Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:37][O:38][C:39](=[O:72])[NH:40][CH:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[C:52]1[NH:53][CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60](B3OC(C)(C)C(C)(C)O3)=[CH:59][CH:58]=2)[N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:60]4[CH:61]=[CH:62][C:57]([C:55]5[NH:56][C:52]([CH:48]6[CH2:49][CH2:50][CH2:51][N:47]6[C:45](=[O:46])[CH:41]([NH:40][C:39]([O:38][CH3:37])=[O:72])[CH:42]([CH3:44])[CH3:43])=[N:53][CH:54]=5)=[CH:58][CH:59]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
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: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)c6ccccc6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C

Procedure:
{1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (crude, <0.101 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (45.1 mg, 0.091 mmol) under an argon atmosphere. Potassium carbonate (27.8 mg, 0.202 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) were added, followed by DME (2.0 mL) and water (0.4 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[1′-Benzoyl-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (20.7 mg): LCMS-ESI+: calc'd for C46H53N9O7: 843.9 (M+). Found: 844.3 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.90-7.84 (m, 10H), 7.66-7.52 (m, 5H), 5.68 (m, 1H), 5.59 (m, 1H), 5.49 (m, 1H), 5.26 (m, 1H), 4.24 (d, J=7.5 Hz, 1H), 4.11 (m, 2H), 3.86 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.46 (d, J=5.7 Hz, 1H), 2.57 (m, 1H), 2.29-2.09 (m, 5H), 1.01-0.85 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]Cl)=[CH:4][C:3]=1[Cl:19].[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[Cl:19][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:11][N:34]1[CH2:35][CH2:36][CH:31]([C:27]2[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:30]=[CH:29][CH:28]=2)[CH2:32][CH2:33]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCC[C@H](Oc1ccc(Cl)c(Cl)c1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(Cl)c(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A using 1,2-dichloro-4-{[(1S)-3-chloro-1-phenylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 525.3 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[NH2:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20]>CO>[N+:8]([C:7]1[C:2]([NH:18][CH:19]([CH3:20])[C:21]([OH:23])=[O:22])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1cccnc1F
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(Nc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A mixture of 2-fluoro-3-nitro-pyridine (12 g), Et3N (30 mL), and racemic alanine (11.87 g) was refluxed in methanol (200 mL) overnight. The mixture was cooled to ambient temperature and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and water. The organic layer was dried over Na2CO3, filtered, and concentrated in vacuo to afford 2-(3-nitro-pyridin-2-ylamino)-propionic acid (7.8 g). This material was dissolved in AcOH (50 mL) and iron (8.2 g) was added. The mixture was refluxed for 1.5 h. After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was washed with water and dried to afford 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.4 g). This material was mixed with 5% aq NaOH (92 mL) and water (18 mL) before 30% aq hydrogen peroxide (9.2 mL) was added. The mixture was stirred at 60° C. for 10 h. After cooling to ambient temperature the pH was adjusted to neutral to precipitate 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (1.2 g). This material was dissolved in DMF (10 mL) and treated with PyBroP (4.6 g) and DIPEA (1.6 mL) at ambient temperature of 16 h. The precipitated white solid was filtered off, washed with ethanol and dried to afford 2-(benzotriazol-1-yloxy)-3-methyl-pyrido[2,3-b]pyrazine (0.4 g). This material (0.4 g) and hydrazine hydrate (0.5 mL) were refluxed in ethanol (5 mL) for 10 min. After cooling to ambient temperature, the precipitated white solid was filtered off, washed with ethanol and dried to afford give IIa (0.2 g) sufficiently pure for the next step.
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(NO)(C)(C)C.C(=O)(O)[O-].[Na+].[H-].[Na+].[C:24]([C:28]1[S:32]/[C:31](=[N:33]\[C:34](=[O:46])[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=2F)/[N:30]([CH2:47][CH2:48][CH2:49][C:50]#[N:51])[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:1]([NH:5][O:6][C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:42])([F:43])[F:44])=[CH:40][C:35]=1[C:34](/[N:33]=[C:31]1\[S:32][C:28]([C:24]([CH3:25])([CH3:27])[CH3:26])=[N:29][N:30]\1[CH2:47][CH2:48][CH2:49][C:50]#[N:51])=[O:46])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nn(CCCC#N)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: CC(C)(C)NO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)NOc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)nn1CCCC#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-tert-butylhydroxylamine (133 mg, 1.50 mmol) (prepared from commercially available N-tert-butylhydroxylamine acetate (Aldrich) by adding saturated sodium bicarbonate solution and extracting the free base with ethyl ether) in anhydrous THF (10 mL) was added sodium hydride (53.9 mg, 1.35 mmol). The mixture was stirred at 0° C. for 20 min. A solution of Example 151A (310 mg, 0.75 mmol) in THF (4 mL) was added and the mixture was stirred at 22° C. for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 using an Analogix® Intelliflash280™ (Hexanes-EtOAc: 0-50% gradient) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (s, 9H), 1.42 (s, 9H), 2.23-2.37 (m, 2H), 2.48 (t, J=7.1 Hz, 2H), 4.54 (t, J=6.5 Hz, 2H), 5.75 (s, 1H), 7.61 (dd, J=8.7, 2.4 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H); MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[N:7][C:2]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cnc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cnc(-c2ccccc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 67.9 %

Procedure:
To a solution of 6-bromo-5-chloropyridin-3-ol (Preparation 239, 100 mg, 0.48 mmol), and phenylboronic acid (117 mg, 0.96 mmol) in 1,4-dioxane (5 mL) under nitrogen was added 2M aqueous Na2CO3 solution (1 mL) and palladium tetrakistriphenylphosphine (28 mg, 0.024 mmol). The mixture was stirred at 80° C. for 3.5 hours. The reaction mixture was allowed to cool to room temperature and partitioned between water and EtOAc. The desired product was in the aqueous phase (pH ˜11). The organic phase was washed with 10 wt % aqueous NaOH solution (2×15 mL). The combined aqueous phases were neutralised with 1N aqueous citric acid solution and extracted with EtOAc (4×30 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography eluting with 0-30% EtOAc in heptane to give the title compound (67 mg, 68%) as a white solid.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[CH3:7]>CO>[CH2:6]([O:8][C:9]1[N:10]=[N:11][CH:12]=[CH:13][C:14]=1[S:5][CH2:2][CH:3]=[CH2:4])[CH3:7]
Reactant: C=CCS
Reactant: CCOc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccnnc1OCC

Procedure:
0.57 g(0.025 mol) of metallic sodium was dissolved in 40 ml of absolute methanol and then mixed with 2.49 ml(0.025 mol) of allylmercaptan. To this mixture was added 3.96 g(0.025 mol) of 3-ethoxy-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.C[O-].[Na+].C1(C)C=CC(S(O[CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[C:23]#[N:24])(=O)=O)=CC=1.O>CO>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([S:7][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[C:23]#[N:24])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(SC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
p-Toluenethiol (5.00 g) was dissolved in 6 ml of methanol, and 1.60 ml of a 2.5 M methanol solution of sodium methoxide was added to the solution at room temperature in a stream of argon. The mixture was stirred under ice cooling. Then, 1.516 g of O-(p-toluenesulfonyl)-m-phenoxymandelonitrile was added, and the mixture was stirred for 30 minutes under ice cooling and then for 10 minutes at room temperature. Water (20 ml) was added, and the mixture was extracted with 30 ml of methylene chloride three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene) to afford 1.334 g (yield 100%) of alpha-(p-tolylthio)(m-phenoxyphenyl)acetonitrile as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:27]=1.[C:28]([C@:30]1([OH:38])[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[C:31]1=[O:37])#[CH:29]>>[OH:38][C@@:30]1([C:28]#[C:29][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:27]=2)[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[C:31]1=[O:37]
Reactant: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCCN(C)C1=O
Product: CN1CCC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)C1=O
Yield: 25.3 %

Procedure:
10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-piperidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 22 mg (25.3%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-3-piperidyl]ethynyl]-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:24]([CH3:36])[CH:23]=3)[C:12]3[C:13]([F:21])=[CH:14][C:15]([OH:20])=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:37])=[N:6]1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:49][CH:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1)(=O)=O.O>CN(C=O)C>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[C:24]([CH3:36])[CH:23]=3)[C:12]3[C:13]([F:21])=[CH:14][C:15]([O:20][CH2:49][CH:50]4[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:57])[CH2:52][CH2:51]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:37])=[N:6]1)([CH3:1])[CH3:3]
Reactant: COc1c(O)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
To a solution of 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-ol (207 mg, 0.42 mmol) in DMF (2 mL) was added cesium carbonate (274 mg, 0.84 mmol) and tert-butyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (135 mg, 0.46 mmol). The mixture was heated to 90° C. and stirred for 1.5 h. After cooling to rt, water was added and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (gradient: 25% ethyl acetate in hexanes to 30% ethyl acetate in hexanes) to provide 1,1-dimethylethyl 4-{[(3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-yl)oxy]methyl}piperidine-1-carboxylate (214 mg, 0.31 mmol, 73% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.51-7.34 (m, 7H), 6.98 (d, 1H), 6.83 (d, 1H), 5.16 (s, 2H), 4.22 (br m, 2H), 3.98 (d, 2H), 3.91 (s, 3H), 2.89 (s, 3H), 2.80 (br m, 2H), 2.37 (s, 3H), 2.12 (m, 1H), 1.93-1.88 (m, 2H), 1.85 (s, 9H), 1.48 (s, 9H), 1.39-1.35 (m, 2H); MS (I) for C41H49FN4O5: 697 (MH+).
Reaction SMILES: C([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([C:20]#[N:21])[C:17]([NH2:19])=[O:18])(=O)C1C=CC=CC=1>CO>[NH2:21][C:20]1[NH:9][C:10]2[C:11]([C:16]=1[C:17]([NH2:19])=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: N#CC(C(N)=O)c1ccccc1NC(=O)c1ccccc1
Solvent: CO
Product: NC(=O)c1c(N)[nH]c2ccccc12
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 53 %

Procedure:
Sodium methylate methanol solution (28%, 96 g, 0.50 mol) was added to a solution of 2-(2-benzoylaminophenyl)-2-cyanoacetamide (Reference compound 17-1, 30 g, 0.11 mol) in anhydrous methanol (200 mL), and the mixture was stirred at 90° C. for 4.5 hours. The reaction mixture was concentrated by half in the volume under reduced pressure. After ice-water (500 mL) was added to the mixture, the whole was extracted with ethyl acetate (400 mL×2). The organic layer was washed with brine (300 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, ethanol (400 mL) was added to the residue and the insoluble solid was removed by filtration. After the filtrate was concentrated under reduced pressure, chloroform (80 mL) was added to the residue and the precipitated solid was washed with diethyl ether (40 mL). The resultant solid was dried under reduced pressure to give the title reference compound (10 q) as a brown solid (yield 53%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc(C)c1Cn1cc(N)cn1
Yield: 99 %

Procedure:
Tert-butyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-ylcarbamate (example 10-41b) (592 mg, 2 mmol) was stirred in a solution of 4N HCl in dioxane (20 mL) at ambient temperature for 2 hours. The solvent was removed and the residue was dissolved in a 1/1 mixture of ethyl acetate/hexanes (30 mL) and concentrated twice. The solid was triturated with hexanes and collected by filtration providing 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (500 mg, 99%) as a white solid. 1H NMR (DMSO-d6, 400 MHz); δ 2.11 (s, 3H), 2.38 (s, 3H), 5.16 (s, 2H), 7.51 (s, 1H), 8.03 (s, 1H), 10.27 (bs, 3H).
Reaction SMILES: [CH3:1][C@@:2]([C:6]([OH:8])=[O:7])([CH2:4][OH:5])[NH2:3].[ClH:9].O1CCOC[CH2:11]1>CO>[ClH:9].[CH3:1][C@@:2]([C:6]([O:8][CH3:11])=[O:7])([CH2:4][OH:5])[NH2:3]
Reactant: C1COCCO1
Reactant: C[C@](N)(CO)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@](C)(N)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
In a three neck 1 L round bottom flask under argon, 2-methylserine (35.0 g, 0.2936 mol) was suspended in methanol (300 mL). To this was added 4N HCl/dioxane (85 mL) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture had become a clear colorless solution. Dry HCl gas was bubbled into the reaction mixture for 5 min. and the reaction mixture was then stirred at 60° C. for 4 h. It was then cooled and the excess reagent/solvent was removed under reduced pressure at 65° C. to 70° C. to give the desired product (yield 48.2 g, 96%) as an yellow sticky oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.Cl[C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>CN(C=O)C>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[NH:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1c(Nc2nc3ccccc3s2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (9.5 mg, 0.024 mmol) and 2-chlorobenzothiazole (4.4 mg, 0.026 mmol) in DMF (0.1 ml) were stirred at 100° C. for 12 hrs. The reaction mixture was concentrated and purified by silica gel flash chromatography to isolate 379 as a yellow film (3.3 mg, 28%). [M+H]+489.14
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.CC[N:17]([CH:21]([CH3:23])[CH3:22])C(C)C.C1(N)CC1>CS(C)=O>[Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:17][CH:21]1[CH2:23][CH2:22]1)[C:8]([CH3:13])=[N:7]2
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CS(C)=O
Product: Cc1nc2ccc(F)c(Br)c2nc1NC1CC1
Temperature: 85 °C
Yield: 72.1 %

Procedure:
A mixture of 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (4.0 g, 14.52 mmol), DIEA (5.07 mL, 29.0 mmol) and cyclopropanamine (2.01 mL, 29.0 mmol) in DMSO (10 mL) in a sealed glass tube was heated in an oil bath at 85° C. for 3 h. The reaction mixture was poured onto 50 g of ice; the insoluble yellow solid was filtered, washed with 2×25 mL of water followed by 2×15 mL of hexanes. The yellow solid was collected and dried in a vacuum oven at 45° C. for 1 h to afford 3.1 g of the title compound. The filtrate was extracted with 2×50 mL of EtOAc. The combined organic extract was dried over MgSO4, filtered and concentrated. The crude residue was purified on a silica gel column (20-50% EtOAc in hexanes) affording 0.9 g of the title compound as a light orange crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (1H, dd, J=9.0, 6.1 Hz), 7.47 (1H, br.), 7.33 (1H, t, J=8.8 Hz), 3.06 (1H, m), 2.47 (3H, s), 0.81 (2H, m), 0.67 (2H, m). 19F NMR (377 MHz, DMSO-d6) δ ppm −104.62. m/z (ESI, +ve) 296/298 (M+H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:37][CH2:36][CH:35]2[C:38]([O-])=[O:39])[CH2:30][CH2:29]1)=[O:27])[CH3:24].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:11][N:10]2[C:38]([CH:35]2[CH2:36][CH2:37][N:34]2[CH:31]2[CH2:30][CH2:29][N:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH2:33][CH2:32]2)=[O:39])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccccc1S[C@H]1CN[C@H](C(=O)NC2(C#N)CC2)C1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](Sc3ccccc3OC)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methoxyphenylthio)pyrrolidine-2-carboxamide 12C and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-(2-methoxyphenylthio)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (67%). MS ISP (m/e): 556.2 (100) [(M+H)]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[C:7](C(=O)C(F)(F)F)=[CH:6][N:5]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[O:22][C:21]3=[O:34])=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+]>CO.C(#N)C>[O:35]=[S:2]1(=[O:1])[CH:3]=[CH:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[O:22][C:21]3=[O:34])=[CH:18][CH:19]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3C=C(C(=O)C(F)(F)F)S(=O)(=O)CC3)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3C=CS(=O)(=O)CC3)cc2)C(=O)O1

Procedure:
The crude sulfone prepared in Step 6 (6.7 mmol) is suspended in 220 mL of MeOH-acetonitrile (2:1) and heated to reflux. Solid K2CO3 (3.4 g, 25 mmol) is then added, and the mixture stirred at reflux for 2 h. Upon cooling, the solution is filtered and the filtrate concentrated. The residue is dissolved in 50 mL of EtOAc—2.5% aq. NaHCO3 (1:1), the layers separated, and the aqueous phase extracted with more ethyl acetate. The combined organic layers are washed with brine and dried (MgSO4), filtered and concentrated. The resulting crude product is purified by column chromatography (0–2% MeOH—CH2Cl2) provided the title compound as a foam.