Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=1[CH3:38])=[O:5])C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:38][C:30]1[CH:31]=[C:32]([C:33]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:34])[CH:36]=[CH:37][C:29]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]2[CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)O)cc3C)cccc2c1CCCOc1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCOCC2)ccc1-c1cccc2c(CCCOc3cccc4ccccc34)c(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 98D (75 mg) and morpholine (32 mg) in dichloromethane (2 mL) was added 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (58 mg) and DMAP (38 mg). The mixture was stirred at room temperature overnight and concentrated. The concentrate was diluted with ethyl acetate (150 mL), washed with 5% HCl, water and brine and dried (Na2SO4), filtered and concentrated. The concentrate was dissolved in THF (4 mL), methanol (2 mL) and water (2 mL). LiOH.H2O (100 mg) was added to the mixture and the mixture was stirred overnight. The mixture was concentrated, the concentrate was acidified with 5% HCl and extracted with ethyl acetate. The extract was washed with brine and dried (Na2SO4), filtered and concentrated. The concentrate was purified by reverse phase HPLC (C-18, 30 to 100% acetonitrile/water/0.1% TFA). 1H NMR (300 MHz, DMSO-d6) δ 12.95 (m, 1H), 10.79 (s, 1H), 8.25 (m, 1H), 7.87 (m, 1H), 7.71 (d, 1H), 7.35-7.57 (m, 6H), 7.27 (s, 1H), 7.08 (m, 2H), 6.90 (d, 1H), 4.21 (t, 1H), 3.64 (m, 8H), 3.37 (t, 2H), 2.26 (t, 2H), 2.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5]Br.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5][N:15]=[N+:16]=[N-:17]
Reactant: ClC(Cl)=C(Cl)c1cc(Cl)cc(CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Cl)cc(C(Cl)=C(Cl)Cl)c1
Yield: 70.7 %

Procedure:
A solution of 3-chloro-5-(trichlorovinyl)benzyl bromide (3.57 g) and sodium azide (813 mg) in 50 ml of ethanol was heated at reflux for 30 minutes. The reaction was then concentrated and the residue chromatographed on silica gel with petroleum ether as eluant to afford 2.24 g of pure 3-chloro-5-(trichlorovinyl)benzyl azide.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([NH:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[O:20])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: NN1CCCC1=O
Product: O=C(NN1CCCC1=O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and 1-amino-2-pyrrolidinone (CAN 6837-14-5) as starting materials; MS (EI) 372.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([C:3]2[CH:2]=[CH:12][CH:11]=[CH:10][C:4]=2[CH3:5])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1Br
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2C)c(C(=O)OCC)cc1-c1ccccc1C

Procedure:
60 g (160 mmol) of diethyl dibromoterephthalate, 43 g (320 mmol) of o-tolylboronic acid, 365 mg (0.32 mmol) of Pd(PPh3)4 and 92 g (660 mmol) of K2CO3 are heated at the boil for 4 h in 300 ml of toluene and 300 ml of water. The mixture is subsequently partitioned between toluene and water, and the organic phase is washed three times with water and dried over Na2SO4. The residue remaining is recrystallised twice from heptane to give colourless crystals. The yield is 51 g (127 mmol, 81%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14]([O:16]C)=O.[F:23][C:24]([F:31])([F:30])[CH2:25][CH2:26]C(O)=O>C1COCC1>[Br:11][C:12]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14](=[O:16])[CH2:26][CH2:25][C:24]([F:31])([F:30])[F:23]
Reactant: O=C(O)CCC(F)(F)F
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCC(F)(F)F)c1cc(Cl)ccc1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A THF solution of sodium bis(trimethylsilyl)amide (1.0M, 194 mL, 194 mmol) was added dropwise to a −78° C. THF (400 mL) solution containing methyl 2-bromo-5-chlorobenzoate (16.10 g, 64.5 mmol) and 4,4,4-trifluorobutyric acid (9.17 g, 64.5 mmol). After stirring for 15 minutes at −78° C. the solution was warmed to 0° C. and stirred for an additional 2 hours. The reaction was quenched with an excess of aqueous 1N HCl (ca 400 mL) and stirred overnight at room temperature. The solution was concentrated to remove the majority of the THF. The solution was then diluted with EtOAc and washed with 1N NaHCO3 (twice) and brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (solid). 1H NMR (500 MHz, CDCl3): δ 7.58 (d, J=8.4 Hz, 1H); 7.41 (d, J=2.5 Hz, 1H); 7.33 (dd, J=8.5, 2.5 Hz, 1H); 3.22 (t, J=7.8 Hz, 2H); 2.68-2.56 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][CH:29]=[C:28]([O:27][CH2:26][CH2:25][F:24])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2cncc(OCCF)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OCCF)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-fluoro-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 181.1.1) to give the title compound as a white solid. (HPLC: tR 2.20 min (Method A); M+H=433 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.36-8.32 (m, 2H), 8.17-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.61-7.57 (m, 1H), 7.47-7.44 (m, 1H), 4.89-4.73 (m, 2H), 4.48-4.36 (m, 2H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](OC(OCC)OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:13]=[N:9][N:8]=2)=[C:4]([OH:12])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1ccc(Cl)cc1O
Product: Oc1cc(Cl)ccc1-c1nnco1
Temperature: 130 °C
Yield: 35 %

Procedure:
A mixture of 4-chloro-2-hydroxybenzoic acid hydrazide (Chemical Abstracts, 93:7808, 475 mg, 2.55 mmol) and triethylorthoformate. (3.6 ml) is heated at 130° C. for 3.5 hours. After cooling, a precipitate formed and is collected by filtration. The filter cake is recrystallized from methanol to give 173 mg (35%) of 5-chloro-2-(1,3,4-oxadiazol-2-yl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield 170 mg (69%) of the title epoxide.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([CH2:8][C:9]([O:11]C)=O)[N:4]=1)[CH3:2].[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([CH2:39][CH3:40])=[N:31][N:32]3[CH:35]3[CH2:38][CH2:37][CH2:36]3)=[CH:28][CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:21][N:22]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([CH2:39][CH3:40])=[N:31][N:32]3[CH:35]3[CH2:36][CH2:37][CH2:38]3)=[CH:28][CH:27]=2)[CH2:23][CH2:24][N:25]1[C:9](=[O:11])[CH2:8][C:5]1[NH:4][C:3]([CH2:1][CH3:2])=[N:7][N:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCc1nc(CC(=O)OC)n[nH]1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nnc(CC(=O)N2CCN(c3ccc4c(CC)nn(C5CCC5)c4c3)C[C@@H]2Cc2ccccc2)[nH]1
Yield: 16 %

Procedure:
Prepared by the method outlined for Example 275 using methyl (5-ethyl-1H-1,2,4-triazol-3-yl)acetate and 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole as starting materials. Product was obtained as a light yellow solid (16%). LC/MS (Method B) 3.56 min, [M+1]+ 512.
Reaction SMILES: O=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].Cl.[NH2:17][OH:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.O>[OH:18][N:17]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: NO
Reactant: O=C(CN1CCCC1=O)c1cccnc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCCN1CC(=NO)c1cccnc1
Yield: 65.2 %

Procedure:
To 0.3 g (1.47 mmol) of 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one prepared from Example 20, 0.15 g (2.21 mmol) of hydroxylamine hydrochloride salt and 0.12 g of sodium sulfate were added in methanol/water (1.5:1). The mixture was reacted at 30˜40° C. for 12˜36 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate for three times, washed with brine for two times, and dried over sodium sulfate. After concentrating under reduced pressure, it was purified by separation with silica gel column chromatography (chloroform/methanol (30:1˜10:1)) to obtain 0.21 g (66% yield) of 1-(2-hydroxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one as E/Z mixture (1.56:1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][NH:5][CH2:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][CH:11]=1.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCOC(C)=O>[CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][N:5]([CH2:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: COC(CNCc1ccc(C)s1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(CN(Cc1ccc(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Crude (2,2-dimethyoxy-ethyl)-(5-methyl-thiophen-2-ylmethyl)-amine (1) (43.41 g ˜75% pure, 0.15 mol) was dissolved in EtOAc (150 mL) resulting in a yellow solution. Triethylamine (22 mL, 0.16 mol) was added. The mixture was cooled to 0° C. in ice bath. p-Toluenesulfonyl chloride (29.68 g, 0.16 mol) was added in small portions keeping the temperature below 15° C. After addition was complete the mixture was left in ice bath and allowed to slowly warm to room temperature and stirred for 20 hrs. The milky-yellow mixture was diluted with EtOAc (300 mL) and washed with water (2×400 mL), 1 M HCl (2×400 mL), water (1×400 mL), sat NaHCO3 (1×400 mL), and brine (1×400 mL), dried (MgSO4) and condensed to provide the title compound as a reddish-yellow liquid, 50.56 g. Product was not purified.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C(OC([N:53]1[CH2:60][CH2:59][CH2:58][C@:54]1([CH3:61])[C:55](O)=[O:56])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:95]([OH:101])([C:97]([F:100])([F:99])[F:98])=[O:96]>ClCCl>[F:98][C:97]([F:100])([F:99])[C:95]([OH:101])=[O:96].[CH3:61][C@:54]1([C:55]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]2[CH2:23][CH2:24][CH2:25][C@H:21]2[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:56])[CH2:58][CH2:59][CH2:60][NH:53]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1)C(C)C
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a stirring solution of #114 (164 mg, 0.259 mmol, 1.0 eq.) and 1-(tert-butoxycarbonyl)-2-methyl-D-proline (71.3 mg, 0.311 mmol, 1.2 eq.) in 4 mL of dichloromethane, HATU (118 mg, 0.311 mmol, 1.2 eq.) was added followed by Hunig's base (0.180 mL, 1.04 mmol, 4 eq.). The reaction was allowed to stir at room temperature for -30 minutes. Reaction was reduced down. Reaction was taken up in 3.5 mL of dichloromethane and placed under nitrogen. To this stirring solution, TFA (1.5 mL, 20 mmol, 76 eq.) was added. The reaction was allowed to stir at room temperature for -1 hour. Reaction was reduced down and placed underneath high vacuum. Purification by (Method J*) affords #131 (119 mg, 54%) as a white solid. HPLC (Protocol A at 45° C.): m/z 744.5 [M+H+], retention time=7.342 minutes (purity >98%). 1H NMR (400 MHz, DMSO-d6), δ 9.08-9.18 (m), 8.79-8.89 (m), 8.76 (t), 8.54 (d), 8.29 (d), 7.14-7.31 (m), 4.70-4.79 (m), 4.57-4.66 (m), 4.45-4.55 (m), 3.96-4.04 (m), 3.74-3.80, 3.66 (d), 3.48-3.61 (m), 3.40-3.48 (m), 3.09-3.34 (m), 3.00-3.09 (m), 2.95-3.00 (m), 2.83-2.93 (m), 2.36-2.53 (m), 2.21-2.35 (m), 2.10-2.19 (m), 1.99-2.10 (m), 1.61-1.09 (m), 1.36-1.53 (m), 1.21-1.35 (m), 1.02-1.10 (m), 0.94-1.0 (m), 0.86-0.93 (m), 0.73-0.82 (m).
Reaction SMILES: [N:1]([C:4]1[C:5]([Cl:23])=[C:6]2[CH:12]=[CH:11][N:10]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:7]2=[N:8][CH:9]=1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:23][C:5]1[C:4]([NH2:1])=[CH:9][N:8]=[C:7]2[N:10]([Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:14]([CH3:15])[CH3:16])[CH:11]=[CH:12][C:6]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(N=[N+]=[N-])cnc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(N)cnc21
Temperature: 25 °C
Yield: 49 %

Procedure:
4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (10 g, 32.5 mmol) was dissolved in THF (250 mL) and cooled to −78° C. Sec-Butyllithium ( 54.8 mL, 1.3M/cyclohexane, 71.4 mmol.) was then added dropwise and the solution was stirred for 20 min. A solution of tosylazide (16 g, 81.2 mmol.) in THF (100 mL) was added and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and warmed to RT. This mixture was extracted with hexanes (2×200 mL) and the combined organic layers were dried. The organic phase was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 100% hexanes) to afford 5-azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine as a mixture with starting material (10.2 g). This mixture was directly used in next step. B. 5-Azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (1.6 g, 4.6 mmol) was dissolved in ethyl acetate (100 mL) and Pd/C (10%, 100 mg) was added. This suspension was stirred at RT and under 1 atmosphere. of hydrogen for 18 h. The solid was removed by filtration over Celite® and the solution was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 95% hexanes, 5% ethyl acetate) to afford 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (730 mg, 43.5%, 2 steps). C. 4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (10.2 g, 31.5 mmol) was diluted in ethyl acetate (200 mL) and acetic acid (100 mL). Zinc dust (50 g, 0.8 mol.) was added in small portions at RT. After stirring the suspension at RT for 4 h, the mixture was filtered over Celite and the filtrate was slowly neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (2×300 mL). The combined organic layers were dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 5% ethyl acetate in hexanes) to afford 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (6.38 g).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40](C(F)(F)F)[CH:41]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1OS(C(F)(F)F)(=O)=O)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[C:48]1(B(O)O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:2]([F:47])([F:46])[F:1])[CH:41]=1)[CH2:6][N:7]([C:8]1[N:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:12][N:13]=1)[CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:22]=1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=S(=O)(Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2ccccc2)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 57.8 %

Procedure:
Trifluoromethanesulfonic acid 2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl ester (200 mg) is dissolved in 1,4-dioxane (3 ml), and thereto are added phenyl boronic acid (69 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (23 mg) and cesium carbonate (183 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. for 1 day. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (52 mg). MS (m/z): 641 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[C:15]([C:19]1[CH:38]=[CH:37][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:15]([C:19]1[CH:38]=[CH:37][C:22]([CH2:23][N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
87 mg (0.44 mol) of 5,6-difluoro-1H-indol-7-carboxylic acid, 134 mg (0.40 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine and 84 mg (0.44 mmol) of EDC.HCl were dissolved in 4 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 78 mg (38%) product as a colorless viscous oil. MS (ISP) 515.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>>[NH2:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:7][C:2]=1[Br:1]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cc1Br
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(N)c(Br)c1)OCC
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Di-tert-butyl [2-bromo-4-(bromomethyl)phenyl]imidodicarbonate (Compound 32E, 6.0 g, 13 mmol) was taken up in triethyl phosphite (5.0 mL, 29 mmol) and stirred at 120° C. for 16 h. The reaction mixture was transferred to a microwave vial and was irradiated in the microwave for 4 h at 190° C. The reaction mixture was concentrated in vacuo. The compound was purified by flash column chromatography eluting with 10 to 100% EtOAc in heptane. The product was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (400 MHz, chloroform-d) δ 7.33 (t, J=2.3 Hz, 1H), 7.04 (ddd, J=2.3, 2.4, 8.2 Hz, 1H), 6.71 (dd, J=0.8, 8.1 Hz, 1H), 3.97-4.06 (m, 4H), 2.96-3.04 (m, 2H), 1.26 (t, J=7.1 Hz, 6H); MS (ESI): m/z: 322.00, 323.96 [M+H]+. UPLC: tR=2.83 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([CH3:20])[CH2:11][NH:12]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>>[NH2:12][CH2:11][CH:10]([CH3:20])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:23][CH:22]=1)=[O:21]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)NCc1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CN)C(=O)NCc1ccc(C#N)cc1
Yield: 73.6 %

Procedure:
A solution of the compound obtained in Step 1 (221 mg, 0.70 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room temperature for 15 min, and concentrated under reduced pressure. To the residue were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give 3-amino-N-(4-cyanobenzyl)-2-methylpropanamide (112 mg, 0.515 mmol, 74.0%) as a white powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6].[N+](C1C=CC=C([N+]([O-])=O)C=1C#N)([O-])=[O:15].CS>[Ni]>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([S:2][CH3:1])[C:4]=1[C:5]([NH2:6])=[O:15]
Reactant: CSc1cccc([N+](=O)[O-])c1C#N
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Ni]
Agent: CS
Product: CSc1cccc(N)c1C(N)=O

Procedure:
2-Amino-6-(methylthio) benzamide is prepared by Raney nickel reduction of 2-(methylthio)-6-nitrobenzonitrile which is prepared from 2,6-dinitrobenzonitrile and methylmercaptan following the procedure set forth in Example 75.