Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13]Br.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C@H:27]([NH2:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH3:17].C(N(CC)CC)C>CN(C=O)C.CCOCC>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C@H:27]([N:33]2[CH2:13][C:5]3[C:4](=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:15])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH3:17]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 54.1 %

Procedure:
A solution of 2-bromomethyl-6-nitro-benzoic acid methyl ester (4.0 g, 14.6 mmol), (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (4.0 g, 14.6 mmol) and triethylamine (4.4 mL, 31.6 mmol) in DMF (40 mL) was heated at 80° C.-90° C. for 1 day. The solvent was removed in vacuo to give an oil. The oil was extracted with ethyl acetate (150 mL) and HCl (2N, 50 mL). The organic layer was washed with HCl (2N, 2×50 mL), water (2×50 mL), brine (2×50 mL) and dried over MgSO4. The solvent was removed in vacuo to give a yellow oil. The oil was slurried in ether (50 mL) to give a suspension. The suspension was filtered and washed with ether to give 2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-nitro-2,3-dihydro-isoindol-1-one as a yellow solid (3.43 g, 54% yield): 1H NMR (CDCl3) δ 1.5 (t, J=7 Hz, 3H, CH3), 2.99 (s, 3H, CH3), 3.69 (dd, J=5, 15 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7 Hz, 2H, CH2), 4.27 (dd, J=11, 15 Hz, 1H, CHH), 4.30 (d, J=17 Hz, 1H, NCHH), 4.54 (d, J=17 Hz, 1H, NCHH), 5.70 (dd, J=5, 10 Hz, 1H, NCH), 6.85 (d, J=8 Hz, 1H, Ar), 6.94-7.00 (m, 2H, Ar), 7.58-7.76 (m, 3H, Ar).
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=1.Cl>CS(C)=O.O>[Br:19][C:20]1[C:21](=[O:26])[N:22]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=2[CH3:12])[CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]cccc1Br
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(Br)c1=O
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
223 g (38% strength, 0.5 mol) of 2-fluoro-1,3-dimethyl-5-nitrobenzene and 138 g (1.0 mol) of potassium carbonate were introduced as initial charge in 1.95 l of DMSO and heated to 120° C. At this temperature, a solution of 100 g (87% purity, 0.5 mol) of 3-bromopyridone in DMSO was added dropwise. The reaction mixture was stirred for 3.5 h at 120° C., cooled to RT, stirred into water, rendered slightly acidic with hydrochloric acid and extracted with ethyl acetate. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with water, dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. The crude product was purified over silica gel with dichloromethane then ethyl acetate/dichloromethane=1:20. The isolated product was stirred into diethyl ether/petroleum ether=1:1.5, filtered off with suction and washed with petroleum ether. This gave 75.2 g (47%) of the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N+](CC)([O-])=[O:13].[CH2:17]1[CH2:27]CN2C(=NCCC2)CC1>C(OCC)(=O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:27](=[O:13])[CH3:17])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC[N+](=O)[O-]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
4-Fluro-3-nitrotoluene (7.5 g, 48.4 mmol) is treated with a solution of nitroethane (15.2 mL, 200 mmol) in ethyl acetate (100 mL) and DBU (21 mL, 145 mmol) and stirred overnight at ambient temperature. The solution is concentrated under vacuum, diluted with methanol, treated with 30% H2O2 (25 mL) and 10% sodium bicarbonate (25 ml) and stirred overnight at ambient temperature. The reaction mixture is concentrated in vacuo, acidified with 5% HCl and extracted with methylene chloride. The organic layer is dried (sodium sulfate) and chromatographed (35% ethyl acetate/hexane) to give the title compound (7.2 g, 40.2 mmol). MS m/z: M+=279; 1H NMR (CDCl3, 300 MHz) δ7.8 (s, 1H), 7.48 (d, 1H), 7.32 (d, 1H), 2.5 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:17][C:16]=2[C:26]([O:28]C)=[O:27])[C@H:10]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.CO>[CH:30]1([C@@H:10]2[CH2:9][NH:8][CH2:13][C:12](=[O:14])[N:11]2[C:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:17][C:16]=2[C:26]([OH:28])=[O:27])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1.[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:17][C:16]=2[C:26]([OH:28])=[O:27])[C@H:10]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CN(C(=O)OC(C)(C)C)C[C@H]1C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)[C@H](C2CCCCC2)C1
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CNC[C@H]1C1CCCCC1
Temperature: 55 °C
Yield: 108.7 %

Procedure:
To a solution of (R)-3-Cyclohexyl-4-(2-methoxycarbonyl-5-phenyl-thiophen-3-yl)-5-oxo-piperazine-1-carboxylic acid tert-butyl ester (1.8 g, 3.6 mmol) in THF/water/MeOH (1/1/1, 30 mL) was added lithium hydroxide monohydrate (0.45 g, 10.8 mmol, 3.0 equiv) and the resulting solution was heated at 55° C. for 1 hour. The reaction was quenched by addition of 1.0 N HCl aq. solution until pH=5. The solution was then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated to give (R)-4-(2-Carboxy-5-phenyl-thiophen-3-yl)-3-cyclohexyl-5-oxo-piperazine-1-carboxylic acid tert-butyl ester 3-((R)-2-Cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (1.7 g, 97%). The material was continued to the next step with no further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:30][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[O:28][CH3:29])[C:7]=2[C:6]=1[CH3:31])=[O:4].[OH-].[Na+].C1COCC1.Cl>O.CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:31])=[C:5]([C:3]([OH:4])=[O:2])[S:30][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[O:28][CH3:29])[CH:16]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCC[C@H]3OC)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.75 g 4-[4-fluoro-2-((1R,2R)-2-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester, 4M sodium hydroxide solution, 20 ml THF and 20 ml MeOH was stirred at rt overnight. The reaction mixture was acidified by addition of hydrochloric acid, diluted with 80 ml water and filtered. The solid was washed with water and dried in vacuo at 65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][S:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([S:22][CH3:21])=[CH:24][CH:25]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CSc1ccc(N)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CSc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 4-(methylthio)aniline (72.0 mg, 0.51 mmol). The title compound was obtained as a solid (28.0 mg, 15% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.53 br), 9.00 (2H, s), 8.74 (1H, m), 7.62 (2H, m), 7.28 (2H, m). MS m/z: 470.13, 472.11 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6](=O)[C:7]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:8]=2[N:9]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:35]>C(Cl)(Cl)Cl>[Cl:35][C:6]1[C:7]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:8]=2[N:9]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=1
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: COCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Reflux a mixture of 2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one (0.500 g, 1.49 mmol), 2,6-lutidine (0.69 mL), and POCl3 (0.555 mL) in CHCl3 (10 mL) for 5 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (MgSO4) and concentrate under reduced pressure. Purified the crude by flash column chromatography on a silica gel (EtOAc eluent) and concentrate under reduced pressure to give 4-chloro-2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine as a white solid.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH2:12][SiH:13]([Cl:15])[Cl:14])[Cl:11].C1C=CC=CC=1>O1CCCC1>[Cl:9][Si:10]([Cl:11])([CH2:12][SiH:13]([Cl:15])[Cl:14])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Reactant: C#Cc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Cl[SiH](Cl)C[Si](Cl)(Cl)C=Cc1ccccc1
Reaction time: 8 h
Yield: 27.3 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)methane in the presence of H2PtCl6 /THF. Into the same apparatus as described in Example 1 were added 1 g of bis(dichlorosilyl)methane, 20 μl of 0.1 M H2PtCl6 in THF (tetrahydrofuran) solution, and 20 ml of dried benzene. The flask content was heated to reflux and 0.52 ml of phenylacetylene was added over a ten minute period. The flask content was refluxed, with stirring, for another 8 hours and then the solvent removed at atmospheric pressure. The products were vacuum distilled at 67 Pa to give a mixture comprising 1.66 g of 3,3,5,5-tetrachloro-1-phenyl-3,5-disilapenta-1-ene (TCD-GC area 27.3%) and 3,3,5,5-tetrachloro-1,7-diphenyl-3,5-disilahepta-1,6-diene (TCD-GC area 26.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:31])[CH:17]([NH2:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:26][CH2:27][CH2:28][N:29]=2)=[CH:21][CH:20]=1>>[CH3:14][O:15][C:16](=[O:31])[CH:17]([NH:30][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][CH2:28][CH2:27][N:26]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)C(N)Cc1ccc(C2=NCCN2)cc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: COC(=O)C(Cc1ccc(C2=NCCN2)cc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-propionic acid methyl ester.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][C:14]=2[CH:23]2[CH2:25][CH2:24]2)[C:8]2[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:7]=2[NH:6][C@H:5]1[CH3:32].[C:33]([N:40]([CH3:46])[C@H:41]([C:43](O)=[O:44])[CH3:42])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:30]([C:28]1[CH:27]=[CH:26][C:8]2[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][C:14]=3[CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:11])[C@@H:4]([NH:3][C:43](=[O:44])[C@@H:41]([N:40]([CH3:46])[C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:42])[C@H:5]([CH3:32])[NH:6][C:7]=2[CH:29]=1)#[N:31]
Reactant: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1N
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a rt solution of (3S,4S)-3-amino-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile dihydrochloride (126 mg, 268 μmol) in DMF (893 μl) was added Boc-N-methyl-L-alanine (59.9 mg, 295 μmol), N,N-diisopropylethylamine (232 μl, 1.34 mmol), and HBTU (112 mg, 295 μmol). The reaction was stirred at rt for 1 h, then diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (144 mg, 92%) as a white solid. MS m/z 583 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:4][CH:3]=1.[CH3:43][Si](C)(C)N[Si](C)(C)C.[K].IC.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH:17]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH3:43])=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:41][CH:42]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC(C)c3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl methoxy) indol-2-yl]-2,2-dimethylpropanoate (420 mg) (EP 419,049, Ex. 1, Step D) in THF (10 mL) at -78° C. was added 0.6M potassium hexamethyldisilazane in toluene (1.75 mL) and stirred at -78° C. for 5 min. Then iodomethane (87 ml) was added followed 15 min later by more 0.6M KHMDS in toluene (1.75 mL). The mixture was finally stirred at -78° C. for 30 min. The reaction mixture was poured into 25% NH4OAc (100 mL), extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), and dried (MgSO4). The filtrate was evaporated to dryness and the residue was chromatographed on flash silica gel using ethyl acetate:hexane (15:85) as eluant to give the title product as a foam.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[C:29]1([S:39](Cl)(=[O:41])=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>N.CO>[C:29]1([S:39]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:41])=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cccc2ccccc12)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Naphthalene-1-sulfonyl chloride (23 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.5 mg). MS m/z 379 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=2)[CH2:23][CH2:22]1.S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:33][C:30]2[CH:31]=[CH:32][C:27]([N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)=[CH:28][C:29]=2[N:34]=1)([O-:3])=[O:2]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Reactant: Nc1ccc(N2CCOCC2)cc1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (214 mg, 0.777 mmol) and 4-morpholinobenzene-1,2-diamine (150 mg, 0.777 mmol) were dissolved in dry THF (10 mL), and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR: (400 MHz, DMSO-d6): δ 9.49 (d, 1H, J=2.0 Hz), 8.41 (dd, 1H, J=2.0 and 9.2 Hz), 8.00 (d, 1H, J=9.2 Hz), 7.71 (m, 1H), 7.12 (m, 2H), 6.05 (dd, 1H, J=2.4 and 9.2 Hz), 4.75 (dd, 1H, J=2.4 and 6.8 Hz), 4.05 (m, 1H), 3.89 (m, 4H), 3.63 (m, 1H), 3.54-3.47 (m, 1H), 3.22 (m, 4H), 2.21 (m, 2H), 1.87 (m, 1H), 1.73 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:18][C:17]3[C:16]4[N:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:20])([CH3:19])[C:7]=2[CH:21]=1.Cl([O-])=[O:23].[Na+].ON1C(=O)C2=CC=CC=C2C1=O>CC#N.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:23])[C:17]3[C:16]4[N:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:19])([CH3:20])[C:7]=2[CH:21]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc2c(c1)C(C)(C)c1oc3cccnc3c1C2
Agent: O=C1c2ccccc2C(=O)N1O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)c1oc3cccnc3c1C2=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-4-aza-benzo[b]fluorene (Compound GT15-3, 22 mg) was dissolved in MeCN (0.26 ml) and water (0.13 ml), added with sodium chlorite (14 mg) and N-hydroxyphthalimide (2.6 mg), and the mixture was stirred at 40° C. for 1 hr. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (16 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.FC(F)(F)S(O[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[C:28]3=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]3[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][C:20]([C@H:23]3[C:28]4=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]4[CH2:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(-c4ccc(Cl)cc4)cc3)C2=N1
Temperature: 50 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (16.0 mg) was added to a mixture of (4-chlorophenyl)boronic acid (76.0 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenyl trifluoromethanesulfonate (100 mg) and sodium carbonate (51.4 mg) in EtOH (3 mL), water (1.5 mL) and DMF (dry) (2 mL). The mixture was stirred at 50° C. under nitrogen for 16 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and crystallized from MeCN-THF/IPE to give the title compound (26.7 mg) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH3:14])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:25])[CH2:23]O)[CH2:17][CH2:16]1.COCCN(S(F)(F)[F:38])CCOC>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH3:14])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:25])[CH2:23][F:38])[CH2:17][CH2:16]1
Reactant: CC(CO)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(C)C3)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(CF)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(C)C3)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (RS)-trans-2-[4-(8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl)-cyclohexyloxy]-propan-1-ol (0.055 g, 0.14 mmol) in dichloromethane (2 ml) was added [bis(2-methoxyethyl)-amino]sulfur trifluoride (0.031 ml, 0.17 mmol) at 0-5° C. Stirring at room temperature for 18 h was followed by addition of further [bis(2-methoxyethyl)-amino]sulfur trifluoride (0.016 ml, 0.08 mmol) and stirring for 4 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (30 ml) and ethyl acetate (30 ml). The layers were separated and the aqueous layer was extracted with two 30-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.020 g, 36%) as white solid. MS m/e: 393 (M+H+).