding the title product (1.877 g, 9.61 mmol, 53% w/w ; HPLC purity 97.9% area; ratio lactol/hydroxy-ketone=6:1 by NMR) as yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([CH3:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][C:2]([F:15])([CH3:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(C)(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(C)(F)F)nc1
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (0.95 g, colorless oil) from 1-(6-(2,2-difluoropropoxy)pyridin-3-yl)ethanone (0.75 g, 3.49 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.