Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]1)[CH3:27]>CS(C)=O.CO>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CC[C@@H](N)C1
Solvent: CO
Solvent: CS(C)=O
Product: CCN1CC[C@H](Nc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 120 °C
Yield: 65.4 %

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.13 g) and (R)-1-ethylpyrrolidin-3-ylamine (Intermediate 193, 1.22 g) in DMSO (0.7 mL) was stirred and heated in a sealed vessel at 120° C. for 22 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.107 g) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=[O:7])[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[OH-].[K+]>CC(C)=O.CCO>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:2]2[CH:3]=[C:4]([C:6]([OH:8])=[O:7])[CH:5]=[N:1]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Temperature: 50 °C

Procedure:
A mixture of ethyl 1H-pyrazole-4-carboxylate (400 mg, 2.85 mmol), K2CO3 (1.97 g, 14.3 mmol) and 4-methoxybenzyl bromide (0.453 ml, 3.14 mmol) in dry acetone (10 ml) was heated to 50° C. for 3 h. The reaction mixture was filtered, and the filtrate was concentrated. EtOH (10 mL) and KOH (320 mg, 5.71 mmol) were added and the mixture was heated to 65° C. for 6 h, before it was concentrated again. The crude product was dissolved in water (5 ml), washed with EA (2×10 ml) and acidified with 1N HCl. The resulting precipitate was collected by filtration, washed with water and dried in vacuo affording the title compound. LCMS RtL=0.86 min, [M+H]+=233.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=[C:15]3[NH:40][C:41](=[O:64])[C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-])=O)=[CH:44][C:43]=2[N:51]([CH:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[C:52](=[O:57])[C:53]([F:56])([F:55])[F:54])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C1CCCCC=1>O1CCOCC1.[Pd]>[NH2:48][C:45]1[CH:46]=[CH:47][C:42]([C:41]([NH:40][C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([S:9]([C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=4)(=[O:10])=[O:11])[CH:13]=3)[N:17]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]=2)=[O:64])=[C:43]([N:51]([CH:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)[C:52](=[O:57])[C:53]([F:56])([F:54])[F:55])[CH:44]=1
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: C1COCCO1
Product: Nc1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-nitro-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide (4.05 g, 4.5 mmol) in 1,4-dioxane (100 mL) was added cyclohexene (10 mL) and 10% Pd/C (405 mg). The mixture was stirred at 90° C. for 5 hours, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/n-hexane 2:1 affording the title compound as white solid (2.9 g).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH3:27])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:27][O:26][C:19]1[CH:18]=[C:17]2[C:16](=[C:25]3[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]3)[NH:15][S:12](=[O:14])(=[O:13])[C:3]1[C:4]2=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][CH:2]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2N)c2ncccc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(c3ncccc13)NS(=O)(=O)c1ccc(C(F)(F)F)cc1-2
Yield: 4.5 %

Procedure:
In a similar fashion using route 20 general procedure 61, 2-amino-N-(5-methoxy-quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide 588 (440 mg, 1.1 mmol), t-butyl nitrite (0.2 ml, 1.6 mmol), AcOH (4.4 ml) and THF (4.4 ml) gave the title compound (19 mg, 5%) after preparative HPLC (neutral conditions).
Reaction SMILES: O=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[NH:3]1.O=P(Cl)(Cl)[Cl:16]>CN(C=O)C.C(Cl)Cl>[Cl:16][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[N:3]=1
Reactant: N#Cc1ccc2[nH]c(=O)cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc2nc(Cl)cnc2c1
Temperature: 100 °C

Procedure:
2-Oxo-1,2-dihydroquinoxaline-6-carbonitrile was suspended in POCl3 (25 mL) and DMF (10 drops) was added. The mixture was heated at 100° C. for 2 h, cooled and concentrated under reduced pressure to leave a black residue. The residue was dissolved in CH2Cl2 (200 mL), washed with satd aq NaHCO3 (25 mL) and brine (25 mL) and dried over Na2SO4. Removal of the solvent left an off white solid (4.50 g). A 0.50-g portion was purified by chromatography on a 40-g silica gel cartridge eluted with a 0-50% EtOAc in hexanes gradient to afford 2-chloroquinoxaline-6-carbonitrile (118 mg). LC-MS Method 1 tR=1.42 min, m/z=190.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:14]([NH2:15])=[C:13]([CH3:19])[CH:12]=1>C(#N)C>[Br:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:14]([NH:15][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:13]([CH3:19])[CH:12]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CCCCCCC(=O)Cl
Solvent: CC#N
Product: CCCCCCC(=O)Nc1c(C)cc(Br)cc1C
Temperature: 70 °C
Yield: 32 %

Procedure:
Heptanoyl chloride (16 mg) was added to 4-bromo-2,6-dimethyl-aniline (20 mg) dissolved in acetonitrile and heated to 70° C. for 16 hours. The reaction mixture was concentrated in vacuo, redissolved in dimethyl sulfoxide/methanol (1:1, 0.5 mL) and subjected to preparative LC-MS purification to furnish 10 mg (33% yield) of the title compound as an oil. LC-MS (m/z) 313 (MH+); tR=3.33, (UV, ELSD) 93%, 100%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[C:28]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][C:14]=1[C:15]([NH:26][C:27]1[C:28]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CCCSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Product: CCCSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1

Procedure:
Using a procedure analogous to Example 1-G, 2-(3-t-butoxycarbonylaminopropoxy)-4-(propylthio)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a solid product (2.82 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].N1C=CC=CC=1.[Cl:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([CH2:20][Cl:19])[CH:22]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-5-chloro-benzoic acid methyl ester (1.5 g) was dissolved in anhydrous methylene chloride (25 ml). Pyridine (1.4 ml) and 3-(chloromethyl)benzoyl chloride (1.4 ml) were added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was then washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to precipitate crystals. The precipitated crystals were collected by filtration through Kiriyama Rohto and were washed with ether to give 5-chloro-2-(3-chloromethyl-benzoylamino)-benzoic acid methyl ester as a useful intermediate (2.4 g, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][C:26]([OH:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH:10]([CH2:12][O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][C:26]([OH:35])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)[C:10](=[O:11])[CH2:12][O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=O)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 12 h
Yield: 75.1 %

Procedure:
Treat a solution of the alcohol from Step 1 (21.5 g, 39.8 mmol) in CH2Cl2 (600 mL) with PDC (22.5 g, 59.9 mmol). Stir the resulting black mixture for 12 h. Filter the reaction mixture through a plug of celite and wash plug with CH2Cl2 (200 mL) and EtOAc (200 mL). Concentrate the filtrate under reduced pressure to give the crude product as a black oil. Purify by silica gel chromatography (column: 10 cm×24 cm; pack column in CH2Cl2 and elute using a gradient of 100% CH2 Cl2 to 5% CH3OH(NH3)/CH2Cl2) to obtain 16 g (29.9 mmol, 75%) of the title compound as a tan foam.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(C1C[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([CH:2]1[CH2:1][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[CH2:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C=O)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
n-Butyl lithium (2.5M solution in hexane, 4.0 mL, 10 mmol) was added to a suspension of methyltriphenylphosphonium bromide (4.19 g, 11.7 mmol) in THF (100 mL) at −78° C. After 10 min., the reaction mixture was allowed to warm to rt. After 1 h, the reaction mixture was cooled to −78° C., and a solution of 1-benzyl 4-tert-butyl 2-formylpiperazine-1,4-dicarboxylate (3.07 g, 8.81 mmol) in THF (10 mL) was added dropwise. After 2 h, the reaction mixture was allowed to warm to rt and was quenched with NH4Cl (saturated, aqueous solution). The reaction mixture was diluted with water (100 mL) and was extracted with EtOAc (3×150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (0 to 20% EtOAc in Hexane gradient) gave 2.33 g (76%) of the desired product as a thick oil. Rf=0.35 in 30% EtOAc/Hexane. LC-MS: RT=10.1 min., [M+H]+=369.1.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[Br:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:2][CH2:3][CH2:4][O:5][CH3:6])[CH:9]=1
Reactant: COCCCI
Reactant: O=c1cc(Br)cc[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COCCCOc1cc(Br)ccn1
Temperature: 45 °C

Procedure:
11 mmol of silver carbonate and 20 mmol of 1-iodo-3-methoxypropane [61542-10-7] are added under an argon atmosphere to a solution of 21 mmol of 4-bromo-1H-pyridin-2-one [36953-37-4] in 30 ml of benzene. The reaction mixture is heated to 45° C. with exclusion of light for 2 days. The mixture is cooled to room temperature and filtered through Hyflo. The filtercake is washed with benzene and with saturated aqueous sodium hydrogencarbonate solution. The phases of the filtrate are separated and the aqueous phase is extracted with dichloromethane (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value by means of flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:2]=[CH2:3].[CH3:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)[NH2:26]>>[CH3:22][C:23]1[CH:24]=[C:25]([NH:26][C:8]2[N:7]=[C:6]3[N:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]3=[CH:10][N:9]=2)[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1ccccn1
Reactant: Cc1cc(N)ccc1N1CCN(C)CC1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)c(C)c3)nc2n1-c1ccccn1

Procedure:
17.0 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 29-1 was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[OH-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([N:17]=[C:18]=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>O>[CH3:2][N:1]([CH2:3][C:4]([OH:6])=[O:5])[C:18]([NH:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1)=[O:19]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(CC(=O)O)C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
To a stirred solution of 89 g. of sarcosine in 300 ml. of water containing 60 g. of sodium hydroxide were added portion-wise over thirty minutes 188 g. of 3,4-dichlorophenyl isocyanate. The reaction mixture was stirred for thirty minutes following the addition, and then was filtered. The filtrate was acidified with concentrated hydrochloric acid, whereupon a white solid precipitated. The solid was collected by filtration and air dried to give 1-methyl-1-(hydroxycarbonylmethyl)-3-(3,4-dichlorophenyl) urea. M.P. 103°-105° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[C:17](OC)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH3:20])[C:17](=[O:21])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: C=C(C)C(=O)OC
Reactant: COc1ccc2[nH]c3ccc(Br)cc3c2c1
Solvent: C1CCOC1
Product: COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
3-bromo-6-methoxycarbazole (20 g) produced in Example 1, step 1 was dissolved in anhydrous tetrahydrofuran (200 ml), and to the solution were added methyl methacrylate (77.6 ml), then Triton B (0.7 ml). The mixture was heated under reflux in an argon atmosphere for 2 hours, and the solvent was evaporated under reduced pressure. The resulting residue was suspended in methanol (60 ml), and sodium hydroxide (6.4 g) dissolved in water (80 ml) was added dropwise at room temperature, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and water and ether were added for phase separation. The aqueous layer was rendered acidic by addition of 4N hydrochloric acid, and ethyl acetate was added for further phase separation. The ethyl acetate layer was washed with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residual crude crystals were washed with hexane and ether and recovered by filtration to obtain the title compound (25.0 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:17][CH:18]1[CH2:22][CH2:21][O:20][C:19]1=[O:23].C[Al](C)C>ClCCCl>[Br:17][CH:18]([CH2:22][CH2:21][OH:20])[C:19]([NH:16][C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]=1[CH:13]([CH3:14])[CH3:15])=[O:23]
Reactant: O=C1OCCC1Br
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: CC(C)c1c(NC(=O)C(Br)CCO)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (1.0 g, 4.54 mmol), 3-bromotetrahydrofuran-2-one (0.462 mL, 5.0 mmol) and AlMe3 (3.4 mL, 6.8 mmol, 2 M in toluene) in DCE (50 mL) was stirred for 2 hrs at rt followed by 45 min at 50° C. The mixture was then cooled to room temperature, quenched with 1N HCl (50 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜100% EtOAc/CH2Cl2 gradient elution) to give 2-bromo-N-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]-4-hydroxy-butanamide (1.38 g, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[CH:21][N:22]([CH3:24])C)#N>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:11]3[C:12](=[CH:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=3)[N:20]=[CH:21][N:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Reactant: Nc1cccc(Br)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 148 °C

Procedure:
A solution of 23.74 ml of 3-bromo aniline and 40.5 g N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine in 100 ml of glacial acetic acid was stirred and heated in an oil bath at 148° C. for 1.5 hours. On cooling, filtration of the resulting solid gives a quantitative yield of N-(3-bromophenyl)-6-nitro4-quinazolinamine: mp=267-270° C.; mass spectrum (m/e): 345.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=1>>[Cl:37][C:35]1[CH:36]=[C:31]([CH2:30][CH2:29][NH:28][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:32]=[C:33]([Cl:39])[C:34]=1[OH:38]
Reactant: NCCc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: Oc1c(Cl)cc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)cc1Cl

Procedure:
Intermediate 7 was coupled with 4-(2-Amino-ethyl)-2,6-dichloro-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 458. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 7.05-7.6 (m, 6H) 7.0 (m, 1H) 4.95 (m, 1H) 3.6-4.0 (m, 3H) 3.4 (m, 2H) 3.1-3.2 (m, 2H) 2.8-2.95 (m, 2H) 2.25 (m, 3H) 1.7 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:21])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].Cl.[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([O:21][C:10]1[C:11]2[O:12][C@H:13]3[C:14](=[O:15])[CH2:16][CH2:17][C@@H:18]4[C@@:5]53[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]4[CH2:20][C:7]([C:6]=25)=[CH:8][CH:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC[C@]23c4c5ccc(OCc6ccccc6)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.1 %

Procedure:
To Hydromorphone HCl (50.0 g, 155.3 mmol) in dimethylformamide (500 mL) was added sodium hydride (14.30 g, 357.4 mmol) portionwise with cooling. The addition was conducted over 25 minutes. The reaction was stirred at room temperature for 1.5 hours before the addition of benzyl chloride (17.88 mL, 357.4 mmol) over 10 minutes with cooling. The reaction was allowed to warm to room temperature and stirred for 40 hours. The reaction was incomplete so additional benzyl chloride (1.79 mL, 15.5 mmol) was added. After 4 hours, the reaction was quenched with water (60 mL), acidified with aqueous HCl (2M, 800 mL) and washed with ethyl acetate/diethyl ether (3:1) (2×800 mL). The aqueous phase was basified with aqueous NaOH (2M, 800 mL) and extracted with ethyl acetate (2×1 L). The organic phases were combined, washed with water/brine (1:1) (2×800 mL) and dried over MgSO4 before concentration under reduced pressure. The residue was taken up in ethyl acetate and washed with water/brine (2×500 mL), dried over MgSO4 before concentration under reduced pressure to give (4R,4aR,7aR,12bS)-9-(benzyloxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (47.9 g, 95% pure by NMR, 82% yield); [M+H]+ 376.2. This was taken onto the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(I)cc1
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Product: Cc1cc(SCC#Cc2ccc(F)cc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-fluoro-4-iodo-benzene gave the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>CS(C)=O.O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 533.4 %

Procedure:
Piperidine (362 mg, 0.2 mmol) was added to a solution of 1-fluoro-4-nitro-benzene (200 mg, 1.4 mmol) in DMSO (10 mL) and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 220 mg (75%) of 1-(4-nitro-phenyl)-piperidine.