Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(Cl)(Cl)Cl.CC(C)=O>O>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:24](=[O:26])[CH3:25])[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Solvent: CC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (100 mg) was dissolved in water (3 ml). To this solution was added acetic anhydride (30 μl), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and acetone (1:1, v/v) to afford 11-acetyl-4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (80.5 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[CH3:14][C:15]1[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][CH:3]=2)=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)cc2)o1

Procedure:
Example 35 was prepared using 2-(4iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and N-[4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 25) with propan-2-ol as the solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:23](=O)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([NH:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)(=[O:10])=[O:11])=[CH:3][C:2]=1[NH:1][CH2:23][CH3:24]
Reactant: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c(N)c2)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)OC)CC2)ccc1Cl
Reaction time: 8 h

Procedure:
A round bottom flask was charged with methyl trans-4-(3-amino-4-chlorophenylsulfonamido)cyclohexamecarboxylate (Intermediate 10, 333 mg, 0.922 mmol) and acetaldehyde (52.1 μl, 0.922 mmol) followed by sodium triacetoxyborohydride (293 mg, 1.383 mmol) in DCE (9217 μl) and the reaction was stirred overnight. The reaction was diluted with DCM/sat'd NaHCO3, and the organic layer was separated and dried over MgSO4, then filtered and chromatographed on a Biotage 25S column to yield the title compound (224 mg, 0.598 mmol, 64.8% yield). Rf (50% EtOAc/heptane): sm=0.43; product=0.58. MS MH+=375.2
Reaction SMILES: Cl.N[C@H]1CCCC[C@H]1CNCCN1CCOCC1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH2:27][NH:28][C:29]([C:31]1[C:32](=[O:66])[C:33]([O:58]CC2C=CC=CC=2)=[C:34]2[C:55](=[O:56])[N:38]3[CH:39]4[CH:44]([CH2:45][N:46]([CH2:47][CH2:48][N:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)[CH:37]3[CH2:36][N:35]2[CH:57]=1)[CH2:43][CH2:42][CH2:41][CH2:40]4)=[O:30]>[Pd]>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH2:27][NH:28][C:29]([C:31]1[C:32](=[O:66])[C:33]([OH:58])=[C:34]2[C:55](=[O:56])[N:38]3[CH:39]4[CH:44]([CH2:45][N:46]([CH2:47][CH2:48][N:49]5[CH2:50][CH2:51][O:52][CH2:53][CH2:54]5)[CH:37]3[CH2:36][N:35]2[CH:57]=1)[CH2:43][CH2:42][CH2:41][CH2:40]4)=[O:30]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C3CCCCC3CN(CCN3CCOCC3)C1C2
Agent: [Pd]
Agent: Cl
Agent: N[C@H]1CCCC[C@H]1CNCCN1CCOCC1
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C3CCCCC3CN(CCN3CCOCC3)C1C2

Procedure:
racemic-4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-1,2,3,4,4a5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide. In a manner similar to that described in example Z-35, from racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}[2-(4-morpholinyl)ethyl]amine hydrochloride (95 mg, 0.272 mmol) and 16a (45 mg, 0.0957 mmol) was prepared racemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (27 mg, 43%). This material was deprotected in a second step similar to the procedure described in example Z-37. From racemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazolino-10-carboxamide (27 mg, 0.0408 mmol) and 10% Pd/C (1 mg) the title compound was prepared as a white solid after purification by HPLC. 1H NMR (CDCl3) 12.30 (br s, <1H), 10.41 (br s, 1H), 8.29 (s, 1H), 7.34 (m, 2H), 6.78 (m, 2H), 4.76 (m, 1H), 4.62-4.54 (m, 3H), 4.29 (m, 2H), 3.65 (m, 4H), 3.01 (m, 1H), 2.76 (m, 2H), 2.58-2.42 (m, 7H), 2.21 (m, 1H), 1.89-1.23 (m, 8H); ES+ MS: 572 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]3[NH:30][CH:29]=[C:28]([C:31]([O:33]C)=[O:32])[CH:27]=3)[CH:21]=2)=[CH:15][CH:14]=1)=[O:11].C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]3[NH:30][CH:29]=[C:28]([C:31]([OH:33])=[O:32])[CH:27]=3)[CH:21]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: COC(=O)c1c[nH]c(-c2cc(Sc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Sc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Temperature: 66 °C

Procedure:
To a stirred solution of methyl 5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylate (86 mg, 0.18 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 2 ml of 1M NaOH (2 mmol) solution. The mixture was heated in a 66° C. bath for 7 hours, cooled to room temperature and poured into 100 ml of water. 2M HCl was added until pH=3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid as light brown solid. Yield: 73 mg, 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=O)[CH3:11].[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:15][NH2:16]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH3:11]
Reactant: COc1ccccc1CC(C)=O
Reactant: NCC(O)c1cccc(Cl)c1
Product: COc1ccccc1CC(C)NCC(O)c1cccc(Cl)c1

Procedure:
N-[2-(2-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine, m.p. 85°-7° C. was prepared from 1-(2-methoxyphenyl)propan-2-one (2.69 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (2.81 g) as a 32:68 mixture of diastereoisomers, by an analogous procedure to that described in Example 1.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[Br:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:15][CH2:16][C:17]([C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([Br:5])[CH:7]=2)[NH:12][CH:13]=1)=[O:18]
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1c[nH]c2ncc(Br)cc12
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (338 mg, 2.54 mmol) in dichloromethane (10 mL) was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.507 mmol). After stirring for 30 min, bromoacetyl chloride (0.21 mL, 2.54 mmol) was added and the reaction mixture was stirred for 2 h, before quenching with MeOH at 0° C. The mixture was concentrated in vacuo, the pH was changed to 7 by addition of a saturated solution of aqueous sodium bicarbonate, and the aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO4 and filtered through a plug of silica gel. Solvent was evaporated to dryness to give 2-bromo-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone as a light yellow solid (160 mg, quantitative). 1H NMR (500 MHz, DMSO-d6) δ 4.70 (s, 2H), 8.44 (d, J=2.0 Hz, 1H), 8.55 (d, J=2.5 Hz, 1H), 8.68 (d, J=3.5 Hz, 1H), 12.9 (s, 1H). MS: m/z 316 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:22]([NH2:24])=[O:23])=[N:10][N:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([NH2:20])=[C:15]([F:21])[CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:27][C:28]1[CH:36]=[N:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:20][C:16]1[C:15]([F:21])=[CH:14][C:13]([N:11]2[C:12]3[C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][N:35]=[CH:36][C:28]=5[Cl:27])[CH:26]=[CH:25][C:5]=4[CH2:6][CH2:7][C:8]=3[C:9]([C:22]([NH2:24])=[O:23])=[N:10]2)=[CH:18][C:17]=1[F:19]
Reactant: NC(=O)c1nn(-c2cc(F)c(N)c(F)c2)c2c1CCc1ccc(N)cc1-2
Reactant: O=C(O)c1ccncc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1nn(-c2cc(F)c(N)c(F)c2)c2c1CCc1ccc(NC(=O)c3ccncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.4 %

Procedure:
To a mixture of the product from step 3 (0.75 g, 0.0021 mol) and 3-chloroisonicotinic cid (0.33 g, 0.0023 mol) in 20 mL of DMF was added 1 mL of diisopropylethylamine, followed by the addition of HATU (0.9 g, 0.0023 mol). The reaction was stirred at room temperature for 16 h and concentrated. The crude was purified by reverse phase HPLC to give 0.15 g of 1-(4-amino-3,5-difluorophenyl)-8-[(3-chloroisonicotinoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide as a pale white solid (15% yield); 1HNMR (DMSO, 400 MHz) δ: 10.56 (s, 1H), 8.76 (s, 1H), 8.63 (d, 1H), 8.56 (s, 1H), 7.54 (d, 1H), 7.49 (dd, 1H), 7.35 (m, 2H), 7.31 (s, 1H), 6.71 (m, 2H), 5.88 (s, 2H), 2.92 (m, 4H); Anal. Calcd. for C24H17FClN6O2+0.5 H2O: C, 57.21; H, 3.60; N, 16.68. Found: C, 56.91; H, 3.70; N, 16.64.
Reaction SMILES: Cl[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:10](=[O:19])[C:9]2[C:4](=[C:5]([I:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O.O>[C:21]([NH:25][C:2]1[N:11]([CH2:12][CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:10](=[O:19])[C:9]2[C:4](=[C:5]([I:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)CCCn1c(Cl)nc2c(I)cccc2c1=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Nc1nc2c(I)cccc2c(=O)n1CCCS(C)(=O)=O
Temperature: 100 °C
Yield: 199.2 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-8-iodo-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-one (50 mg, 0.117 mmol) and tert-butylamine (0.123 mL, 1.172 mmol) in DMSO (0.5 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The reaction was repeated on 150 mg scale. The reaction mixture were combined and diluted with water (20 mL). The mixture was extracted with CHCl3/iPrOH (4:1, 40 mL×3) and the combined organic layers were washed with water, dried (MgSO4), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 10-70% EtOAc in Hexanes) to give 2-(tert-butylamino)-8-iodo-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-one (108 mg, 50% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 464 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38](=[O:44])[C:39](I)=[CH:40][O:41][CH3:42].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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>[CH3:36][O:37][C:38](=[O:44])[C:39]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:10][CH:11]=1)=[CH:40][O:41][CH3:42]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Reactant: COC=C(I)C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC=C(C(=O)OC)c1ccc(CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
A mixture of (3-tert-butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-carbamic acid tert-butyl ester (6.00 g, 12.25 mmol), 2-iodo-3-methoxy-acrylic acid methyl ester (4.45 g, 18.38 mmol), K3PO4 (7.79 g, 36.75 mmol), Pd(PPh3)4 (0) (0.68 g, 0.61 mmol), dioxane (60 mL) and water (12 mL) was degassed and heated at 80° C. for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0%-30% EtOAc in heptane) to give desired product (5.35 g, 91%) as brown oil. 1NMR (300 MHz, CDCl3): δ 7.56 (s, 1H), 7.30 (d, J=8.1 Hz, 2H), 7.20 (br.d, 2H), 5.20 (br.s, 0.5H), 4.62 (br.s, 0.5H), 4.39 (br, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.27 (m, 2H), 3.08 (m, 2H), 1.62 (m, 2H), 1.50 (br.d, 9H), 1.43 (s, 9H). LCMS (EI) m/z: 501 (M+Na+).
Reaction SMILES: [B:1]1(B2OC(C)(C)C(C)(C)O2)[O:5]C(C)(C)C(C)(C)[O:2]1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([O:27][CH3:28])[N:21]=1>CCCCCCC.C(OCC)(=O)C.C[OH2+].C[OH2+].C1CC=CCCC=C1.C1CC=CCCC=C1.[Ir].[Ir]>[Cl:26][C:25]1[CH:24]=[C:23]([B:1]([OH:5])[OH:2])[C:22]([O:27][CH3:28])=[N:21][C:20]=1[Cl:19]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COc1ccc(Cl)c(Cl)n1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: C[OH2+]
Solvent: CCOC(C)=O
Solvent: C1=CCCC=CCC1
Solvent: CCCCCCC
Product: COc1nc(Cl)c(Cl)cc1B(O)O
Reaction time: 0.17 h

Procedure:
To a round-bottomed flask was added (1,5-cyclooctadiene)(methoxy)-iridium(i) dimer (0.223 g, 0.337 mmol), 4,4-di-tert-butyl-2,2-dipyridyl (0.181 g, 0.674 mmol) and bis(pinacolato)diboron (2.85 g, 11.23 mmol) in heptane (112 ml). The reaction mixture was vacuumed and refilled with dry nitrogen (3×). After stirring for 10 minutes, 2,3-dichloro-6-methoxypyridine (2.0 g, 11.23 mmol) was added. The resulting reaction mixture was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed twice with 1N HCl solution. The organic layer was extracted twice with 1N sodium hydroxide solution, and the combined aqueous layers were acidified with concentrated HCl solution and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford (5,6-dichloro-2-methoxypyridin-3-yl)boronic acid as an oily light yellow solid. m/z (ESI) 222.1 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38]C)=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][CH2:60]O)=[CH:55][CH:54]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:95]([C@@H:98]([C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1)[CH3:99])=C=O>C(Cl)Cl>[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][CH2:60][O:51][C:48]2[CH:49]=[CH:50][C:45]([C@H:43]3[CH2:42][O:41][C:13]4=[CH:14][C:15]5[CH2:16][C@@H:17]([C:18]([NH:19][C@@H:20]([CH2:21][C:22]6[CH:27]=[CH:26][C:25]([C:28]7[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=7[CH3:35])=[CH:24][CH:23]=6)[C:36]([OH:38])=[O:37])=[O:40])[N:8]([C:6](=[O:7])[NH:95][C@@H:98]([C:100]6[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=6)[CH3:99])[CH2:9][C:10]=5[CH:11]=[C:12]4[O:44]3)=[CH:46][CH:47]=2)=[CH:55][CH:54]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)CO3
Reactant: OCCc1ccc(Cl)cc1
Reactant: C[C@@H](N=C=O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@H](C)c3ccccc3)O[C@@H](c3ccc(OCCc4ccc(Cl)cc4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C

Procedure:
(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (30 mg) was dissolved in DCM and 2(4-chloro-phenyl)-ethanol (5 equiv), triphenyl phosphine (5 eq.) and DIAD (4.5 eq.) added. The reaction mixture stirred at room temperature and was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was dissolved in 2 mL DCM and 1 mL 4N HCl (dioxane) was added. The mixture was stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, and TEA (3 eq.) was added to the mixture used in the following reaction sequence. ((R)-1-isocyanato-ethyl)-benzene (5 eq.) was added and reaction stirred at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 866.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:25]O)=[C:5]([C:20]([O:22]CC)=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[CH2:25][O:22][C:20](=[O:21])[C:5]=2[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Yield: 61 %

Procedure:
A solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (592.5 mg) and p-toluenesulfonic acid (catalytic amount) in ethanol (6 ml) was refluxed for 4 hours. After the resultant solution was concentrated, diethyl ether was added to the residue. The precipitating crystals were collected by filtration to give ethyl 2-methyl-4-(2-chlorophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (317.5 mg). The crude product was recrystallized from ethyl acetate to give colorless granules (210.3 mg). m.p. 211° to 212° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Solvent: C1CCOC1
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)Nc1cccc(Cl)c1

Procedure:
A mixture of 3-(3-Chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (100 mg, 0.3 mmol, 1 eq), 1-Chloro-3-isocyanato-benzene (56 mg, 0.36 mmol, 1.2 eq), in THF (2 ml) was stirred at room temperature overnight. It was concentrated, dissolved in acetonitrile and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 479.3
Reaction SMILES: C(=O)=O.[C:4]([NH:7][CH:8]([C:12]1([CH3:17])[CH2:16][CH:15]=[CH:14][O:13]1)[C:9]([OH:11])=O)(=[O:6])[CH3:5].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:4]([NH:7][CH:8]([C:12]1([CH3:17])[CH2:16][CH:15]=[CH:14][O:13]1)[C:9]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:11])(=[O:6])[CH3:5]
Reactant: NCc1ccccc1
Reactant: CC(=O)NC(C(=O)O)C1(C)CC=CO1
Agent: CC(C)COC(=O)Cl
Agent: O=C=O
Solvent: CN1CCOCC1
Product: CC(=O)NC(C(=O)NCc1ccccc1)C1(C)CC=CO1
Yield: 42.6 %

Procedure:
Employing the mixed carbonic anhydride coupling procedure with 18 (2.40 g, 12.2 mmol), 4-methylmorpholine (1.23 g, 12.2 mmol), isobutylchloroformate (1.83 g, 13.4 mmol), and benzylamine (1.43 g, 12.7 mmol) gave 4 (1.50 g, 43%) as a thick oil: Rf 0.29 (2% MeOH/CHCl3); 1H NMR (CDCl3) δ 1.94 (s, CH3), 1.98 (s, C(O)CH3), 4.40 (d, J=5.6 Hz, CH2), 6.20 (br s, NH), 6.34-6.37 (m, C3H, C4H), 7.05-7.36 (m, NH, C5H, 5 PhH); 13C NMR (CDCl3) 22.31 (C(O)CH3), 23.81 (CH3), 43.77 (CH2), 58.50 (C(CH3)), 107.94 (C4), 110.67 (C3), 126.99 (2C2 ' or 2C3 '), 127.41 (C4 '), 128.60 (2C2 ' or 2C3 '), 137.52 (C1 '), 142.38 (C5), 152.94 (C2), 169.03 (C(O)NH), 171.16 (COCH3) ppm; mass spectrum, m/e (relative intensity) 287 (M+ +1, 4), 228 (4), 153 (99), 152 (96), 138 (15), 111 (63), 110 (100), 91 (75); Mr (EI) 286.13074 (calcd for C16H18N2O3, 286.13174).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 90 from tert-butyl (±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (124 mg, 0.27 mmol) and corresponding 2,3-dichlorophenylboronic acid (104 mg, 0.54 mmol), to afford after chromatographic purification the title compound (157 mg, 99%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.30-7.40 (m, 1H), 7.20 (s, 1H), 7.18 (d, 1H, J=3.6 Hz), 6.99 (s, 1H), 6.94 (s, 1H), 3.80-3.90 (m, 1H), 3.60-3.80 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.47 (s, 9H) ppm. MS (CI, NH3): 445 (base, M+H).