Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[CH3:18])#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:5][C:4]=1[CH3:18])#[N:2]
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1C#N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1C#N
Yield: 97.3 %

Procedure:
To a solution of tert-butyl 3-(4-cyano-3-methylphenyl)acrylate obtained in step 1, (5.3 g) in ethyl acetate (50 mL) was added palladium on carbon (500 mg) and the mixture was placed under a pressure of 3 kg of hydrogen for 3 h at RT. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to afford the title compound as white solid (5.2 g, 98%). 1H-NMR (CDCl3, 400 MHz) δ 7.51-7.53 (1H, d), 7.16 (1H, s), 7.10-7.12 (1H, d), 2.91-2.94 (2H, t), 2.53-2.57 (2H, t), 2.52 (3H, s), 1.42 (9H, s). LC/MS: 246.0 (M+H)+. HPLC (Method C) Rt 3.23 min (Purity: 96.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(#N)C.O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:1][C:19](=[O:20])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc2ccccc2n1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
2-Aminoquinoline (300 mg, 2.08 mmol) was dissolved in acetonitrile. To the reaction mixture was added pyridine (0.2 mL, 2.5 mmol) and phenyl chloroformate (0.27 mL, 2.18 mmol), respectively and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl quinolin-2-ylcarbamate (296 mg, 54%).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][CH:8]=C[C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[N:29]=[CH:30][N:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:32]=4)[CH:25]=[C:26]([CH3:27])[C:21]=3[N:20]=[C:19]2[CH2:39][CH2:40][CH3:41])=[CH:13][CH:12]=1)(C)(C)C.F[C:43](F)(F)[C:44]([OH:46])=[O:45]>C(Cl)Cl>[CH2:39]([C:19]1[N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[C:43]([C:44]([OH:46])=[O:45])=[CH:8][CH:9]=[CH:10][CH:5]=3)=[CH:12][CH:13]=2)[C:22]2[CH:23]=[C:24]([C:28]3[N:29]=[CH:30][N:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:32]=3)[CH:25]=[C:26]([CH3:27])[C:21]=2[N:20]=1)[CH2:40][CH3:41]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(C)(C)C)cc4)c3c2)c1
Solvent: ClCCl
Product: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)c1

Procedure:
Prepared analogously to Example 1 from tert,butyl 4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride,
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(NC(C(C)C)C)(C)C.O>CN1CCCC1=O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: Fc1cccc(F)n1
Reactant: NCc1ccc(Cl)cc1
Agent: CC(C)NC(C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1cccc(NCc2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 2,6-difluoropyridine (58, 9.85 g, 0.0856 mol) in N-methylpyrrolidinone (50.0 mL) were added p-chlorobenzylamine (61, 10.5 mL, 8.63 mmol) and N,1-diisopropylethylamine (30.0 mL, 0.172 mol). The reaction was stirred at 90° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane, then washed with ethyl acetate/hexane to give a white solid (536, 10 g, 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1>>[Cl:11][C:12]1[C:13]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:23])([F:22])[F:24])[C:18]([C:25]([OH:27])=[O:26])=[CH:17][C:16]=2[CH:30]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc([N+](=O)[O-])cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-nitrophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 246.4-248.3° C. 1H NMR (acetone-d6/300 MHz) 8.34 (d, 2H, J=9.3 Hz), 7.96 (s, 1H), 7.82 (s, 1H), 7.29 (d, 2H, J=9.3 Hz), 7.02 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)-79.3 (d, J=7.2 Hz). ESLRMS m/z 433 (M+NH4). ESHRMS m/z 433.0463 (M+NH4, Calc'd 433.0414). Anal. Calc'd for C17H9ClF3NO6: C, 49.12; H, 2.18; N, 3.37; Cl, 8.53. Found: C, 48.94; H, 2.05; N, 3.32; Cl, 8.72.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([O:18][CH3:19])[CH:5]=1.Cl.NO.C([N:34](CC)CC)C>C(O)C.C(OCC)(=O)C.O>[NH2:1][CH2:2][CH:3]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]([NH2:34])=[NH:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([O:18][CH3:19])[CH:5]=1
Reactant: COc1cc(C(CN)Nc2ccc(C#N)cc2)ccc1OCc1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(CN)Nc2ccc(C(=N)N)cc2)ccc1OCc1ccccc1
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
4-[2-Amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzonitrile D (300 mg, 0.8 mmoles) was dissolved in ethanol (3 ml) and hydroxylamine-hydrochloride (350 mg, 5 mmoles) and triethylamine (1 ml, 5.7 mmoles) were added. The reaction was heated to 65-70 degrees C. for 2 hours. The residue was taken up in ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and replaced with 4 ml methanol with 0.5 ml acetic acid. Raney nickel (ca. 300 ul suspension in sodium hydroxide, Aldrich) was added and the reaction placed under a hydrogen atmosphere. The reaction was stirred vigorously for 3 hours, the catalyst filtered off and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate:acetone:methanol:ammonia, 2:1:1:0.05) to yield 160 mgs of 4-[2-Amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzamidine E. MS (M+H)=391.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1COCC1.ClCCCl.C(N(CC)CC)C.Cl.[CH3:29][N:30]([CH3:35])[CH2:31][C:32](Cl)=[O:33]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:32](=[O:33])[CH2:31][N:30]([CH3:35])[CH3:29])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)CC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 66.8 %

Procedure:
To a solution of 4-chloro-3-nitroaniline (1.0 g, 5.81 mmol) in 1:1 THF/DCE (200 mL) was added triethylamine (3.53 g, 34.9 mmol, Aldrich), 2-dimethylaminoacetyl chloride hydrochloride (1.82 g, 11.6 mmol, Alfa Aesar), and catalytic DMAP (Aldrich). After heating overnight at 65° C., the crude reaction mixture was diluted with dichloromethane (300 mL), washed with saturated NaHCO3 (50 mL), evaporated, and purified by column chromatography (dichloromethane to 5% methanol/dichloromethane) to provide N1-(4-chloro-3-nitrophenyl)-N2,N2-dimethylglycinamide (1.0 g, 67%) as a brown solid. ESIMS (M+H)+=258.
Reaction SMILES: [OH:1][C@:2]12[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][C@:15]1([CH3:21])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9](=[O:22])[CH2:8][CH2:7]3)[CH2:4][CH2:3]2.[CH2:23]1[CH2:46]OC2(CC[C@H]3[C@H]4[C@H](CC[C@]23C)[C@]2(C)C(C[C@@H](O)CC2)=CC4)[O:24]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:46]1[CH2:23][O:24][C:9]2([CH2:8][CH2:7][C@H:6]3[C@H:5]4[C@H:14]([CH2:13][CH2:12][C@:10]23[CH3:11])[C@:15]2([CH3:21])[C@:2]([OH:1])([CH2:19][C:18](=[O:20])[CH2:17][CH2:16]2)[CH2:3][CH2:4]4)[O:22]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC21OCCO1
Yield: 55 %

Procedure:
Following the procedures described for the preparation of 5α-hydroxyandrostane-3,17-dione (II-ad, Prepn. 4), starting from 17,17-(ethylendioxy)-5-androsten-3β-ol after epoxidation with mCPBA, reduction with LAH, and oxidation with IBX, 17,17-(ethylendioxy)-5α-hydroxyandrostane-3-one was obtained in 55% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ4.29 (s, 1H), 3.78 (m, 4H), 2.69-1.10 (m, 21H), 1.07 (s, 3H), 0.76 (s, 3H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:17]([O:16][C:14]([CH2:13][CH:2]([C:1]#[N:5])[C:3]#[N:4])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#CCC#N
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CC(C#N)C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
13.2 g of malononitrile was dissolved in 50 ml of N,N-dimethylformamide and 28 g of potassium carbonate was added thereto, followed by stirring for 1 hour at room temperature. To the solution was added 19.6 g of tert-butyl bromoacetate at about 0° C. and stirred for 15 minutes at the same temperature and for additional 4 hours at room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue obtained was added about 50 ml of mixed solution of hexane and ethyl acetate (hexane/ethyl acetate=3/1) and filtered. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography to give 6.13 g of 2-(tert-butoxycarbonylmethyl)malononitrile.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH:11](O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:6]([CH:11]=[N:9][N:8]=2)[N:7]=1
Reactant: O=CO
Reactant: Cc1cc(Cl)nnc1NN
Product: Cc1cc(Cl)nn2cnnc12
Reaction time: 0.5 h

Procedure:
A mixture of 37.6 g of 6-chloro-3-hydrazino-4-methylpyridazine and 50 ml of formic acid was heated, with stirring, on a boiling water bath for 30 minutes. The mixture was cooled and excess acid was removed by distillation under reduced pressure. The residual damp solid was dissolved in 300 ml of methylene chloride and washed with aqueous saturated sodium bicarbonate solution. The organic solution was then dried over anhydrous sodium sulfate and filtered through Celite and the solvent was evaporated to leave a residual tan solid. This was recrystallized from ethyl acetate to give 6-chloro-8-methyl-1,2,4-triazolo[4,3-b]pyridazine melting at about 134-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=O)=[C:7]2[OH:17].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.CCOCC>O>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=1)=[O:14])=[C:7]2[OH:17]
Reactant: CCOC(=O)c1cnc2c(N)cc(CN3CCOCC3)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Solvent: CCOCC
Product: Nc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 180 °C

Procedure:
A mixture of ethyl 8-amino-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (Preparation 2, 1.0 g) and 4-chlorobenzylamine (4 mL) is heated at 180° C. The solution is cooled and stirred with ether (6 mL) and water (6 mL). The resulting precipitate is removed by filtration, washed with water followed by ether and dried to afford 1.05 g of the title compound. Physical characteristics: 1H NMR (DMSO-d6) δ2.35, 3.45, 3.57, 4.54, 5.65, 7.02, 7.39, 8.62, 10.6, 11.1.
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=1)[CH3:13].COCCO>O>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[NH:3][C:4](=[O:11])[C:5]3[NH:6][CH:7]=[N:8][C:9]=3[N:10]=2)=[CH:17][N:16]=1)[CH3:13]
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Reactant: CCOc1ccc(N)cn1
Solvent: COCCO
Solvent: O
Product: CCOc1ccc(Nc2nc3nc[nH]c3c(=O)[nH]2)cn1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of 2-bromohypoxanthine (6.3 g; 29.3 mmol), 2-ethoxy-5-aminopyridine (12.1 g; 87.9 mmol), 2-methoxyethanol (90 mL), and water (15 mL) is heated under reflux for 3 h. The reaction mixture is cooled to room temperature, the precipitate collected by filtration and washed with water and methanol to afford N2-(2-Ethoxypyridin-5-yl)guanine (6.4 g), m.p. >350° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[N:34]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][NH2:47])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([NH:47][CH2:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(Cl)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: NCc1ccccc1N1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(NCc4ccccc4N4CCCCC4)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 120 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-chloropyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.6 mmol) and [2-(1-piperidinyl)phenyl]methanamine (CAS#: 72752-54-6) (105 mg, 0.8 mmol) in i-PrOH (2 mL) was added diisopropylethyl amine (0.5 mL). The reaction was heated to 120° C. for 2 h followed by heating to 140° C. for 1 h under microwave conditions, then cooled to RT and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=[CH:11][C:4]=2[N:3]=1.[CH3:15][C:16]1[N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]([CH3:23])=[CH:19][C:20]=1[CH:21]=O>CN(C=O)C.[OH-].[Na+].[Cl-].[Cl-].[Zn+2]>[CH3:14][N:12]([CH3:13])[C:9]1[CH:8]=[C:5]2[C:4](=[CH:11][CH:10]=1)[N:3]=[C:2](/[CH:1]=[CH:21]/[C:20]1[CH:19]=[C:18]([CH3:23])[N:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]=1[CH3:15])[CH:7]=[CH:6]2
Reactant: Cc1cc(C=O)c(C)n1-c1ccccc1
Reactant: Cc1ccc2cc(N(C)C)ccc2n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/c2ccc3cc(N(C)C)ccc3n2)c(C)n1-c1ccccc1
Temperature: 160 °C
Reaction time: 8 h
Yield: 2.1 %

Procedure:
To a solution of compound 3 (316 mg, 1.7 mmol) and compound 5 (507 mg, 2.55 mmol) in DMF (25 mL) was added ZnCl2 (232 mg, 1.7 mmol). The reaction mixture was stirred at 160° C. overnight. Then the reaction mixture was diluted with aqueous NaOH (10%) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure, the residue was purified by column chromatography (hexane:EtOAc=20:1) to give 13 mg of the target product (2.1%). MS[M++1]=368, LC-MS: tR=1.909 min
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[C:2]#[CH:3].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C1COCC1.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>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:2](=[CH2:3])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:23][CH2:24][CH3:25]
Reactant: C#CC(=O)OCc1ccccc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C(=O)OCc1ccccc1)[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 6.42 g (40.1 mmol) of benzyl propiolate from step A above in 25 ml of anhydrous THF was added 0.93 g (0.80 mmol) of tetrakis(triphenylphosphine)palladium(0) followed by a solution of 12.6 g (42.1 mmol) of tributyltin hydride in 25 mL of anhydrous THF over 15 min. After stirring at room temperature overnight the solvent was removed under reduced pressure. The residue was filtered through a pad of Celite® which was then washed with hexanes. The filtrate was concentrated in vacuo and the crude product was purified by silica gel chromatography eluting with a 0-15% ethyl acetate in hexane gradient to afford the title compound as a colorless oil (13 g, 73%). 1H NMR (CDCl3, 500 MHz) δ 7.39 (m, 5H), 6.99 (d, J=2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 5.20 (s, 2H), 1.47 (m, 6H), 1.30 (m, 6H), 0.96 (m, 6H), 0.89 (t, J=7.4 Hz, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH2:21]([B-](F)(F)F)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[K+]>>[CH2:21]([C:12]1[N:8]2[CH2:9][CH2:10][O:11][C:5]3[CH:4]=[C:3]([F:20])[C:2]([Br:1])=[CH:19][C:6]=3[C:7]2=[N:14][C:13]=1[C:15]([NH2:17])=[O:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Reactant: F[B-](F)(F)Cc1ccccc1
Agent: [K+]
Product: NC(=O)c1nc2n(c1Cc1ccccc1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (70 mg) was reacted with potassium benzyltrifluoroborate similar to as described in Example 5 and purified by reverse phase hplc to give 3-benzyl-10-bromo-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 4.9 mg of 3-benzyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 420 (M)+. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=8.2 Hz, 1H), 7.28 (d, J=7.1 Hz, 1H), 7.22-7.15 (m, 3H), 6.69 (d, J=9.9 Hz, 1H), 5.46 (s, 1H), 4.59 (s, 2H), 4.31 (dd, J=5.2, 3.1 Hz, 2H), 4.04 (dd, J=5.1, 3.1 Hz, 2H), 1.65 (s, 6H).
Reaction SMILES: O.[OH-].[Li+].[C:4]([S:8]([CH2:11][C@@H:12]([N:16]1[C@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=2)[C@@H:20]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)[CH2:19][C@@:18]([CH2:38][C:39]([NH:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48]C)=[O:47])=[C:44]([O:52][CH3:53])[CH:43]=2)=[O:40])([CH3:37])[C:17]1=[O:54])[CH:13]1[CH2:15][CH2:14]1)(=[O:10])=[O:9])([CH3:7])([CH3:6])[CH3:5]>O.O1CCCC1.CO>[C:4]([S:8]([CH2:11][C@@H:12]([N:16]1[C@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=2)[C@@H:20]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)[CH2:19][C@@:18]([CH2:38][C:39]([NH:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([OH:48])=[O:47])=[C:44]([O:52][CH3:53])[CH:43]=2)=[O:40])([CH3:37])[C:17]1=[O:54])[CH:13]1[CH2:15][CH2:14]1)(=[O:10])=[O:9])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)c1ccc(NC(=O)C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)c(F)c3)N([C@H](CS(=O)(=O)C(C)(C)C)C3CC3)C2=O)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(=O)C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)c(F)c3)N([C@H](CS(=O)(=O)C(C)(C)C)C3CC3)C2=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of lithium hydroxide monohydrate (18.2 g, 433 mmol) in water (295 mL) was added to a solution of methyl 4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetamido)-2-methoxybenzoate (164.9 g, 217 mmol, Example 5, Step A) in tetrahydrofuran (591 mL) and methanol (197 mL) at room temperature. After stirring for 15 hours at room temperature, a trace amount of the ester remained, so the reaction mixture was heated at 50° C. for 1 hour. When the reaction was complete, the mixture was concentrated under a vacuum to remove the tetrahydrofuran and methanol. The thick mixture was diluted with water (1 L) and 1 M hydrochloric acid (1 L) was added. The resulting white solid was collected by vacuum filtration in a Büchner funnel. The vacuum was removed, and water (1 L) was added to the filter cake. The material was stirred with a spatula to suspend it evenly in the water. The liquid was then removed by vacuum filtration. This washing cycle was repeated three more times to provide a white solid. The solid was dried under vacuum at 45° C. for 3 days to provide the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)([O-:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=3)=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3ccc([N+](=O)[O-])cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 71 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.5 g, 1.0 mmol), 4-Nitro-phenylamine (0.35 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4-Nitro-phenyl)-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine as brown solid in 71% yield.