Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=4[N:13]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:37]=[CH:38][C:39]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:40]([CH:44]=1)[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([N:8]3[C@@H:1]4[C@@H:6]([CH2:5][CH2:4][N:3]([C:41]([C:40]5[CH:44]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=5[N:45]5[N:49]=[CH:48][CH:47]=[N:46]5)=[O:42])[CH2:2]4)[CH2:7]3)=[N:13][C:12]=2[CH:14]=1
Reactant: Clc1ccc2oc(N3C[C@@H]4CCNC[C@@H]43)nc2c1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN(c3nc4cc(Cl)ccc4o3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 2-((1R,6S)-3,8-diazabicyclo[4.2.0]octan-8-yl)-5-chlorobenzo[d]oxazole (Intermediate 32) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C22H18ClFN6O2, 452.88; m/z found 453.1 [M+H]+. 1H NMR (CD3OD): 8.02-7.63 (m, 2H), 7.48-7.24 (m, 3H), 7.21-6.69 (m, 3H), 4.86-3.35 (m, 7H), 3.15-2.95 (m, 1H), 2.27-1.72 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][CH2:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][CH2:55][O:56][CH3:57]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:52]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH2:51][CH2:50][CH2:49][O:48][CH3:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: COCCCNCCCOC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CCCOC)CCCOC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with bis-(3-methoxy-propyl)-amine (prepared from bis-(3-chloro-propyl)-amine and sodium methoxide) to give the title compound. HR-MS (ES, m/z) calculated for C44H59Cl2N5O5 [(M+H)+] 808.3966, observed 808.3965.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:26])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.NC1N=C(OC)C(C(=O)CCC2CCN(C(OC(C)(C)C)=O)CC2)=CC=1Cl>>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:26])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: COc1nc(N)ccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: COc1nc(N)c(Cl)cc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1nc(N)ccc1C(=O)CCC1CCNCC1

Procedure:
The title compound was prepared according to the procedure of step 5 in the example 9 using tert-butyl 4-[3-(6-amino-2-methoxy-3-pyridinyl)-3-oxopropyl]-1-piperidinecarboxylate (step 3 in example 9), instead of tert-butyl 4-{3-[6-amino-5-chloro-2-(methyloxy)-3-pyridinyl]-3-oxopropyl}-1-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:5]2[OH:28].C(Cl)(Cl)Cl.CO.Cl>O1CCOCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH2:14][OH:15])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:5]2[OH:28]
Reactant: CCOC(=O)c1cnc2c(CCO[Si](C)(C)C(C)(C)C)c(F)c(Cl)cc2c1O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(CCO)c(F)c(Cl)cc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
5.62 g (13 mmol) of the compound (129) obtained above was added in a mixture solvent of 100 ml of chloroform and 100 ml of methanol, and 15 ml of 4N hydrochloric acid solution in dioxane was added to the solution. After stirring at room temperature for 30 minutes, the solvent was removed from the solution by distillation. Crystals obtained were dispersed in ethanol and filtrated. They were washed with ethanol and ether in this order to obtain 3.70 g of the subject compound (130) in a 90% yield.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][S:25]([NH:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])(=[O:27])=[O:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][S:25]([NH:28][C:29]1[CH:30]=[C:31]([NH:32]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 3-methylsulphonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:18])[C:5]=2[CH:4]=1)=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(Cl)Cl>ClCCCl>[OH:2][CH2:1][C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:18])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cn(C)c2cc(C=O)sc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1cn(C)c2cc(CO)sc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.4 %

Procedure:
To a solution of ethyl 2-formyl-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (1.0 g, 3.8 mmol) in 1,2-dichloroethane (23 mL) was added sodium triacetoxyborohydride (1.6 g, 7.5 mmol). The reaction was stirred at room temperature for 24 hours. The reaction was poured into sat. aq. sodium bicarbonate (50 mL) and methylene chloride (30 mL), before it was quenched with water (50 mL). The mixture was allowed to stand at 0° C. overnight. The solid ppt. was collected by vacuum filtration and washed with water. Drying in vacuo yielded an off-white solid (0.36 g, 36%). The filtrate was concentrated to near dryness and diluted with water (20 mL). Filtration followed by treatment with high vacuum gave a second crop of product (0.45 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12](=O)[NH:11]2)=[CH:6][CH:5]=1.P(Cl)(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][C:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:17])([F:16])[F:1])=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=C1CCN(c2ccc(OC(F)(F)F)cc2)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(N2CCC(Cl)=N2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The general procedure was taken from Wang et al. Tetrahedron Lett. 2005, 46, 2631. To a solution of 1-(4-trifluoromethoxyphenyl)-pyrazolidin-3-one (120 mg, 0.49 mmol, 1.00 eq) in toluene (20 mL) was slowly added phosphoryl chloride (22.5 mg, 1.47 mmol, 3.00 eq). The mixture was then heated at 80° C. for 1 h before cooling to room temperature and quenching with H2O (10 mL). The vessel was stirred under an atmosphere of nitrogen (N2) for 8 h before the product was extracted into EtOAc (200 mL), dried (MgSO4), and concentrated under reduced pressure. GC-MS proved 88% formation of the desired intermediate, which was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:20]Br)=[C:16]([Br:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>CN(C=O)C>[C:22]([O:25][CH2:20][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[Br:19])[N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH:11]=[CH:12]2)(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CBr)c(Br)cc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1Br
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Under a nitrogen stream, to a solution of 1-benzenesulfonyl-6-bromo-5-bromomethyl-1H-indole (14 mg, 0.03 mmol) in DMF (0.2 mL) was added sodium acetate (4 mg, 0.05 mmol), and the resultant mixture was then stirred for 2 hours at 80° C. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (2:5)), to thereby obtain the titled compound (11 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][N:4]=1.Cl([O-])=[O:14].[Na+].O.P([O-])(O)(O)=O.[Na+].O>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([OH:14])=[O:12])=[CH:5][N:4]=1
Reactant: COc1ncc(C=O)c(OC)n1
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ncc(C(=O)O)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-Bis(methyloxy)-5-pyrimidinecarbaldehyde (commercially available from Toronto, 1.400 g, 8.33 mmol) at 0° C. in t-Butanol (14.00 mL) an aqueous solution (7 mL) of Sodium chlorite (1.807 g, 19.98 mmol) was added over 25 min and sodium dihydrogen phosphate hydrate (3.64 g, 23.33 mmol). The yellow mixture obtained was warmed to 25° C. and after 6 h 14 mL of t-Butanol, 7 mL of water, and Sodium chlorite (2.26 g, 25 mmol) were added. The reaction mixture was stirred at room temperature overnight. After 24 h, the mixture was evaporated in vacuo, and the crude material purified by SPE 25 g cartridge eluting with DCM/MeOH 8:2 to recover 1 g of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:27](=[C:7]1[C:8](=[O:10])[O:9][C:4]([C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Cl:1])=[N:6]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)CNC(=O)c1ccccc1Cl
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccccc2Cl)=NC1=Cc1ccccc1
Temperature: 60 °C
Yield: 90 %

Procedure:
To the stirred mixture of (2-chloro-benzoylamino)-acetic acid 21 (23.41 mmol), anhydrous sodium acetate (70.23 mmol), acetic anhydride (7 ml), and benzaldehyde (25.75 mmol) were added dropwise at 30° C. This mixture was then heated to 60° C. for 1 hr. The reaction mixture was poured into an ice-water solution and the resulting solids were filtered, washed with ethanol and dried on vacuum. The desired compound was obtained with a 90% yield.
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:30][S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[C:6]([OH:40])=[O:5])=[O:29])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
8-5 (497 mg, 1.04 mmol) in 5 mL CH2Cl2 was treated with 5 mL TFA at 0° for 30 min then RT for 10 min. Concentration provided 9-1 as a yellow oil. Rf 0.52 (silica, 10:1:1 ethanol/NH4OH/H2O).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:19])[CH2:11][CH2:12][CH:13]1[S:18][CH2:17][CH2:16][CH2:15][S:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]1([O:22][CH2:21][CH2:20][O:19]1)[CH2:11][CH2:12][CH:13]1[S:18][CH2:17][CH2:16][CH2:15][S:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: O=C(CCC1SCCCS1)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: c1ccc(COCC2(CCC3SCCCS3)OCCO2)cc1
Reaction time: 1 h

Procedure:
Treatment of 1-benzyloxy-4-(1,3-dithian-2-yl)-butan-2-one (89.8 g) in benzene (3.5 l) with distilled ethylene glycol (220 ml) and p-toluenesulfonic acid (11.7 g) at reflux temperature in a Dean-Stark apparatus for 18 hours gives a mixture which is concentrated to 500 ml in vacuo and allowed to stir for one hour. After the addition of sodium carbonate (10 g), the mixture is then partitioned between ether (300 ml) and brine (300 ml). The aqueous phase is extracted with ether (600 ml) and the combined extracts are washed with 0.05% sodium carbonate (1.2 l), filtered through phase-separating paper and dried (sodium sulfate). The solvent is removed in vacuo to give a residue (102.15 g; 99%). A 200 mg portion of the residue is purified on Quantagram PQ1F plates (chloroform) to give 1-benzyloxy-2,2-ethylenedioxy-4-(1,3-dithian-2yl)-butane (180 mg);
Reaction SMILES: [CH:1]1[C:6]2[N:7]=[C:8]3[C:20]4[C:12]([C:13]5[C:18]([N:19]=4)=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2)C=CC=1>[Cu](I)I.ClCCl.O>[C:22]1([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[C:12]4[C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=5[NH:19][C:20]4=3)[C:5]3[C:6]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Ic1ccccc1
Reactant: c1ccc2c(c1)N=c1c-2ccc2c1=Nc1ccccc1-2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Solvent: O
Product: c1ccc(-n2c3ccccc3c3ccc4c5ccccc5[nH]c4c32)cc1
Temperature: 190 °C
Reaction time: 72 h
Yield: 40.6 %

Procedure:
In a 1,000-ml three-necked flask that had been deaerated and filled with nitrogen were placed 26.0 g (101.4 millimoles) of indolo[2,3-a]carbazole, 122.7 g (601.4 millimoles) of iodobenzene, 54.7 g (287.2 millimoles) of copper iodide, 66.7 g (482.6 millimoles) of potassium carbonate, and 800 ml of quinoline and the mixture was stirred at 190° C. for 72 hours. The mixture was cooled to room temperature, 500 ml of water and 500 ml of dichloromethane were added, and the yellow crystals formed were filtered off. The filtrate was separated into an organic layer and an aqueous layer and the organic layer was washed three times with 500 ml of water. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solvent was stripped off under reduced pressure. The residue was purified by silica gel column chromatography to yield 13.7 g (41.2 millimoles, 40.6% yield) of 11-phenylindolo[2,3-a]carbazole as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@H:14]([OH:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@H:14]([O:16][S:27]([CH3:26])(=[O:29])=[O:28])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](O)c1cccc(C(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C[C@@H](OS(C)(=O)=O)c1cccc(C(=O)OC(C)(C)C)c1
Yield: 102.5 %

Procedure:
(R)-1-(3-Tert-butyloxycarbonylphenyl)ethanol (3.28 mmol) was dissolved in CH2Cl2 (10 mL), diisopropylethylamine (4.92 mmol) added and the resultant solution cooled to 0° C. This mixture was stirred as methanesulfonyl chloride (3.94 mmol) was added dropwise. After 45 min the mixture was poured into water and extracted 3× with diethyl ether. The organic extracts were combined, washed with brine, dried (MgSO4) and concentrated under reduced pressure to yield 1.01 g of an oil which was used with out further purification. 1H NMR (500 MHz, CDCl3): δ 8.03 (m, 1H); 8.01 (m, 1H); 7.60 (m, 1H); 7.48 (t, J=7.6 Hz, 1H); 5.80 (q, J=6.6 Hz, 1H); 2.81 (s, 3H); 1.76 (d, J=6.6 Hz, 3H); 1.63 (s, 9H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([SH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[OH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:14]2[C:13]([S:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:16][C:15]=2[CH:23]=1
Reactant: COc1cccc(S)c1
Reactant: CCOC(=O)c1sc2cc(CO)ccc2c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(CO)ccc2c1Sc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--1.1 ml, 7.23 mmol) was added to a mixture of ethyl 3-(chloro)-6-(hydroxymethyl)benzo[b]thiophene-2-carboxylate (Preparation 15--1.63 g, 6.02 mmol) and 3-methoxybenzenethiol (1.1 ml, 9.03 mmol) in anhydrous dimethylformamide (8 ml) under a nitrogen atmosphere. The solution was stirred at ambient temperature for 18 hours, and then heated to 60° C. for 3 hours. The solution was partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was crystallised from diethyl ether and hexane to give the title compound as a colourless solid (1.77 g).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[O:9].[CH2:18]([O:20][C:21](=[O:27])[C:22](OCC)=[O:23])[CH3:19].Cl>C1C=CC=CC=1>[Cl:17][C:12]1[CH:11]=[C:10]([C:8](=[O:9])[CH2:7][C:22](=[O:23])[C:21]([O:20][CH2:18][CH3:19])=[O:27])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)c(Cl)c1

Procedure:
To a solution of t-BuOK (0.05 mol, 5.6 g) in benzene (200 mL) was added dropwise a benzene (50 mL) solution of 3,4-dichloroacetophenone 5.1 (0.05 mol, 9.45 g) and diethyloxalate (0.055 mol, 8.1 g). The resultant mixture was stirred for 8 h at room temperature, then 10% aqueous HCl solution (100 mL) was added to the mixture. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography using dichloromethane as eluent to yield the title compound. Yield: 7.5 g (52%).
Reaction SMILES: [Br-].[Br:2][C:3]1[C:4]([NH:31][C:32](=O)[C:33]([F:36])([F:35])[F:34])=[C:5]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[C:7]([C:9]#[N:10])[CH:8]=1>CN(C=O)C>[F:34][C:33]([F:36])([F:35])[C:32]1[NH:31][C:4]2[C:5]([CH:11]=1)=[CH:6][C:7]([C:9]#[N:10])=[CH:8][C:3]=2[Br:2]
Reactant: N#Cc1cc(Br)c(NC(=O)C(F)(F)F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1
Temperature: 130 °C
Reaction time: 3 h
Yield: 36.2 %

Procedure:
({3-bromo-5-cyano-2-[(trifluoroacetyl)amino]phenyl}methyl)(triphenyl)phosphonium bromide (Intermediate 3, 37.2 g) was dissolved in DMF (150 mL) and the reaction mixture was heated to 130° C. stirring for 3 h. The reaction mixture was allowed to cool to room temperature then quenched with water (400 mL). The reaction mixture was then extracted with ethyl acetate (3×300 mL). The organic extract was washed with a 1:1 mixture of water:brine (2×600 mL), dried (MgSO4), filtered and the solvent was removed. The resulting residues were then purified by filtration through a pad of silica gel eluting with 2-10% EtOAc:isoHexane. Fractions 1 to 4 were combined and the solvent was removed to give the title compound as an off-white solid (6 g);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([OH:17])=[O:16])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl:27]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([Cl:27])(=[O:17])=[O:16])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(S(=O)O)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)Cl)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 51.9 %

Procedure:
N-(3,4-Dichlorobenzyl)-2-ethoxycarbonylindole-3-sulphinic acid (0.48 g), N-chlorosuccinimide (0.16 g) and triethylamine (0.16 ml) were stirred in dichloromethane for 4 hours. The reaction was then concentrated in vacuo and the residue purified by chromatography using iso-hexane:10% ethyl acetate as eluent to give the product as a white crystalline solid (0.27 g, 52%); NMR d (CD3SOCD3) 1.43 (t, 3H), 4.48 (q, 2H), 5.53 (s, 2H), 6.98 (m, 1H), 7.30-7.50 (m, 5H), 8.22 (m, 1H); M/z (−) 444 (M−H+), 426, 410.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CCl)nc3cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′B)-one from Step A (203 mg, 0.64 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (761 mg, 6.40 mmol) and the resulting mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted further with CH2Cl2 (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=336 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccc(Cl)cc2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 91.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.2 g) is alkylated using 1-bromomethyl-4-chloro-benzene (0.98 g; 4.77 mmol) and K2CO3 (1.8 g; 13 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated using hydrochloric acid (60 ml; 6 N) at reflux. After aqueous work-up 5-amino-1-(4-chloro-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.44 g) is obtained and used without further purification.