Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:35])[C:12]2[C:13](=[O:34])[C:14]3[C:19]([O:20][C:21]=2[C:22]=1[CH2:23][CH:24]=[CH2:25])=[C:18]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:17]=[CH:16][CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I.CO>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:35][CH3:38])[C:12]2[C:13](=[O:34])[C:14]3[C:19]([O:20][C:21]=2[C:22]=1[CH2:23][CH:24]=[CH2:25])=[C:18]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:17]=[CH:16][CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCc1c(OCc2ccccc2)cc(O)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)cc(OC)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Temperature: 50 °C
Yield: 85.2 %

Procedure:
To a solution of xanthone 6 (63 g, 135 mmol) in dry DMF (300 mL) was added sodium hydride (9 g 60% in oil, 225 mmol) portionwise at room temperature. Methyl Iodide (180 g, 1.28 mol) was added and the mixture was heated to 50° C. for 90 minutes. The reaction was then chilled with an ice bath and methanol was added dropwise (20 mL) until the remaining sodium hydride was consumed. The reaction mixture was diluted with ethyl acetate (1.2L) and washed with brine (3×500 mL), dried over magnesium sulfate, filtered over a pad of silica gel (60×100 mm) and the solvent was removed in vacuo to afford the xanthone 7 as a solid (55 g, 115 mmol, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]2)=[N:4][N:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:33])[C@@H:14]([CH3:18])[CH2:13]2)=[N:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-chloro-4-(3-methylpiperazin-1-yl)phthalazine (3.64 g, 13.9 mmol) was dissolved in dry dichloromethane (30 mL) and triethylamine (4.26 mL, 30.6 mmol). Benzoyl chloride (1.77 mL, 15.3 mmol) was added and stirred at rt for 1 hour. The reaction was added to saturated NaHCO3 (150 mL) and the aqueous layer was extracted with 3× dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/30-100% ethyl acetate gave an off-white solid. MS (M+H)+=367.1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([S:30]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:22][CH2:21][C:19]2[O:20][C:16]([CH3:15])=[CH:17][CH:18]=2)=[N:9]3)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4cccc(F)c4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=412.1 (M+H+), was prepared in accordance with the general method of example 58 from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3-fluorobenzenesulfonylchloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:31][C:32]5[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[O:34][N:33]=5)=[O:30])=[CH:24][CH:23]=4)=[CH:20][N:21]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].[C:41](O)(=O)[CH3:42].[CH:45](=O)[CH3:46].C([BH3-])#N.[Na+]>CO>[C:37]([C:35]1[O:34][N:33]=[C:32]([NH:31][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:19]3[N:16]4[CH:17]=[CH:18][C:13]([C:10]5[CH:11]=[CH:12][C:7]([S:4]([CH2:3][CH2:2][N:1]([CH2:41][CH3:42])[CH2:45][CH3:46])(=[O:5])=[O:6])=[CH:8][CH:9]=5)=[CH:14][C:15]4=[N:21][CH:20]=3)=[CH:23][CH:24]=2)[CH:36]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(=O)O
Reactant: CC=O
Reactant: CC(C)(C)c1cc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccc(S(=O)(=O)CCN)cc5)ccn34)cc2)no1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCS(=O)(=O)c1ccc(-c2ccn3c(-c4ccc(CC(=O)Nc5cc(C(C)(C)C)on5)cc4)cnc3c2)cc1
Reaction time: 3 h

Procedure:
Combine 2-(4-{7-[4-(2-Amino-ethanesulfonyl)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-N-(5-tert-butyl-isoxazol-3-yl)-acetamide (0.87 g, 1.38 mmol) with acetic acid (1 mL), methanol (20 mL) and acetaldehyde (0.152 g, 3.45 mmol) at ambient temperature under nitrogen for 10 minutes. Add sodium cyanoborohydride at ambient temperature. The reaction is complete within 3 hours. Evaporate under vacuum, re-dissolved in methanol and dichloromethane and load onto an SCX column. Wash the column with dichloromethane (50 mL) and methanol (50 mL) and elute with methanolic ammonia. Chromatography on silica (0→2→4→5%) methanol and dichloromethane gives the title compound (21.0 mg). MS(ES), m/z 614 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=3)[O:11][C:9]=2[N:10]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:60]([O:64][C:65](=[O:71])[C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)([CH3:63])([CH3:62])[CH3:61].Cl>CN(C)C=O.O>[C:60]([O:64][C:65]([C@@H:66]1[CH2:70][CH2:69][CH2:68][N:67]1[C:22](=[O:23])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:11][C:9]3[N:10]=[C:5]([O:4][C:3]4[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=4[F:1])[N:6]=[CH:7][C:8]=3[N:13]=2)=[CH:15][CH:16]=1)=[O:71])([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Reaction time: 16 h
Yield: 39.5 %

Procedure:
140 mg of {(E)-3-{4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenyl}-acrylic acid were dissolved in 2 ml of N,N-dimethylformamide, and 98 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 19 mg of 1-hydroxy-7-azabenzotriazole and 397 μl of N,N-diisopropylethylamine were added, followed by the addition of 49 mg of L-proline tert-butyl ester after 5 min. After 16 h at room temperature, 10 ml of water were added, and the mixture was brought to pH 3 by addition of 2 M aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers were washed with a saturated sodium hydrogencarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC. 60 mg of the title compound were obtained.
Reaction SMILES: O=[C:2]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[S:20]=[C:2]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(F)(F)F
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=S)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.21 h
Yield: 95.3 %

Procedure:
To a stirred solution of (R)-tert-butyl 1-oxo-1-(2,2,2-trifluoroethylamino)propan-2-ylcarbamate (100 mg, 0.37 mmol) in CH2Cl2 (10 mL) was added P2S5 (24 mg, 0.11 mmol) and hexamethyldisiloxane (HMDO) (0.13 mL, 0.59 mmol) at room temperature and the mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature and another portion of P2S5 (24 mg, 0.11 mmol) was added and the resulting mixture was refluxed for 18 h. The volatiles were evaporated, pentane (25 mL) was added to the residue and stirred for 10-15 min. The pentane layer was decanted, concentrated in vacuo and the residue was passed through a short silica pad eluting with pentane followed by CH2Cl2 to give the title compound as colorless liquid (30 mg, 30%): 1H NMR (400 MHz, DMSO-d6) δ 10.27 (t, J=5.4 Hz, 1H), 7.00 (d, J=6.8 Hz, 1H), 4.57-4.35 (m, 3H), 1.32 (s, 9H), 1.25 (d, J=7.6 Hz, 3H); ESIMS m/z 286.2 ([M+H]+); IR (thin film) 3233, 1683, 1257 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([B:17]([OH:19])[OH:18])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:20]C1C=C(F)C=CC=1N1C2=NC=CC(I)=C2C=N1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+]>CS(C)=O>[F:20][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([B:17]([OH:19])[OH:18])=[C:11]2[CH:10]=[N:9]1
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)c(F)c1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1F
Temperature: 85 °C

Procedure:
Intermediate 63A was prepared according to the general procedure described in Intermediate 5A, except that the reaction mixture was heated at 85° C. for 75 min, using Intermediate 13A (100 mg, 0.280 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (133.1 mg, 0.524 mmol), potassium acetate (115.0 mg, 1.172 mmol), and DMSO (1.5 mL). The desired product was confirmed to be present by LC/MS (Condition B): 76%; ret. T=2.9 min; (M+H)+ 276.00.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N+]=[N-])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])=[CH:8][CH:9]=1)[O:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH3:18]
Reactant: OC1CCOCC1
Reactant: CCOC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CC2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
Ethyl 2-(4-cyclopropylsulfonylphenyl)-2-diazo-acetate (36 g, 121.62 mmol) was dissolved in DCM (608 mL) under argon atmosphere. To this solution, 4-hydroxy tetrahydropyran (12.75 mL, 133.78 mmol) was added followed by rhodium(II)acetate dimer (1.12 g, 0.021 mmol). Mixture was stirred at 25° C. for 1 hr. Reaction mixture was diluted with DCM (500 mL), organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a product (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid ethyl ester (50 g).
Reaction SMILES: C(=O)([O-])[O-].FC(F)(F)C(O)=O.[CH:12]([C:15]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([NH:26][NH2:27])[CH2:22][CH2:21]2)[O:17][N:16]=1)([CH3:14])[CH3:13].[Cl:28][C:29]1[C:34]([CH:35]=O)=[C:33](Cl)[N:32]=[CH:31][N:30]=1>C(#N)C>[Cl:28][C:29]1[N:30]=[CH:31][N:32]=[C:33]2[N:26]([CH:23]3[CH2:24][CH2:25][N:20]([C:18]4[O:17][N:16]=[C:15]([CH:12]([CH3:14])[CH3:13])[N:19]=4)[CH2:21][CH2:22]3)[N:27]=[CH:35][C:34]=12
Reactant: CC(C)c1noc(N2CCC(NN)CC2)n1
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1noc(N2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 140 °C
Yield: 19.8 %

Procedure:
SiliaBond Carbonate (Silicycle, Quebec City, Canada; 0.69 mmol/g loading; 395 mg, 0.27 mmol) was added to a mixture of [1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-hydrazine trifluoroacetic acid salt (from Step 4; 185 mg, 0.55 mmol) and 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 81 mg, 0.45 mmol) in anhydrous acetonitrile (3 mL). The reaction mixture was heated in a Biotage Optimizer microwave at 140° C. for 5 min. The resin was filtered off and washed with acetonitrile. The solvent was evaporated and the residue was purified on a silica column (ISCO 12 g) eluting with 0-3% methanol/dichloromethane to give 4-chloro-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (31 mg, 20%). Mass spectrum (ES) MH+=348.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([C:22]1[CH:37]=[CH:36][C:25]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=3)[CH:27]=[N:28][C:24]=2[CH:23]=1)(=[O:21])[CH3:20]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([C:22]1[CH:37]=[CH:36][C:25]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:6]4[S:7][CH:8]=[CH:9][N:10]=4)[CH:30]=3)[CH:27]=[N:28][C:24]=2[CH:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
To a solution of (33) (3.6 g, 9.7 mmol) in dry THF (20 ml) was added 5-acetyl-1-(3-bromophenyl)benzimidazole (1.5 g, 4.8 mmol) and (PPh3)2PdCl2 (340 mg, 0.48 mmol) under argon. The reaction mixture was stirred at 80° C. for 24 hr in a 50 ml sealed tube. After cooling the mixture was concentrated, triturated with water (100 ml) and extracted with CH2Cl2 (200 ml×3). The extract was washed with brine, dried and concentrated under reduced pressure. The residue was washed with ether to afford crystaline (34) (1.5 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30]C(O)=O)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl.NC[C:39]([NH:41][C@@H:42]([C:46]([O:48]C(C)(C)C)=[O:47])C(C)C)=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)[F:78].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:78])=[CH:21][CH:22]=3)=[O:16])[C@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:39]([NH:41][CH2:42][C:46]([OH:48])=[O:47])=[O:40])=[CH:34][CH:35]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](NC(=O)CN)C(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Reactant: F[B-](F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A mixture of [4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (0.0153 g, 0.031 mmol), tert-butyl glycyl-D-valinate hydrochloride (0.0099 g, 0.037 mmol) and N-methylmorpholine (0.010 ml, 0.091 mmol) in DCM (2 ml) was stirred at room temperature. TBTU (0.016 g, 0.050 mmol) was added and the mixture was stirred for 3.5 h. Trifluoroacetic acid (0.5 ml) was added and after 3.5 h the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a Kromasil C8-column using a gradient of 5-100% MeCN in 0.15% trifluoroacetic acid buffer as eluent. The solvent was removed under reduced pressure and 0.015 g (74%) of the title product was obtained. M/z 652.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:20])=[N:10]2.S(=O)(=O)(O)O.C1C(=O)N([Br:33])C(=O)C1.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[Br:33][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([C@:9]23[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]2[CH2:13][S:12][C:11]([NH2:20])=[N:10]3)[CH:4]=1
Reactant: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CF)[C@H]2CS1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
(4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (700 mg, 2.32 mmol) was dissolved in TFA (2.1 mL) and sulfuric acid (864 μL, 16.2 mmol). NBS (453 mg, 2.55 mmol) was added and the reaction was stirred at 60° C. for 45 minutes. The reaction was cooled to room temperature and basified with 2N NaOH. The mixture was then extracted with EtOAc (×3). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified using column chromatography, eluting with 20-80% EtOAc in n-hexane to give the title compound. (620 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 7.67 (t, J=8.13 Hz, 1H), 6.94 (dd, J=8.01, 11.55 Hz, 1H), 4.65 (d, J=4.16 Hz, 1H), 4.47-4.57 (m, 3H), 3.84-3.98 (m, 1H), 3.01-3.20 (m, 2H), 2.77-2.91 (m, J=13.40 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:16]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:15]=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([NH:30][NH2:31])=[O:28])[C:11]=1[NH:10][C:9]([C:12]1[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=1)=[O:8]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)cccc12
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)c1cccc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.27 g of 8-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-4H-3,1-benzoxazine-4-one, 0.025 ml of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of chloroform and methyl t-butyl ether to obtain 0.21 g of N-[2-chloro-6-(hydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]([CH3:17])=[C:7]2[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[ClH:18].[CH2:22]([O:21][C:19]([N:4]1[CH2:5][CH2:6][C:7]2[C:8](=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]=2[CH3:17])[CH:2]([CH3:1])[CH2:3]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)C(C)CNCC2
Product: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(C)C1
Product: Cl
Yield: 84 %

Procedure:
1,2,4,5-Tetrahydro-5,11-dimethyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-5,11-dimethyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:29][CH:14]4[CH2:15][C:16]([NH:18][CH2:19][C:20]([N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[C:27]#[N:28])=[O:21])([CH2:17]2)[CH:12]([CH2:13]4)[CH2:11]3)=[CH:6][CH:5]=1)([O-])=O.O.C1COCC1.[NH4+].[Cl-]>[Fe].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:29][CH:14]4[CH2:15][C:16]([NH:18][CH2:19][C:20]([N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[C:27]#[N:28])=[O:21])([CH2:17]2)[CH:12]([CH2:13]4)[CH2:11]3)=[CH:8][CH:9]=1
Reactant: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N)cc1)(C3)C2
Temperature: 25 °C
Yield: 48.4 %

Procedure:
To a stirred solution of the compound obtained from example 29 (0.2 g, 0.51 mmol) in a 1:2:4 mixture of water, THF, and ethanol (7 mL) respectively was sequentially added solid NH4Cl (0.1 g, 1.87 mmol) and Fe powder (0.1 g, 1.78 mmol). The reaction mixture was heated to reflux for 2 h. After cooling the reaction mixture to room temperature, it was filtered through a small pad of celite and washed the bed with EtOAc. The filtrate was evaporated under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain (2S)-1-{N-[2-(4-aminophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as off-white solid (0.09 g) in 50% yield. m/z (M+1) 365; 1H NMR (CDCl3) 300 MHz δ 7.05 (d, J=8.5 Hz, 2H), 6.63 (d, J=8.5 Hz, 2H), 4.90-4.75 (m, 1H), 3.80-3.40 (m, 4H), 2.45-1.70 (m, 15H), 1.65-1.57 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=O)=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(O)(C(F)(F)F)=O>>[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]3[C:5]4[NH:6][C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]=4[CH2:3][CH2:2][NH:1]3)=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: O=Cc1ccc2c(c1)CCC2
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)CCC2)NCC3
Yield: 15.6 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.28 g, 8.0 mmol), indan-5-carboxaldehyde (1.3 g, 1.1 equiv.) and TFA (1.2 mL, 2 equiv.) to give the title compound (0.36 g, 14%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CO.C(Cl)Cl.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:12]([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[O:13])[CH2:9]3)=[CH:4][CH:3]=2)[CH2:27]1
Reactant: O=C(C1CCOCC1)N1CCc2ccc(Br)cc2C1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CN(C(=O)C2CCOCC2)CC3)C1
Temperature: 85 °C
Yield: 52.8 %

Procedure:
A vial was charged with (7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-(tetrahydro-pyran-4-yl)-methanone (162 mg, 0.5 mmol), (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl (90 mg, 0.55 mmol), and sodium tert-butoxide (69 mg, 0.7 mmol), tris(dibenzylideneacetone)dipalladium-(0) (4.6 mg, 0.005 mmol), BINAP (9.3 mg, 0.015 mmol), and toluene (4 mL) under argon. The vial was capped with a septum and was heated to 85° C. (external) with stirring until the starting material was completely consumed as monitored by TLC analysis. The mixture was allowed to cool to room temperature, taken up in ether (5.0 mL), filtered, and concentrated. The crude product was then purified further by flash chromatography on silica gel, eluted with 3% MeOH in DCM and 7.5% MeOH in DCM to 105 mg (53% yield) of the title compound as a tan solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.[CH2:15](N)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[Cl:1][CH2:2][C:3](=[O:10])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CC1CCCCC1)C(=O)CCl
Reaction time: 24 h

Procedure:
A mixture of ethyl 4-chloro-3-oxo-butanoate (57.3 ml), cyclohexylaldehyde (53.65 ml), acetic acid (2.75 ml) and benzylamine (4.38 ml) is kept for 24 hrs at room temperature. It is then diluted with 150 ml of ethyl acetate and washed with 100 ml of water, then with 100 ml of saturated sodium carbonate solution and finally with 100 ml of a saturated solution of NaH2PO4. The solvent is evaporated to give 108.43 g of 4-chloro3-oxo-2-ethoxycarbonyl-1-cyclohexyl-but-1-ene.