Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].[BH4-].[Na+].II>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.7 %

Procedure:
A suspension of 4-bromo-3-fluorobenzoic acid (84) (1.61 g, 7.35 mmol) in anhydrous THF (10 mL, then 4×3 mL to rinse) under N2 was added drop-wise (over 40 min) to a suspension of sodium borohydride (400 mg, 10.6 mmol) in anhydrous THF (15 mL) under N2, and then the mixture was cooled in an ice bath. A solution of iodine (1.008 g, 3.97 mmol) in anhydrous THF (10 mL, then 2×3 mL) was added drop-wise (over 35 min) to the stirred solution and then the mixture was stirred at room temperature for 14 h. The mixture was concentrated under reduced pressure and then treated successively with water (20 mL), 10% HCl (3.4 mL) and water (20 mL), and extracted with CH2Cl2 (4×50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel, eluting with 50% CH2Cl2/petroleum ether, to give (4-bromo-3-fluorophenyl)methanol (85) (1.096 g, 73%) as a white solid: mp (CH2Cl2/petroleum ether) 39-40° C.; 1H NMR (CDCl3) δ 7.52 (dd, J=8.0, 7.2 Hz, 1H), 7.16 (dd, J=9.3, 1.8 Hz, 1H), 7.02 (dd, J=8.2, 1.8 Hz, 1H), 4.67 (d, J=5.9 Hz, 2H), 1.75 (t, J=5.9 Hz, 1H); HREIMS calcd for C7H6BrFO m/z (M+) 205.9567, 203.9586, found 205.9566, 203.9580.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[C:34]([CH3:35])=[C:33]([I:36])[S:32][C:31]=1[CH:37]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:37][C:31]3[S:32][C:33]([I:36])=[C:34]([CH3:35])[C:30]=3[Br:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1c(I)sc(C=O)c1Br
Product: Cc1c(I)sc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1Br

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-bromo-5-iodo-4-methyl-thiophene-2-carbaldehyde. MS (ESI) m/z 693.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14](I)[CH:13]=3)[C:6]=2[N:5]=[CH:4]1)[CH3:2].CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)O1>>[CH2:1]([N:3]1[C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=4)[CH:13]=3)[C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: CCn1cnc2c(-c3ccc(F)c(I)c3)cnnc21
Product: CCn1cnc2c(-c3ccc(F)c(-c4ccc(S(N)(=O)=O)cc4)c3)cnnc21
Yield: 57 %

Procedure:
Prepared according to the method described above for Example 1 using 7-ethyl-4-(4-fluoro-3-iodophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 10) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (Preparation 80) to afford the title compound in 57% yield, 24.8 mg.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]1([O:31][C:32]2[N:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[F:50][C:51]([F:64])([F:63])[C:52]1[NH:53][C:54]2[C:59]([CH:60]=1)=[CH:58][C:57]([CH2:61][NH2:62])=[CH:56][CH:55]=2>CN(C=O)C>[O:31]([C:32]1[N:37]=[CH:36][C:35]([C:38]([NH:62][CH2:61][C:57]2[CH:58]=[C:59]3[C:54](=[CH:55][CH:56]=2)[NH:53][C:52]([C:51]([F:64])([F:50])[F:63])=[CH:60]3)=[O:40])=[CH:34][CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1ccc(Oc2ccccc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(Oc2ccccc2)nc1
Reaction time: 24 h
Yield: 16.7 %

Procedure:
To a stirred solution of HATU (121 mg, 0.319 mmol) in DMF (1 ml) was added 6-(phenyloxy)-3-pyridinecarboxylic acid (Maybridge; 51.5 mg, 0.239 mmol) in DMF (0.5 ml), followed by DIPEA (0.084 ml, 0.479 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 40 mg, 0.160 mmol) in DMF (1 ml). The solution was stirred for 24 hrs. DMF was removed using a rotary evaporator followed by addition of DCM and sodium bicarbonate solution. The mixture was poured through a phase separation cartridge, the organic layer evaporated to dryness and purified using MDAP to give the title compound as a white solid (11 mg);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]2.[CH:15]([C:17]1[CH:18]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:21][CH:22]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:15]([C:17]1[CH:18]=[C:19]([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][CH:11]=2)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]3)[CH:20]=[N:21][CH:22]=1)=[O:16]
Reactant: NC(=O)N1CCCc2cc(Br)cnc21
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(C=O)c3)cnc21
Yield: 60.6 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (500 mg, 2.0 mmol) in a mixture of 1,4-dioxane (9 mL) and water (1 mL) is added 5-formylpyridine-3-boronic acid pinacol ester (501 mg, 2.1 mmol), sodium carbonate (290 mg; 2.7 mmol), and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (159 mg, 0.20 mmol). The resultant mixture is stirred at 100° C. for 2 h. EtOAc is added and the mixture is washed with saturated aqueous sodium bicarbonate solution, brine and is dried (MgSO4). The solvent is evaporated and the crude product is purified by silica gel column (0-10% MeOH in DCM) to afford 6-(5-formyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (342 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)[C:12]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>>[NH:19]1[CH2:20][CH2:21][C@@H:17]([CH2:16][O:15][C:13]2[C:12]([C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:33][CH:34]=3)=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][CH2:6]3)[N:14]=2)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OC[C@@H]3CCNC3)n2)CC1

Procedure:
Using the procedure of Example 1 Step 4, (R)-tert-butyl 3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate was deprotected by TFA to provide the title compound at quantitative yield. MS (ESI) m/z: Found: 452.3 (M+1). Calc. 451.3 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.CCCCCC>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])[CH2:16][CH2:15][S:14](=[O:33])[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCSCC1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: O=S1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.3 %

Procedure:
In dichloromethane (30 ml) was dissolved 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)tetrahydrothiopyran (200 mg, 0.508 mmol). Under ice cooling, 3-chloroperbenzoic acid (106 mg, 0.614 mmol) was added. After stirring at room temperature for 14 hours, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diethyl ether, whereby the title compound (163 mg, 0.403 mmol, 79%) was obtained as a white powder.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34](=[O:36])[NH2:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:10]1)=O)(C)(C)C>CO>[F:22][C:20]1[CH:19]=[CH:18][C:17]([NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([NH2:35])=[O:36])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[C:16]([O:15][C@H:11]2[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:21]=1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCNC3)c12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
HCl in methanol (4M; 2.5 ml) was added into a suspension of (S)-3-[2-(6-carbamoyl-5-methyl-thieno[2,3-d]pyrimidin-4-ylamino)-5-fluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (0.96 g) in methanol (10 ml). The reaction was stirred at room temperature for 3.5 h. The solvent was removed in vacuo and the residue co-evaporated with chloroform. The crude HCl salt was purified by chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Product: CN(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 56 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using N-methylbenzylamine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 56%).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.OS(O)(=O)=O.O=S(=O)=O>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(N)cc1
Agent: O=S(=O)=O
Product: COc1ccc(N)cc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
123 parts of fused p-anisidine are added dropwise over 30 minutes to 240 parts of 100% sulfuric acid, while keeping the temperature at 55°-60° C. After stirring for 15 minutes the p-anisidine is completely dissolved. This sulfuric acid solution is then run into 242 parts of 66% oleum over 30 minutes, while keeping the temperature at 30°-40° C. by cooling with an ice bath. Stirring is continued for 30 minutes at 40° C., after which time no more educt can be detected by HPLC. The batch is poured into 1000 parts of ice/water and the precipitated 4-methoxyaniline-3-sulfonic acid is filtered with suction and washed with 500 parts of ice/water, affording 179 parts of moist 97.0% 4-methoxyaniline-3-sulfonic acid, corresponding to a yield of 85%, based on p-anisidine. No more p-anisidine and no more 4-methoxyaniline-2-sulfonic acid is detectable by HPLC (<0.1%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11]([O:14][C:15](=O)[CH3:16])(=O)[CH3:12]>>[CH2:11]([O:14][CH2:15][C:16]1[NH:10][C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1)[CH3:12]
Reactant: NC(=O)c1nccnc1N
Reactant: CC(=O)OC(C)=O
Product: CCOCc1nc2nccnc2c(=O)[nH]1

Procedure:
A mixture of 8.3 g (0.060 mole) of 3-amino-2-pyrazinecarboxamide [prepared according to R. C. Ellingson et al., J. Am. Chem. Soc. 1945, 67, 1711], 49.5 g (0.24 mole) of triethyl orthoethoxyacetate [prepared according to S. M. McElvain and P. M. Walters, J. Am. Chem. Soc. 1942, 64, 1963] and 53 ml of acetic anhydride is refluxed under a nitrogen atmosphere for 3 hours. The temperature of this reflux falls with the passage of time from 124° and 96° C. and then remains constant at the latter temperature. After cooling, the precipitate formed is isolated by filtration. Yld: 5.5 g (44%) m.p. 168°-169° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])(=[O:25])=[O:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
4-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.5 g) was dissolved in pyridine (20 ml) at RT and 2-chlorobenzenesulfonylchloride (0.49 g) was added and the mixture was stirred overnight at RT. The pyridine was evaporated off, the residue then dissolved in AcOEt and washed with 0.05M HCl and brine. The layers were separated, the organic layer dried over sodium sulphate and concentrated in vacuo. The residue was chromatographed over silica gel (AcOEt/heptane, gradient from 0 to 25%) to give the desired 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.448 g) as light brown oil. MS (ESI): 390.11 (MH+).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[NH:7][CH:6]=1)C.[OH-].[Na+].[N+:24]([CH:27]([CH3:29])[CH3:28])([O-:26])=[O:25]>CCOCC>[CH3:28][C:27]([N+:24]([O-:26])=[O:25])([CH3:29])[CH2:4][C:5]1[C:9]2[C:8](=[C:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(Cc1c[nH]c2c(OCc3ccccc3)cccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 29 h
Yield: 92.1 %

Procedure:
A mixture of 7-benzyloxy gramine (1.99 g, 7.10 mmol), solid NaOH (298 mg, 7.22 mmol) and 2-nitropropane (4.5 mL, 50 mmol) is heated to reflux. After 10 minutes at reflux, a thick slurry developed which is difficult to stir. Gas evolution is observed, and an additional 1 mL of 2-nitropropane is added to loosen the mixture. After 29 hours, the mixture is allowed to cool to ambient temperature. Ether (30 mL) is added and the mixture is filtered. The filtrate is treated with 10% acetic acid (6 mL), the layers are separated and the organic layer is rinsed with water (2×25 mL). The organic layer is dried (Na2SO4) and concentrated to give 2.12 g of 3-(2-methyl-2-nitropropyl)-7-(benzyloxy)indole (92%). MS (ES+) m/z 325.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C:9](=[O:21])[CH2:8]3)[CH2:3]2.CCC(C)[BH-](C(C)CC)C(C)CC.[K+].[OH-].[Na+].OO>C1COCC1>[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C@H:9]([OH:21])[CH2:8]3)[CH2:3]2
Reactant: C[C@@]12CCC(=O)C[C@H]1CC[C@@H]1C[C@]3(C)C(=O)CC[C@H]3C[C@H]12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@]3(C)C(=O)CC[C@H]3C[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
To a solution of compound 21 (460 mg, 1.6 mmoL) in THF (20 mL) was added K-selectride (2.0 mmol, 2.0 mL, 1.0 M) at −78° C. After 3 h, 10% aqueous NaOH (30 mL) and 30% H2O2 (20 mL) were added at −78° C. The reaction was then warmed to room temperature for 1 h. The product was extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give compound 22 (294 mg, 64%) as a white solid: mp 179-181° C., [α]D25 +46.9 (c 0.16, CHCl3); 1H NMR (CDCl3) δ 4.05 (s, br, 1H), 0.85 (s, 3H), 0.79 (s, 3H); 13C NMR (CDCl3) δ 221.1, 66.4, 54.6, 47.8, 45.8, 39.8, 39.1, 36.4, 35.7, 34.8, 32.0, 31.8, 28.8, 28.7, 24.1, 24.0, 13.6, 11.2; IR νmax 3434, 1736 cm−1. Anal. Calcd for (C19H30O2): C, 78.57; H, 10.41. Found: C, 78.45; H, 10.28.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH2:22])=[O:23])=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(N)=O)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1ccc(NC2CCNCC2)nc1

Procedure:
A solution of 4-(5-carbamoyl-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.63 g, 1.97 mmol) in 4 M HCl in dioxane (20 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 221.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=1[NH:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.C(=O)(O)[O-].[Na+]>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]3[NH:1][C:33](=[O:35])[N:19]([CH2:20][C:21]([OH:24])([CH3:22])[CH3:23])[C:3]=3[CH:4]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:6]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(NCC(C)(C)O)c(N)c(-c2ccc(F)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2[nH]c(=O)n(CC(C)(C)O)c2c1
Temperature: 30 °C
Yield: 83.4 %

Procedure:
To a solution of methy 6-amino-4′-fluoro-5-[(2-hydroxy-2-methylpropyl)amino]biphenyl-3-carboxylate (180 mg, 0.542 mmol) in dichloromethane (16.2 mL) was added triethylamine (0.091 mL, 0.650 mmol) followed by triphosgene (80.0 mg, 0.271 mmol) in dichloromethane (5.42 mL). Reaction heated at 30° C. for 4 h. Reaction was cooled, diluted with saturated sodium bicarbonate and dichloromethane. Adjusted aqueous layer to pH=14. Wash aqueous with dichloromethane (5×). Combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% NOH) gave the title compound (81.0 mg): LC-MS [M+1]=359.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)O)=[CH:4][S:5][CH:6]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:7][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:4][S:5][CH:6]=1
Reactant: OC(c1cccc(Cl)c1)c1cscc1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(Cc2cscc2Br)c1
Reaction time: 0.5 h

Procedure:
To (4-bromo-3-thienyl)(3-chlorophenyl)methanol from Example 3, Step 1 (144 mg, 0.474 mmol) in CH2Cl2 (1 mL) at 0° C., were successively added triethylsilane (303 μL, 1.90 mmol), quickly and TFA (364 μL, 4.74 mmol) dropwise. After 30 min., the reaction was concentrated to dryness and the residue was dissovled in CHCl3 and washed with 5% aq. NaHCO3. The aqueous layer was extracted with CHCl3 and the combined organics were washed with water and brine, dried (Na2SO4) and concentrated. The crude product was purified on silica gel (toluene/hexane 5:95) to afford the desired product as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:16](=[O:19])[CH2:17][CH3:18])[C:11]([O:13]CC)=O)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:9][C:10]([C:16](=[O:19])[CH2:17][CH3:18])=[C:11]2[OH:13]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)CC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 250 °C
Reaction time: 1.25 h
Yield: 73.7 %

Procedure:
Dowtherm A (200 mL) was heated to 240° C. Ethyl 2-(((4-bromophenyl)amino) methylene)-3-oxopentanoate (25.1 g, 77 mmol) was added portionwise. The reaction was then heated to 250° C. and stirred for 1.25 h. The reaction mixture was slowly cooled to room temperature and a precipitate formed. The suspension was diluted with hexanes (500 mL) and filtered to afford the desired product (15.9 g, 73%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.64 (br s, 1H), 8.56 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.88 (dd, J=8.8, 2.4 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 3.10 (q, J=7.2 Hz, 2H), 1.05 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][NH2:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:13]([C:20]([C:22]([F:25])([F:24])[F:23])=O)[C:14]([C:16]([F:19])([F:18])[F:17])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]([C:22]([F:23])([F:25])[F:24])=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[N:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(NN)ccc1[N+](=O)[O-]
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(-n2nc(C(F)(F)F)cc2C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 92.8 %

Procedure:
(3-Methyl-4-nitrophenyl)-hydrazine (3.0 g) and hexafluoroacetylacetone (3.7 g) were dissolved in toluene and the solution was refluxed for 6 hours. After cooling, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (5.6 g). nD20 1.4890.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]5([CH3:37])[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[ClH:38]>O1CCOCC1>[ClH:38].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]5([CH3:37])[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCN(C(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCNCC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
tert-Butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpiperidine-1-carboxylate (100 mg, 0.20 mmol) was dissolved in 30 mL of a saturated solution of HCl (g) in dioxane and the solution was stirred at room temperature for 16 hours. The reaction mixture was filtered, washed with dichloromethane (20 mL), diethyl ether (30 mL) and dried to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(4-methylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide hydrochloride (29 mg, 33.2%) as a white solid. MS: (M+H)+=408; 1H NMR (300 MHz, DMSO): δ 9.16 (s, 1H), 8.57-8.41 (m, 4H), 7.92 (s, 1H), 7.75 (d, 1H, J=10.5 Hz), 7.32-7.26 (m, 1H), 6.98-6.93 (m, 1H), 5.75 (d, 2H, J=6.9 Hz), 4.19 (s, 3H), 3.16 (brs, 5H), 1.96 (brs, 3H), 1.61 (s, 3H).