Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]3[CH2:20][CH2:19]3)[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]3[CH2:20][CH2:19]3)[C:11]3[N:12]([C:14]([C:22]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Clc1ccc(-c2cc(C3CC3)c3ncc(I)n3c2)cc1
Product: Nc1ccc(C#Cc2cnc3c(C4CC4)cc(-c4ccc(Cl)cc4)cn23)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-cyclopropyl-3-iodo-imidazo[1,2-a]pyridine (example C.27 step 5) (592 mg, 2 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (230 mg, 2 mmol) according to general procedure II. Obtained as a yellow solid (128 mg, 22%). MS (ISP) 385.2 [(M+H)+], 387 [(M+2+H)+]; mp 246° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29]C)[CH2:27]C)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.C(CC(NC(C1C=CC(OCCN(C)C)=CC=1)CCC)=O)#N>>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:29])=[CH:21][CH:22]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Agent: CCCC(NC(=O)CC#N)c1ccc(OCCN(C)C)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(C)C)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 2-cyano-N-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-butyl)acetamide (30) was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 4:96 methanol/dichloromethane, to give 35 (120 mg, 76%) as a yellow oil: MS (ES+) m/z 471.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:21][C:18]([F:19])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH:8]([NH2:7])[CH2:11]2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccc(C(F)(F)F)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CN(c2ccc(C(F)(F)F)cn2)C1
Yield: 92.9 %

Procedure:
D6 (750 mg, 1.28 mM) in dichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml) overnight at ambient temperature. The solution was concentrated and then partitioned between dichloromethane and 2M sodium hydroxide. The dichloromethane solution was washed with brine, dried and concentrated to give the title compound as a colourless solid, (477 mg).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9](O)=[O:10].N1C=CC=CC=1>ClCCl>[Br:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([Cl:4])=[O:10]
Reactant: CC(C)CC(Br)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CC(Br)C(=O)Cl
Reaction time: 20 h

Procedure:
A solution of sodium nitrite (31.55 g) in water (70 ml) was added dropwise to a stirred solution of D-leucine (20 g) in 47% aqueous hydrobromic acid (140 ml)/water (211 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, then diluted with diethyl ether (600 ml). The organic layer was separated and washed with aqueous sodium metabisulphite (200 ml), dried over sodium sulphate, filtered and the solvent removed under reduced pressure to give 2-bromo-4-methyl-pentanoic acid as a yellow oil (27.6 g) [1H NMR (CDCl3): δ0.93 (d, 3H), 0.98 (d, 3H), 1.75-1.85 (m, 1H), 1.91-1.95 (m, 2H), 4.30 (t, 1H)]. Oxalyl chloride (9.56 ml) was added dropwise to a stirred solution of the 2-bromo-4-methylpentanoic acid (10.7 g) and pyridine (0.1 ml) in dichloromethane (60 ml). The reaction mixture was stirred for 20 hours and the solvent was removed under reduced pressure to give 2-bromo-4-methylpentanoyl chloride (12 g) [1H NMR (CDCl3); δ0.95 (d, 3H), 1.01 (d, 3H), 1.80-2.07 (m, 3H), 4.52 (t, 1H)]. A solution of this 2-bromo-4-methylpentanoyl chloride (12 g) in dichloromethane (40 ml) was added dropwise to a stirred solution of 2,6-dimethoxy-4-methylphenol (9.41 g) and triethylamine (15.6 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 20 hours and was then chromatographed on silica gel, eluting with dichloromethane, to give the title compound as a viscous yellow oil (14.7 g).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: OB(O)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1ccncc1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.6 %

Procedure:
A mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.1 g, 0.21 mmol), 4-pyridylboronic acid (52 mg, 0.42 mmol), cupric acetate (58 mg, 0.32 mmol) and triethylamine (60 μL, 0.42 mmol) in dichloromethane (2 mL) was stirred for 2 d at room temperature. Chromatography on silica gel (ethyl acetate) yielded the desired product (26 mg, 21%), MS: m/e=549.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[CH:8][C:7]1=2
Reactant: N#Cc1cccc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 85 °C
Yield: 25.2 %

Procedure:
A mixture of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (2.22 g, 10 mmol), 3-bromobenzonitrile (2.18 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0) (0.6 g, 0.52 mmol), and sodium carbonate (2.2 g, 21 mmol) in a mixture of DME and water (70 mL/15 mL) was degassed to remove the oxygen and then heated at 85° C. under a blanket of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (100 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/1:1) to give 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile as an off-white solid (0.7 g, 25%): mp 236-237° C.; 1H-NMR (DMSO-d6) δ 10.34 (s, 1H, D2O exchangeable), 8.21 (s, 1H), 8.02 (d, 1H, J=8.1 Hz), 7.79 (d, 1H, J=7.7 Hz), 7.60-7.70 (m, 3H), 6.98 (d, 1H, J=8.2 Hz), 1.71 (s, 6H); Anal. Calcd. For C17H14N2O2.0.1H2O: C, 72.89; H, 5.11; N, 10.00. Found: C, 72.75; H, 5.05; N, 9.65.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=CC=1[N+]([O-])=O.[O:20]1CCC(CN)[CH2:22][CH2:21]1.C(N(CC)CC)C.[H][H]>[C].[Pd].O.C(#N)C>[O:20]1[CH2:2][CH2:7][CH:6]([CH2:5][C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:22][CH2:21]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NCC1CCOCC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: c1ccc2oc(CC3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
2-(4-Fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (900 mg, 3.5 mmol) was added to an acetonitrile (5 mL) solution containing (tetrahydropyran-4-yl)methylamine (520 mg, 3.9 mmol) and triethylamine (500 mg, 4.3 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a tetrahydrofuran solution (20 mL) of the crystals obtained was added 10% palladium-carbon (100 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred overnight at room temperature. After the reaction was finished, this was filtered through Celite, and the filtrate was concentrated to yield the title compound (790 mg, 70% yield) as a white solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[C:8]([Cl:15])[C:9]([Cl:14])=[C:10]([Cl:13])[C:11]([Cl:12])=[C:4]2[C:3]1=[O:16].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:1][N:2]1[C:3](=[O:16])[C:4]2=[C:11]([Cl:12])[C:10]([Cl:13])=[C:9]([Cl:14])[C:8]([Cl:15])=[C:5]2[C:6]1=[O:7])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON1C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C1=O
Yield: 87 %

Procedure:
N-Methanesulfonyloxytetrachlorophthalimide was prepared by the following procedure. To a flask equipped with a stirrer and addition funnel were added N-hydroxytetrachlorophthalimide (9.00 g, 0.030 mol), methanesulfonyl chloride (3.60 g, 0.032 mol), and 200 mL of methylene chloride. The mixture was cooled in ice and a solution of triethylamine (5.0 mL, 0.036 mol) in 25 mL of methylene chloride was added slowly. Upon completion of this addition the reaction mixture was diluted with 200 mL of methylene chloride and washed successively with water (250 mL), 5% aqueous sodium bicarbonate (250 mL), and water (250 mL). The organic layer which contained a substantial amount of precipitated product was evaporated, and the resulting solid was dried by addition of toluene and evaporation to give 9.89 g (87.0%) of pale yellow crystalline N-methanesulfonyloxytetrachlorophthalimide: mp 240°-241°; uv (CH3CN) 240 (51,400), 329 (2736), 340 nm (2937); ir (KBr) 3040 (w), 3020 (w), 2940 (w), 1800 (m), 1700 (vs), 1375 (s), 1330 (m), 1310 (m), 1180 (s), 1120 (m), 1030 (s), 965 (m), 790 (m), 725 (s); nmr (CDCl3) 3.53 (s); mass spectrum 376.8472 (calcd for C9H3NO5Cl4S: 376.8783). Anal. Calcd for C9H3NO5Cl4S: C, 28.52; H, 0.80; N, 3.70; O, 21.11; Cl, 37.42; S, 8.46. Found: C, 28.52, 28.94, 28.92; H, 0.80, 1.07, 1.05; N, 3.70, 3.84, 3.82; Cl, 37.42, 37.08.
Reaction SMILES: COC1C=CC(C[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH:20][C:21]([CH:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26](=[O:33])[N:25]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]4[OH:40])[CH:24]3[C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])=[O:22])[CH:13]=2)[C:9]([O-:11])=[O:10])=CC=1.FC(F)(F)C(O)=O>C(Cl)CCl>[Cl:48][C:42]1[CH:43]=[C:44]([Cl:47])[CH:45]=[CH:46][C:41]=1[CH:24]1[CH:23]([C:21]([NH:20][CH2:19][CH2:18][C:14]2[CH:13]=[C:12]([CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:16][CH:15]=2)=[O:22])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[OH:40]
Reactant: COc1ccc(CC(C(=O)[O-])c2cccc(CCNC(=O)C3c4ccccc4C(=O)N(C4CCCCC4O)C3c3ccc(Cl)cc3Cl)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(O)Cc1cccc(CCNC(=O)C2c3ccccc3C(=O)N(C3CCCCC3O)C2c2ccc(Cl)cc2Cl)c1
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To a mixture of 990 mg of 4-methoxybenzyl(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetate and 10 ml of ethylene chloride was added 10 ml of trifluoroacetic acid at room temperature, followed by stirring for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 20 mL of methanol, and 20 mL of a saturated aqueous sodium hydrogen carbonate solution was added thereto at room temperature, followed by stirring for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and neutralized with 1 M hydrochloric acid. The product was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 339 mg of (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetic acid as a colorless solid.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[NH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17]1>N1C=CC=CC=1.C1C=CC=CC=1.C(Cl)(Cl)Cl>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: Nn1cc(-c2ccccc2)c2ccccc21
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nn2cc(-c3ccccc3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
11.7 G (0.05 mol) of p-acetaminobenzene sulphonyl chloride were added in portions and with stirring to a solution of 15.6 g (0.075 mol) of 1-amino-3-phenyl-indole in 100 ml of pyridine. The temperature of the mixture rose to about 45° C. The mixture was then heated to 60° C. and stirred for 3 hours at this temperature. The red solution obtained was then concentrated by evaporation under vacuum. The viscous, oily residue which was obtained was taken up in a mixture of benzene and chloroform (1:1 by volume) and chromatographically purified through a column of 300 ml Alox Woelm neutral Akt. II. The resulting oily product was crystallised from a little ethanol and was recrystallised from ethanol/water. The crystals of 1-(p-acetaminobenzene sulphonylamino)-3-phenyl-indole melted at 190°-193° C. and were obtained in a yield of 16.5 g (55% of the theoretical).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C([N-]C(C)C)(C)C.[Li+].[Cl:22][CH2:23][CH2:24][CH2:25]I>O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)N1CCC(C#N)CC1
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C#N)(CCCCl)CC1
Temperature: -10 °C
Yield: 64.6 %

Procedure:
To a solution of ethyl 4-cyano-1-piperidinecarboxylate (6.0 g) in tetrahydrofuran (120 ml) at -70° C., under nitrogen, was added a solution of lithium diisopropylamide (4.6 g) in tetrahydrofuran (21.5 ml), dropwise, with stirring. The reaction was allowed to warm to -10° C. and after 30 min was recooled to -70° C. A solution of 1-chloro-3-iodopropane (7.4 g) in tetrahydrofuran (20 ml) was added to the mixture over 30 min. The reaction mixture was quenched with water and allowed to warm to ambient temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was flash chromatographed (silica), eluting with 2:1 heptane/ethyl acetate. The appropriate fractions were collected and concentrated to afford 5.5 g (64%) of product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[O-:11][S:12]([O-:14])=O.[Na+].[Na+].C(Cl)(=O)C(Cl)=O.[CH:23]([NH2:26])([CH3:25])[CH3:24]>CCO.O.[Cl-].[Na+].O.CCOC(C)=O>[C:6]([C:5]1[CH:4]=[C:3]([CH2:2][S:12]([NH:26][CH:23]([CH3:25])[CH3:24])(=[O:14])=[O:11])[CH:10]=[CH:9][CH:8]=1)#[N:7]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)N
Reactant: O=S([O-])[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)NS(=O)(=O)Cc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 3-bromomethyl-benzonitrile (2 g, 10.2 mmol) in EtOH (50 mL) is added a solution of Na2SO3 (1.3 g, 10.3 mmol) in H2O (50 mL) and the mixture is heated at reflux for 4 hours. The mixture is concentrated in vacuo. The residue is suspended in DCM (100 mL) and DMF (1 mL), cooled to 0° C. and treated with oxalyl chloride (4.5 mL, 24.4 mmol). The mixture is warmed to room temperature for 3 hours. The mixture is diluted with brine (100 mL), extracted with DCM (2×100 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue is dissolved in THF (100 mL), and treated with isopropyl amine (3.5 mL, 40.8 mmol). The mixture is stirred for 12 h, diluted with EtOAc (200 mL), washed with saturated aqueous NH4Cl (2×100 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford C-(3-cyano-phenyl)-N-isopropyl-methanesulfonamide as a powder. MS: 237 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.10 (d, J=6.6 Hz, 6H), 3.36 (m, 1H), 4.42 (s, 2H), 7.09 (m, 1H), 7.57 (m, 1H), 7.74 (m, 1H), 7.85 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[F:20][C:21]([F:40])([F:39])[C:22]([NH:24][CH2:25][C:26]1[C:27]([CH3:38])=[C:28]([C:34]([CH3:37])=[CH:35][CH:36]=1)[C:29]([N:31]=[C:32]=[O:33])=O)=[O:23].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:32](=[O:33])[NH:31][C:29]([C:28]3[C:27]([CH3:38])=[C:26]([CH:36]=[CH:35][C:34]=3[CH3:37])[CH2:25][NH:24][C:22](=[O:23])[C:21]([F:40])([F:39])[F:20])=[N:10]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(=O)N=C=O
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Yield: 45.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.00 g, 3.63 mmol), 3-((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzoyl isocyanate (Intermediate-65, 1.00 g, 3.33 mmol), DCM (20 mL), trifluoro acetic acid (5.0 mL) to afford 0.700 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 2.20 (s, 3H), 2.22 (s, 3H), 4.40 (d, J=4.2 Hz, 2H), 7.21 (d, J=6.0 Hz, 1H), 7.29 (d, J=6.0 Hz, 1H), 7.82 (d, J=6.6 Hz, 1H), 8.17 (d, J=6.6 Hz, 1H), 9.95 (t, J=6.9 Hz, 1H), 12.32 (br s, 1H); MS (m/z): 457.26 (M−H)−.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:34]([NH2:36])=[O:35])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@H:27]6[NH:31][CH2:32][CH2:33][C@@H:26]56)[N:24]=4)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH:46]1([C:49]([Cl:51])=[O:50])[CH2:48][CH2:47]1>CN1C(=O)CCC1>[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:19]4[C:20]([C:34]([NH2:36])=[O:35])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@H:27]6[N:31]([C:49]([CH:46]7[CH2:48][CH2:47]7)=[O:50])[CH2:32][CH2:33][C@@H:26]56)[N:24]=4)=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:51]
Reactant: O=C(Cl)C1CC1
Reactant: NC(=O)c1ncc(N2CCC[C@H]3NCC[C@H]32)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: NC(=O)c1ncc(N2CCC[C@@H]3[C@H]2CCN3C(=O)C2CC2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 994.2 %

Procedure:
3-(4-(1-Cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide (420) (82 mg, 0.16 mmol) was dissolved in 3 mL NMP. To it were added DIEA (290 μL, 1.68 mmol) and then cyclopropanecarbonyl chloride (61 μL, 0.67 mmol). The mixture was stirred at RT for 2 hours, quenched with 0.5 mL TFA, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-1-(cyclopropanecarbonyl)dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide (422) as HCl salt (58 mg, 62%). LC-MS (ESI): m/z (M+1) 558.8. UV: λ=266, 274, 304, 334, 372 nm.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[N:26]=[CH:25][N:24]=[C:23]([O:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:22]=1)[CH2:16][CH2:15]2)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.[CH2:50]([S:54](Cl)(=[O:56])=[O:55])[CH2:51][CH2:52][CH3:53]>ClCCl>[CH2:50]([S:54]([N:31]1[CH2:32][CH2:33][CH:28]([O:27][C:23]2[N:24]=[CH:25][N:26]=[C:21]([N:17]3[C:18]4[C:14](=[CH:13][C:12]([S:9]([CH3:8])(=[O:10])=[O:11])=[CH:20][CH:19]=4)[CH2:15][CH2:16]3)[CH:22]=2)[CH2:29][CH2:30]1)(=[O:56])=[O:55])[CH2:51][CH2:52][CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCS(=O)(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Trifluoroacetic acid (727 μL) was added at 0° C. to a dichloromethane (2.90 mL) solution of the tert-butyl 4-({6-[5-(methylsulfonyl)indolin-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (145 mg, 0.306 mmol) produced in Example 1, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. To a dichloromethane (3.70 mL) solution of the obtained residue and diisopropylethylamine (1.07 mL, 6.14 mmol), a dichloromethane (1.85 mL) solution of 1-butanesulfonyl chloride (72.0 mg, 0.461 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 1 hour and then at 80° C. for 3 hours. The solvent was distilled off under reduced pressure. To the residue, methanol was added, and the deposit was collected by filtration. The obtained crude product was washed with methanol to obtain the title compound as white powder (125 mg, yield: 82%).
Reaction SMILES: C([C:5]1[C:13]([CH2:14][N:15]([C:17](=[O:24])[CH:18](O)CC(C)C)C)=[C:12]([NH2:25])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:25][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:13]=1[CH2:14][N:15]([O:27][CH2:26][CH3:28])[C:17]([CH3:18])=[O:24]
Reactant: CC(C)CC(O)C(=O)N(C)Cc1c(N)ccc(C(=O)O)c1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCON(Cc1cc(C(=O)O)ccc1N)C(C)=O
Reaction time: 12 h

Procedure:
To a stirred solution of t-butyl-4-amino-3-[(2-hydroxy-4,N-dimethylpentanoylamino)methyl]benzoic acid (2.98 g, 9.67 mmole) in CH2Cl2 (20 mL) at RT was added TFA (20 mL). After 12 hr, the reaction contents were concentrated, washed with hexanes and dried under high vacuum overnight affording the title compound as an orange oil (3.51 g, 9.60 mmol). This product was used without further purification: MS (ES) m/e 253 (M+H-TFA)+.