Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C:12](=[O:15])[NH:13][CH3:14])[C:6](=[O:16])[C:5]2=[O:17].[NH2:18][C:19]([NH2:21])=[S:20].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:12](=[O:15])[N:13]([CH3:14])[C:5]2([OH:17])[C:6]([NH:18][C:19]([NH2:21])=[S:20])=[O:16]
Reactant: NC(N)=S
Reactant: CNC(=O)N1C(=O)C(=O)c2cc(Cl)c(Cl)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)Nc2cc(Cl)c(Cl)cc2C1(O)C(=O)NC(N)=S
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.4 %

Procedure:
5,6-Dichloro-1-methylcarbamoylisatin (9.6 g) is suspended in tetrahydrofuran (100 ml) and thereto are added thiourea (3.0 g) and triethylamine (5.6 ml), and the mixture is stirred at room temperature for 5 hours. The resulting precipitates are taken by filtration to give 6,7-dichloro-3-methyl-4-hydroxy-4-thioureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (4.1 g). M.p. 225-228° C.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[CH:18]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:26](=[CH:25][C:20]5[O:21][CH2:22][CH2:23][O:24][C:19]=5[CH:18]=4)[O:27][CH2:35]3)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (68%) as a colorless solid: mp 183-185° C. (methanol); 1H NMR (300 MHz, CDCl3) δ7.41-7.28 (m, 10H), 7.15 (dd, J=6.8, 1.4 Hz, 1H), 7.06 (s, 1H), 7.04-6.93 (m, 2H), 6.52-6.48 (m, 2H), 6.21 (s, 1H), 4.95 (d, J=8.9 Hz, 1H), 4.69 (d, J=8.9 Hz, 1H), 4.22-4.17 (m, 2H), 4.15-4.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.3, 144.7, 141.8, 138.4, 137.7, 137.5, 132.6, 128.83, 128.75, 128.5, 128.44, 128.36, 128.02, 127.98, 123.9, 123.2, 121.5, 112.3, 111.6, 99.5, 80.4, 64.6, 64.0, 58.8, 57.9; MS (ES+) m/z 462.3 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][S:25][CH2:26][C@H:27]([O:43][C:44](=[O:56])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:28][O:29][C:30](=[O:42])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:3](=[O:23])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@@H:2]([CH2:24][S:25][CH2:26][C@H:27]([O:43][C:44](=[O:56])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:28][O:29][C:30](=[O:42])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:3](=[O:23])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)O)OC(=O)NCCCCCCCCCC

Procedure:
A solution of (15R,19R)-tert-butyl 15-amino-19-(decylcarbamoyloxy)-14,22-dioxo-4,7,10,21-tetraoxa-17-thia-13,23-diazatritriacontan-1-oate in 30% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of the tert-butyl group (4 hours). The reaction was diluted with DCM and concentrated with a stream of nitrogen then purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM with 0.5% AcOH to afford (15R,19R)-15-amino-19-(decylcarbamoyloxy)-14,22-dioxo-4,7,10,21-tetraoxa-17-thia-13,23-diazatritriacontan-1-oic acid as a clear oil. 1H NMR (DMSO-d6): δ 12.21 (br s, 1H), 8.22 (t, 1H), 7.23 (m, 2H), 4.92 (m, 1H), 4.18 (dd, 2H), 3.94 (m, 1H), 3.57 (t, 2H), 3.30-3.54 (m, 12H), 3.37 (t, 2H), 2.90-3.08 (m, 4H), 2.60-2.82 (m, 4H), 2.48 (t, 2H), 1.32 (m, 4H), 1.22-1.28 (m, 28H), 0.79 (t, 6H). LRMS [M+H]=765.5.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([O:16][CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][C:13]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([O:16][CH3:17])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC1(c2ccc(Cl)cc2)CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC1(c2ccc(Cl)cc2)CCN(c2ccc(N)cc2)CC1
Yield: 89.8 %

Procedure:
A mixture of 1-(4-nitrophenyl)-4-(4-chlorophenyl)-4-methoxypiperidine (8.9 g), iron powder (10.7 g) and ammonium chloride (1.07 g) in ethanol (445 ml) and water (44.5 ml) was stirred at reflux for 5.5 hours. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. To the residue was added a mixture of ethyl acetate (150 ml), water (100 ml) and saturated sodium hydrogen carbonate (50 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. To the residue was added a mixture of diisopropyl ether (10 ml) and n-hexane (20 ml). The precipitate was collected by filtration, and dried under reduced pressure to give 1-(4-aminophenyl)-4-(4-chlorophenyl)-4-methoxypiperidine (7.3 g).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCCCC=CC1CCCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCC1CCCCN1C(=O)OC(C)(C)C

Procedure:
A solution of N-Boc-2-(1-heptenyl)piperdine (3.92, 13.93 mmol) in 7 mL of ethanol was shaken under 58 psi of H2 pressure over 0.78 g Pd/C catalyst overnight, and then the mixture was filtered through Celite and concentrated to give 3.94 g (quantitative) of the product. No further purification was necessary. 1H NMR (250 MHz) δ 4.20-4.15 (br s, 1H), 3.99-3.85 (br d, 1H), 2.79-2.70 (dt, 1H), 1.59-1.25 (m, 21H), 0.89-0.85 (t, 3H); 13C NMR (62.7 MHz) 155.1 (s), 78.8 (s), 50.3 (s), 38.6 (s), 31.8 (s), 29.6 (s), 29.5 (s), 29.3 (s), 28.4 (s), 26.3 (s), 25.6 (s), 22.6 (s), 18.9 (s), 14.0 (s) ppm.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:5]([F:15])=[C:6]([C:9]([F:14])=[C:10]([F:13])[C:11]=1[F:12])[CH:7]=[O:8]>CO>[CH3:3][C:4]1[C:5]([F:15])=[C:6]([C:9]([F:14])=[C:10]([F:13])[C:11]=1[F:12])[CH2:7][OH:8]
Reactant: Cc1c(F)c(F)c(F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(F)c(F)c(F)c(CO)c1F

Procedure:
Sodium borohydride (0.3 g) was added in small portions to a solution of 3-methyl-2,4,5,6-tetrafluorobenzaldehyde (1.5 g) in methyl alcohol (15 ml) at the ambient temperature, after which the mixture was heated at the reflux temperature for 30 minutes. The methyl alcohol was removed by evaporation under reduced pressure and the residue partitioned between dilute hydrochloric acid (20 ml of a 0.1 N solution) and ether (20 ml). The ethereal phase was separated, washed with saturated sodium bicarbonate solution and with water and then dried over anhydrous magnesium sulphate. After evaporation of the ether under reduced pressure the product was distilled in a Kugelrohr apparatus to yield 3-methyl-2,4,5,6-tetrafluorobenzyl alcohol (1.2 g) - approximate b.p. 100° C./14 mm Hg. N.m.r. (1H(ppm)CDCl3): 2.20 (s,3H); 3.20 (t,1H); 4.6 (m,2H) Infra red (liquid film): 3300, 1650, 1480, 1120, 1110 cm-1
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>O1CCCC1.O>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cnc2[nH]ccc2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a reaction vial, 1H-Pyrrolo[2,3-b]pyridin-5-ylamine (35, 0.1 g, 0.8 mmol) is dissolved in 7 mL of tetrahydrofuran and triethylamine (0.10 mL, 0.75 mmol) and nicotinoyl chloride (36, 0.16 g, 1.1 mmol) are added. The reaction is stirred at room temperature for 16 hours, then diluted with water and extracted 3× with ethyl acetate. The organic layers are combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16](=[O:18])[NH2:17])[NH:8][CH2:7][CH2:6]2.[O-:19][CH2:20]C.[Na+].C(=O)(OCC)OCC>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[O:18])[NH:17][C:20](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=CC(N)=O)NCC2
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: COc1cc2c(cc1OC)-c1cc(=O)[nH]c(=O)n1CC2

Procedure:
A solution of 6,7-dimethoxy-1-carbamoylmethylene-1,2,3,4-tetrahydroisoquinoline (5.0g) and an excess of sodium ethoxide (prepared from 12.0 g of sodium metal and 600 ml of ethanol) in ethanol is heated. 150.0 ml of diethyl carbonate is added to the solution. The reaction mixture is refluxed for an additional 2.5 hr. The solvent is removed under vacuum and the residue is acidified to give a white precipitate, yield 4.80 g. The product crystallizes from dimethylformamide, mp. 323°-325° C.
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1>>[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6][S:1]2(=[O:8])=[O:7])[CH:13]=[N:12][CH:11]=1
Reactant: O=S1(=O)CCCCN1
Reactant: ClCc1cncc(Br)c1
Product: O=S1(=O)CCCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], [1,2]thiazinane 1,1-dioxide has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as off-white solid. MS: 305.1, 307.1 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([N:12]1[CH2:100][CH2:99][CH2:98][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:58]([NH:60][CH2:61][C:62]([N:64]1[CH2:97][CH2:96][CH2:95][C@H:65]1[C:66]([NH:68][C@H:69]([C:74]([N:76]1[CH2:94][CH2:93][CH2:92][C@H:77]1[C:78]([NH:80][C@H:81]([C:89]([OH:91])=[O:90])[CH2:82][C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)=[O:79])=[O:75])[CH2:70][CH2:71][S:72][CH3:73])=[O:67])=[O:63])=[O:59])[CH2:53][CH2:54][CH2:55][CH2:56][NH2:57])=[O:50])[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1)=[O:40])[CH2:37][OH:38])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH:101](C(OC(C)(C)C)=O)[C@H:102]([C:108](O)=[O:109])[CH2:103][CH2:104][C:105](=[O:107])[NH2:106]>>[NH2:101][C@H:102]([C:108]([NH:1][C@H:2]([C:10]([N:12]1[CH2:100][CH2:99][CH2:98][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:58]([NH:60][CH2:61][C:62]([N:64]1[CH2:97][CH2:96][CH2:95][C@H:65]1[C:66]([NH:68][C@H:69]([C:74]([N:76]1[CH2:94][CH2:93][CH2:92][C@H:77]1[C:78]([NH:80][C@H:81]([C:89]([OH:91])=[O:90])[CH2:82][C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)=[O:79])=[O:75])[CH2:70][CH2:71][S:72][CH3:73])=[O:67])=[O:63])=[O:59])[CH2:53][CH2:54][CH2:55][CH2:56][NH2:57])=[O:50])[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1)=[O:40])[CH2:37][OH:38])=[O:34])[CH2:29][CH:30]([CH3:31])[CH3:32])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:109])[CH2:103][CH2:104][C:105](=[O:107])[NH2:106]
Reactant: CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Product: CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The resin of Example 25 was further condensed with Boc-Gln, followed by the same treatment and purification procedure and lyophilization from diluted aqueous hydrochloric acid, to give 21 mg of a white powder.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2
Agent: Br
Product: Oc1ccc2c(c1)CCNC2
Reaction time: 24 h
Yield: 100 %

Procedure:
Combine 6-Methoxy-1,2,3,4-tetrahydro-isoquinoline (5.0, 20.5 mmol) and 48% HBr(aq), 20 ml at room temperature. After the reaction refluxes for 24 hours, cool the reaction to room temperature and concentrate under reduced pressure. Triturate with ethyl acetate and filter to afford 5.5 g, 20.5 mmol (99% yield) of the title compound as a tan solid: 1H NMR (500 MHz, DMSO); 2.8-2.9 (2H, m), 3.3-3.4 (2H, m), 4.1 (2H, s), 6.5-6.7 (2H, m), 6.9-7.1 (1H, m), 8.8-9.0 (2H, br s), 9.4-9.5 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[NH2:11])=[O:5])[CH3:2].[N:12]([O-])=O.[Na+]>Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[NH:11][NH2:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1scnc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1scnc1NN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To 100 ml of a concentrated hydrochloric acid solution containing 19.3 g of 4-aminothiazole-5-carboxylic acid ethyl ester, 12 ml of an aqueous solution of 8.5 g of sodium nitrite was added dropwise at 0 to 5° C. This mixture was stirred at 0° C. for 30 minutes, and then 120 ml of a concentrated hydrochloric acid solution containing 84.9 g of stannous chloride was added dropwise thereto at 0 to 10° C. The mixture was further stirred at the same temperature for 2 hours and then stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was carefully added to 2 liters of an ethyl acetate suspension containing 500 g of potassium carbonate and 100 g of celite with stirring. Further, the filtered substance was added to this ethyl acetate suspension, and then the suspension was made basic with 150 ml of a 5 N sodium hydroxide aqueous solution. The mixture was allowed to stand, and then most of the supernatant (organic layer A: 1.5 liters) was collected. The remaining suspension was filtered through celite, and the celite was washed with 1 liter of ethyl acetate and 500 ml of water. The filtrate was separated into organic layer B and aqueous layer A. Ethyl acetate (1 liter) and anhydrous magnesium sulfate were added to the filtered substance, and the mixture was stirred and then filtered. Aqueous layer A was re-extracted with the resulting filtrate. Washing of the filtered substance and re-extraction of aqueous layer A were repeated 4 times in the same manner. Organic layer A and organic layer B were combined with the obtained organic layers, and the mixture was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (11.9 g) as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1cc(O)ccc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(O)ccc1Cl
Yield: 74.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-chloro-5-hydroxybenzeneboronic acid (available from Combi-Blocks Inc.; 69 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-hydroxy-biphenyl-2-carboxylic acid (71 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ 13.01 (br s, 1H), 9.76 (s, 1H), 8.48 (s, 2H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.78 (dd, J=8.7, 2.9 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH3:23])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1.P(N)([NH2:34])(=O)OC1C=CC=CC=1.[OH-].[Na+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH3:23])[C:15]=3[N:14]=[C:13]([NH2:34])[C:12]=2[CH2:11][CH2:10]1
Reactant: NP(N)(=O)Oc1ccccc1
Reactant: COc1ccccc1N1CCc2c1c1cccc(OC)c1[nH]c2=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccccc1N1CCc2c(N)nc3c(OC)cccc3c21
Temperature: 230 °C
Yield: 24.1 %

Procedure:
1-(2-Methoxyphenyl)-4-oxo-6-methoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (1.5 g) and phenyl phosphorodiamidate (2.5 g) were fused at 230° C. After 45 minutes the mixture was diluted with diphenyl ether (10 ml), further phenyl phosphorodiamidate (2 g) added, and heated for a further 15minutes at 230° C. Aqueous sodium hydroxide was added and the product extracted into dichloromethane. Chromatography (silica gel. 2.5-4%methanolic ammonia in dichloromethane) to remove unchanged starting material was followed by recrystallisation from ethanol/ethyl acetate to yield 1-(2-methoxyphenyl)-4-amino-6-methoxy-2,3-dihydropyrrolo[3,2-c]quinoline (0.36 g), m.p. 244°-247° (dec).
Reaction SMILES: [C:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C>[C:1]1([CH:7]2[N:10]([Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17])[C:9](=[O:11])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
4-Phenylazetidin-2-one (10.4 gm, 71.0 mmole) (Graf, Chem. Ber, 111 (1963); Durst et al. J. Org. Chem., 35, 2043 (1970)) was dissolved in DMF (200 ml) and was treated with tert.-butyldimethylsilyl chloride (12.8 gm, 85 mmol) and triethylamine (11.8 ml, 85 mmol). The mixture was stirred at room temperature for 16 hrs. and taken up in either (500 ml). The ethereal solution was washed with 1N hydrochloric acid (1×100 ml), water (2×50 ml) and brine (1×50 ml). After the solution was dried (anhyd. magnesium sulfate) and evaporated, the residue was flash chromatographed on SiO2 -gel column. Elution with 15% ethyl acetate in hexane afforded 4-phenyl-1-(tert.-butyldimethylsilyl)azetidin-2-one (18.4 gm, 99%) as an oil which solidified on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25](O)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].C(C1C=CC(OS(C(F)(F)F)(=O)=O)=C(OC)C=1)=O.ClC1C=CC=CC=1B(O)O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:85][NH:86][CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][N:89]=1>CN(C)C=O.O>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:4]1[CH:5]=[CH:6][C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:86]([CH3:85])[CH2:87][C:88]4[CH:93]=[CH:92][CH:91]=[CH:90][N:89]=4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1Cl
Reactant: CNCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)N(C)Cc4ccccn4)n3Cc3ccccc32)ccc1-c1ccccc1Cl
Reaction time: 8 h

Procedure:
To a solution of 10-{[2-methoxy-2′-chloro[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid (0.230 g, 0.54 mmol) [prepared from trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester of Example 7, Step A and 2-chlorophenyl boronic acid, in the manner of Example 7, Steps B–E], in N,N-dimethylformamide (15 mL) is added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.120 g, 0.625 mmol) and 1-hydroxybenzotriazole (0.625 mmol). To the homogeneous solution was added methyl-pyridin-2-ylmethyl-amine (0.625 mmol) and the stirring was continued at room temperature overnight. At the end of this time the solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried and concentrated and the residue was chromatographed on silica gel, eluting with 95:5 chloroform:methanol. The pure fractions were concentrated, and the residue azeotroped and triturated several times with hexane to yield the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CC1(C)O[C:16](=O)[CH2:15][C:13](=[O:14])[O:12]1>O>[NH:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:15]([C:13]([OH:14])=[O:12])[CH2:16]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccccc1C=O
Solvent: O
Product: O=C(O)C1=Cc2ccccc2NC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
2-Aminobenzaldehyde (84.1 mg, 0.69 mmol) and Meldrum's acid (100 mg, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 86.2 mg of 1,2-dihydro-quinoline-3-carboxylic acid with a yield of 66%.