Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=[C:21]=[N:22][CH2:23][CH3:24].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:34][CH:35]=[C:36]([CH2:38][S:39][C:40]3[C:45]([C:46]#[N:47])=[C:44]([C:48]4[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH2:56]O)=[CH:50][CH:49]=4)[C:43]([C:58]#[N:59])=[CH:42][N:41]=3)[N:37]=2)=[CH:29][CH:28]=1>CN(C=O)C.ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:56][CH2:55][O:54][C:51]1[CH:52]=[CH:53][C:48]([C:44]2[C:45]([C:46]#[N:47])=[C:40]([S:39][CH2:38][C:36]3[N:37]=[C:33]([C:30]4[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][CH:31]=4)[S:34][CH:35]=3)[N:41]=[C:42]([N:22]3[CH2:21][CH2:24][CH2:23]3)[C:43]=2[C:58]#[N:59])=[CH:49][CH:50]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
101 mg (0.536 mmol) of N-(tert-butoxycarbonyl)-beta-alanine were initially charged in 2 ml of DMF/dichloromethane (1:1). 44.5 mg (0.232 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 10.9 mg (0.89 mmol) of 4-dimethylaminopyridine and 100 mg (0.179 mmol) of 2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 8) were added, and the mixture was then stirred at RT overnight. The crude product was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 118 mg (90% of theory) of the target compound.
Reaction SMILES: [C:1]1([N:7]([C:23]2[CH:28]=CC=CC=2)[C:8]([NH:10][S:11]([C:14]([CH3:22])=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12])=[O:9])C=CC=[CH:3][CH:2]=1.N1CCCCC1.CN(C)C=O>CCOCC>[N:7]1([C:8]([NH:10][S:11]([C:14]([CH3:22])=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:13])=[O:12])=[O:9])[CH2:1][CH2:2][CH2:3][CH2:28][CH2:23]1
Reactant: CC(=Cc1ccccc1)S(=O)(=O)NC(=O)N(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=Cc1ccccc1)S(=O)(=O)NC(=O)N1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 1.9g. of N-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide and 1.7g of piperidine in 10ml. of N,N-dimethylformamide is maintained at ca. 95°C. for 6 hours. It is then cooled to ambient temperature, and 100 ml. of ether is added. The mixture is extracted with 50 ml. of water, and then the water extract is acidified using concentrated hydrochloric acid. This causes the crude product to precipitate. It is filtered off, and then it is recrystallized from a mixture of acetone and water giving 670 mg. of N-(piperidinocarbonyl)-1-phenylpropene-2-sulfonamide, m.p. 159°-161° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])[CH3:21].O>CS(C)=O>[CH3:21][CH:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[CH3:13])[CH2:25][CH2:24]1)[CH3:22]
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCN(C(C)C)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 86.3 %

Procedure:
To a solution of 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (1.3 g, 7.03 mmol) in dimethylsulfoxide was added potassium carbonate (1.9 g, 14.0 mmol) and isopropylpiperazine (2.0 mL, 14 mmol). The resulting suspension was warmed at 70° C. for 12 hours, poured into water, and extracted with diethyl ether. The ether layers were washed with aqueous saturated sodium chloride, dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on SiO2 to afford 1-(1-methylethyl)-4-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperazine (1.78 g, 86% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm. 1.11 (d, J=6.60 Hz, 6 H), 2.24 (s, 3 H), 2.72 (s, 4 H), 2.79 (s, 1 H), 3.06 (s, 4 H), 3.93 (s, 3 H), 6.57 (s, 1 H), 7.81 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:35]1([NH2:45])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1>CN(C=O)C.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:45][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1nccc2ccccc12
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Nc2nccc3ccccc23)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-amino-3-nitrobenzoic acid (546 mg), EDCI (576 mg) and HOBt (405 mg) in DMF (7 mL) was added isoquinolin-1-ylamine (432 mg) and the mixture was stirred at ambient temperature for 18 h. Water was added and the orange precipitate was filtered to give 4-amino-N-isoquinolin-1-yl-3-nitrobenzamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C([Li])CCC.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.O>CCOCC.CCCCCC>[CH3:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[B:18]([OH:19])[OH:17]
Reactant: Cc1ccncc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: Cc1ccncc1B(O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-4-methylpyridine (5.96 g) in ether (20 ml) was added dropwise to n-butyl lithium in hexane (1.57M;22 ml) in ether (100 ml) at -78° under nitrogen. After 10 min stirring at -78° triisopropylborate (10.2 ml) was added during 2 min. The mixture was stirred at -78° for 30min and allowed to warm to room temperature during 2 h. Water (30 ml) was added and the organic layer was extracted with aqueous sodium hydroxide (0.5N; 33 ml). The combined aqueous layers were washed with ether (30 ml) and then acidified to pH6 with hydrochloric acid (2N). The mixture was stirred until the resulting gum had solidified. Filtration gave the title compound as a white solid (1.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[C@@H:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:19]1[C:31]([OH:33])=[O:32])=[O:17].[C:34]([O-])([O-])=O.[K+].[K+].IC.[OH-].[Na+]>CN(C=O)C>[CH3:34][O:32][C:31]([C@H:19]1[C@H:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@H:18]1[C:16](=[O:17])[NH:15][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:7][C:2]=1[F:1])=[O:33]
Reactant: COc1ccc(OC[C@@H]2[C@@H](C(=O)Nc3ccc(-n4ccccc4=O)cc3F)[C@H]2C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H]1[C@H](COc2ccc(OC)cc2)[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reaction time: 3 h
Yield: 101.5 %

Procedure:
A solution of 90 mg (0.19 mmol) of (1S,2R,3R) 2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-(4-methoxy-phenoxymethyl)-cyclopropanecarboxylic acid in 3 ml of DMF was treated with 100 mg of K2CO3 and 0.5 ml ml of iodomethane. The mixture was stirred for 3 hrs and poured into a diluted aqueous solution of NaOH. Extraction with AcOEt, drying of the combined organic phases over Na2SO4, filtration and evaprotation of the solvent gave 90 mg (97%) of (1S,2R,3R) 2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-(4-methoxy-phenoxymethyl)-cyclopropanecarboxylicacid methyl ester. Yellow oil. MS: 467 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.CC(C)([O-])C.[K+].C(S[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:32]([F:42])[CH:31]=2)[N:21]=1)C.CO.ClCCl>CN(C)C=O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)=[C:32]([F:42])[CH:31]=4)[N:21]=3)=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: CCSc1nc(-c2ccc(-c3ccccc3)c(F)c2)nc2ccccc12
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: Fc1cc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A solution of 5-aminoindazole (0.020 g, 0.15 mmol) in dry N,N-dimethylformamide (4 mL) was added dropwise to a solution of potassium t-butoxide (0.017 g, 0.15 mmol) in dry N,N-dimethylformamide (1 mL). The reaction mixture went from green to red within a 20-minute period, and the contents were stirred at room temperature for 1 hour before the flask was treated with a solution of the compound of Example 37 (0.050 g, 0.14 mmol) in dry N,N-dimethylformamide (2 mL). The contents were stirred at room temperature for 2 hours, at which time TLC (silica gel 60, 5% methanol/dichloromethane, UV detection) analysis indicated complete consumption of starting quinazoline. The reaction mixture was poured into ethyl acetate (20 mL), and the organics were washed with brine (20 mL, 3×30 mL), dried over sodium sulfate and concentrated. The material was air-dried for 2 hours to give the product (0.031 g, 51%) as a pale-green solid. The NMR data was identical to that obtained in Example 5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]([CH3:31])[C:26](=[O:30])[CH2:27][NH:28]C.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][NH:28][CH2:27][C:26]([N:25]([CH3:31])[CH3:24])=[O:30])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reactant: CNCC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (0.21 g, 0.60 mmol) was added to a stirred solution of N1,N1,N2-trimethylglycinamide (Me2N-Gly-Nme) (0.348 g, 1.81 mmol) and DIPEA (0.234 g, 1.81 mmol) in dimethylformamide (1 ml) at 140° C., over a period of 5 minutes. The reaction mixture was stirred for 5 minutes, cooled to room temperature and purified by preparative LCMS (standard acidic system) to give N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.193 g, 74.2%) as a white solid. 1H NMR Spectrum: (DMSO-d6) 2.27 (s, 3H), 2.80 (s, 3H), 2.98 (s, 3H), 3.71 (s, 2H), 3.94 (s, 3H), 7.19 (s, 1H), 7.27 (t, 1H), 7.47-7.52 (m, 2H), 8.30 (s, 1H), 8.43 (s, 1H), 9.85 (s, 1H); Mass Spectrum: (M+H)+ 432. Solid N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.150 g, 0.348 mmol) was added over a period of 1 minute to a stirred solution of anhydrous lithium iodide (0.232 g, 1.74 mmol) in 2,4,6-collidine (0.5 ml) at 130° C., previously stirred for 30 minutes at 130° C. The reaction mixture was allowed to stir for 5 hours, cooled, concentrated and purified by preparative LCMS (standard acidic system) to afford N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-hydroxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.080 g, 55.2%) as an orange foam; Mass Spectrum: (M+H)+ 418.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[N:24][CH:25]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2ccc(F)cn2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-5-fluoro-pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[CH3:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:19])([F:20])[F:18])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:37]([C:34]3[CH:33]=[N:32][C:31]([CH3:30])=[CH:36][N:35]=3)=[O:38])[CH:3]=[CH:4][C:5]=2[F:29])[N:9]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Product: Cc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-methyl-pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.72 (s, 3H), 2.88 (dd, J=13.6, 3.8 Hz, 1H), 3.21 (dd, J=13.6, 3.0 Hz, 1H), 3.42-3.49 (m, 1H), 3.94 (d, J=8.3 Hz, 1H), 4.39-4.80 (m, 4H), 7.14 (dd, J=11.9, 8.8 Hz, 1H), 7.62 (dd, J=7.1, 2.8 Hz, 1H), 7.93-7.99 (m, 1H), 8.46 (d, J=1.0 Hz, 1H), 9.39 (d, J=1.3 Hz, 1H), 9.65 (s, 1H)
Reaction SMILES: [OH-].[Na+].C([S:6][CH2:7][CH:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:10])(=O)C>CO.C(OCC)(=O)C>[SH:6][CH2:7][CH:8]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:10]
Reactant: COC(=O)CCCCNC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CCCCNC(=O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1N Sodium hydroxide (12.9 ml., 3.8 equiv.) is added dropwise over 10 minutes to a chilled solution (ice bath) of the product from part (b) (1.20 g., 3.41 mmole) dissolved in methanol (13 ml.) under a nitrogen atmosphere. The mixture is stirred at 0° for 10 minutes and then allowed to warm to room temperature and stirred for 3 hours. The mixture is concentrated to half volume in vacuo. The residue is diluted with water (40 ml.) washed with chloroform (2×20 ml.), and acidified to a pH of about 1.5 with concentrated hydrochloric acid. The resulting white suspension is extracted with ethyl acetate (3×15 ml.). These organic extracts are combined, washed with water and brine (20 ml. each), dried (Na2SO4) and concentrated to yield a white waxy solid (0.82 g.). This solid is dissolved in ethyl acetate, filtered, concentrated and the residue triturated with ether to give (±)-5-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino] pentanoic acid as white solids; m.p. 78°-79°. TLC (silica gel, 4:1 benzene/acetic acid) Rf =0.30 (slight tailing).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[N:10]=[C:9]([CH3:17])[C:8]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)C.[S-2:27].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([SH:27])[N:10]=[C:9]([CH3:17])[C:8]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: [S-2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C)nc(S)c([N+](=O)[O-])c1NCCCN(C)C

Procedure:
34.5 g. of 4-[[3-(dimethylamino)propyl]amino]-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester are dissolved in 100 ml. of ethanol. 15 g. of sodium sulfide in 10 ml. of water are added and the mixture is stirred without cooling for 1 hour. After this time, the precipitated 4-[[3-(dimethylamino)propyl]amino]-6-mercapto-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester is filtered off and recrystallized from methanol, yield 18 g. (53%), m.p. 131°-132°.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]#[N:16])=[CH:7][N:8]2[CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:17].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:19]1.C([O-])(=O)C.[K+].OOS([O-])=O.[K+]>O1CCOCC1.O.C(OCC)(=O)C>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:17])=[C:2]([OH:19])[CH:10]=3)[C:6]([C:15]#[N:16])=[CH:7]2)[CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: N#Cc1cn(C2CCC2)c2cc(Br)c(F)cc12
Agent: CC(=O)[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cn(C2CCC2)c2cc(O)c(F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of 6-bromo-1-cyclobutyl-5-fluoro-1H-indole-3-carbonitrile (29.9 g, 102 mmol), bis(pinacolato)diboron (33.7 g, 133 mmol), PdCl2dppf-CH2Cl2 complex (4.16 g, 5.1 mmol) and potassium acetate (30 g, 306 mmol) in dioxane (300 mL) was stirred at 80° C. overnight. The mixture was then cooled to room temperature, treated with ethyl acetate (200 mL) and filtered through a silica-celite pad. The filtrate was concentrated, dissolved in acetone (300 mL) and cooled to 0° C. Into this solution was added a slurry of Oxone (125.5 g, 204 mmol) in water (300 mL). The mixture was stirred at room temperature for 15 min, diluted with ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate. The organic extractions were combined and washed with sat. aq. NaHSO3, and brine, dried over Na2SO4 and concentrated. The residue was purified on silica gel to provide 1-cyclobutyl-5-fluoro-6-hydroxy-1H-indole-3-carbonitrile as a light grey solid (19.2 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[OH-].[K+]>C(O)COCCO>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=1[NH2:1]
Reactant: NN=C(c1cc(Cl)ccc1N)c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(Cl)cc1Cc1ccccc1F

Procedure:
In the manner given in Preparation 11, 2-amino-2'-fluoro-5-chlorobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 2-(0-fluorobenzyl)-4-chloroaniline.
Reaction SMILES: [OH:1][CH2:2][C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:20][C@H:21]1[C:29]2[C:24](=[C:25]([C:30]3[N:34]=[C:33]([C:35]4[CH:36]=[CH:37][C:38]([O:43][CH:44]([CH3:46])[CH3:45])=[C:39]([CH:42]=4)[C:40]#[N:41])[O:32][N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>CN(C=O)C.CC(=O)OCC>[C:40]([C:39]1[CH:42]=[C:35]([C:33]2[O:32][N:31]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH2:23][CH2:22][C@H:21]4[NH:20][C:3](=[O:5])[CH2:2][OH:1])[N:34]=2)[CH:36]=[CH:37][C:38]=1[O:43][CH:44]([CH3:46])[CH3:45])#[N:41]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: O=C(O)CO
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NC(=O)CO)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
Prepared using General Procedure 7. To 2-hydroxyacetic acid (7 mg, 0.08 mmol) in DMF (2 mL) was added HOBt (12 mg, 0.09 mmol) and EDC (17 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 0.5 h until the acid was fully activated. (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (25.0 mg, 0.07 mmol) was added in one portion and the reaction was stirred at room temperature for 12 h. The reaction mixture was diluted with EA and washed with NaHCO3. The combined aqueous layers were back-extracted with EA. The resulting combined organic layers were dried over Na2SO4 and concentrated to a brown oil which was purified by chromatography (MeOH/DCM) to provide 14 mg (48%) of (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxy acetamide 65 as a white solid. LCMS-ESI (m/z) calculated for C22H22N4O4: 418.5; found 419.0 [M+H]+, tR=2.47 min. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 5.61 (d, J=8.1 Hz, 1H), 4.80 (dt, J=12.2, 6.1 Hz, 1H), 4.20 (s, 2H), 3.49 (m, 1H), 3.23 (dd, J=17.1, 8.5 Hz, 1H), 2.80-2.60 (m, 1H), 1.93 (dd, J=13.0, 8.4 Hz, 1H), 1.47 (t, J=5.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.11, 171.21, 168.78, 162.78, 144.48, 143.21, 134.11, 133.88, 128.56, 127.42, 126.83, 123.29, 116.76, 115.26, 113.55, 103.90, 72.77, 62.25, 54.00, 33.52, 31.71, 21.72.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:10][C:11]=2[I:12])[CH:6]=[CH:7][N:8]=1>C(O)(C)C.C1COCC1>[NH2:1][C:3]1[C:4]2[N:5]([C:9]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:10][C:11]=2[I:12])[CH:6]=[CH:7][N:8]=1
Reactant: CC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC1(O)CC(c2nc(I)c3c(N)nccn23)C1
Temperature: -78 °C

Procedure:
A solution of 2M ammonia in isopropanol (80 mL) and THF (5 mL) was added to 3-(8-chloro-1-iodoimidazo[1,5-α]pyrazin-3-yl)-1-methylcyclobutanol (2.77 g, 7.62 mmol) in a Parr pressure reactor. The mixture was cooled to at −78° C. then ammonia gas was bubbled into the solution for 4-6 min. The reactor was sealed then heated at 110° C. for 15 h. The solvent was then removed in vacuo and the residue purified by chromatography over silica gel eluting with 7% MeOH in DCM to afford desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 3 H), 2.32-2.51 (m, 4 H), 3.33-3.52 (m, 1 H), 6.61 (br.s., 2 H), 7.03 (d, J=5.05 Hz, 1 H) and 7.62 (d, J=5.05 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[C:3]=1I.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]([CH3:35])=O.CN(C1CCCCC1)C1CCCCC1>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:11]([O:10][C:9]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26])[C:6]1[N:7]=[C:2]2[NH:1][C:33]([C:32]([O:37][CH2:38][CH3:39])=[O:36])=[CH:35][C:3]2=[C:4]2[N:29]([CH3:30])[CH:28]=[N:27][C:5]=12)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N)c(I)c3c2ncn3C)c(OC)c1
Reactant: CCOC(=O)C(C)=O
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc2c(nc(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)c3ncn(C)c32)[nH]1
Temperature: 60 °C
Yield: 85.8 %

Procedure:
To a flask charged with tert-butyl 6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example 1E, 3.49 g, 6.47 mmol) in DMA (43.1 mL) was added Pd2(dba)3 (0.474 g, 0.518 mmol), ethyl pyruvate (7.22 mL, 64.7 mmol), and N-methyldicyclohexylamine (2.77 mL, 12.94 mmol). The reaction mixture was sparged with argon for 10 min and heated at 60° C. 6 h. The reaction was complete by LCMS. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and saturated aqueous NaHCO3. The resultant emulsion was vacuum filtered through a pad of Celite and transferred to a separatory funnel The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 10% aqueous LiCl solution (2×). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The brown residue was purified by flash chromatography using an Isco 120 g column eluting with 40-80% ethyl acetate/hexane to yield ethyl 4-(tert-butoxycarbonyl(2,4-dimethoxybenzyl)amino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylate (2.830 g, 86% yield)