Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CS(C)=O>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Nc1ccccc1Cl
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: O=c1c(Nc2ccccc2O)c(Nc2ccccc2Cl)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-chloroaniline (0.023 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 315 (M+).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)[CH3:2].[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:18]=1[NH2:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:19][C:18]1[C:17]([Cl:16])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:24])[CH3:2]
Reactant: CCN(CC)C(=O)Cc1ccccc1I
Reactant: Nc1c(Cl)cccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCN(CC)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Yield: 81.8 %

Procedure:
A mixture of 6.0 g (0.019 mole) of N,N-diethyl(o-iodophenyl)acetamide, 3.38 g (0.021 mole) of 2,6-dichloroaniline, 2.93 g (0.021 mole) of anhydrous potassium carbonate, 1.0 g of copper powder and 1.0 g of cuprous iodide was reacted in 85 ml of xylene for 24 hours to obtain 5.46 g of a colorless needle having a melting point of 99° to 101° C. The yield was 81.4%.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:19])=[C:3](/[C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:20](OCC)(OCC)OCC.C(OC(=O)C)(=O)C>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]2[C:9](=[O:18])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:19])[N:1]=[CH:20]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)/C(C(=O)Nc1ccc(Cl)cc1)=C(/C)N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(C)ncn(-c2ccc(Cl)cc2)c1=O
Yield: 87.3 %

Procedure:
To a 2-l. three-necked flask are charged 250 g (0.88 mole) of ethyl 3-amino-2-(4-chlorophenylcarbamoyl)crotonate, 523 g. (3.54 moles) of triethyl orthoformate and 135 g (1.32 moles) of acetic anhydride. While stirring, reflux is initiated causing all solid to dissolve. After 15 to 16 hours at reflux, lower boiling liquid is distilled off (up to a head temperature of 90°-95° C.) and the dark reaction solution is subjected to rotary evaporation. Addition of the viscous residue to 4 l. of hot hexane with continued heating and agitation effects solidification. There is obtained 225 g (87%) of ethyl 1-(4-chlorophenyl)-1,6-dihydro-4-methyl-6-oxopyrimidine-5-carboxylate as a brown solid, m.p. 98°-100° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:25][N:26](CC)CC.ClC(OCC(C)C)=O.Cl.CN>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:21]([NH:26][CH3:25])=[O:23])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of t-boc-gly-phe 7a (5.3 g, 1.6×10-2 mole) in dry THF (80 ml) under argon at -10° C. is added in turn Et3N (2.5 ml, 1.8×10-2 mole) and isobutyl chloroformate (2.4 ml, 1.8×10-2 mole). The resulting mixture is stirred at -10° C. for 10 minutes before a freshly neutrallized mixture of methylamine hydrochloride (3.3 g, 4.9×10-2 mole), Et3N (6.9 ml, 4.9×10-2 mole), THF (80 ml), and H2O (40 ml) is added in one portion. The cooling bath is then removed and the mixture allowed to warm to room temperature. After stirring overnight the reaction is quenched into saturated aqueous NaHCO3. The aqueous alkaline mixture is extracted with Et2O (3 times) and CH2Cl2 (2 times). The ethereal extracts are combined and subsequently washed with saturated aqueous NaCl as are the CH2Cl2 extracts. The ethereal and CH2Cl2 extracts are then combined and dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives a yellowish foam which when triturated with Et2O affords 8a as a colorless solid which crystallizes from aqueous ethanol as colorless matted needles, 4.1 g (74%), m.p. 158°-160° C. In a similar fashion, t-boc-gly-phe-leu-NHEt is prepared from 7a and leucine ethylamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:30]1[CH:31]=[C:32]([C:35]([F:37])([F:38])[F:36])[CH:33]=[CH:34][C:29]=1[F:28])=[CH:13][CH:12]=[C:11]([C:24]([F:25])([F:26])[F:27])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C(F)(F)F)ccc1F

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 2-fluoro-5-trifluoromethylphenylboronic acid (142 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(2-fluoro-5-trifluoromethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a slight yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[Cl:24]>N1C=CC=CC=1>[Cl:24][C:20]1[C:19]2[C:23](=[C:15]([NH:14][S:2]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:16]=[CH:17][CH:18]=2)[NH:22][CH:21]=1
Reactant: Nc1cccc2c(Cl)c[nH]c12
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2cccc3c(Cl)c[nH]c23)cc1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
2.82 g (12.8 mmol) of 4-(chlorosulfonyl)benzoic acid and 1.42 g (8.54 mmol) of 7-amino-3-chloro-1H-indole were reacted with each other in pyridine at room temperature under stirring overnight, to give 2.33 g of 4-[N-(3-chloro-1H-indole-7-yl)sulfamoyl]benzoic acid. To 303 mg (0.86 mmol) of the product were successively added 260 μl of dimethylformamide, 204 μl (0.95 mmol) of diphenylphosphorylazide, 132 μl (0.95 mmol) of triethylamine and 113 μl (0.94 mmol) of 2-(2-aminoethyl)pyridine, followed by stirring at room temperature overnight. After concentrating, ethyl acetate and an aqueous saturated sodium bicarbonate were added thereto. The organic layer was separated and washed with brine. After evaporating the solvent, the residue was purified by silica gel column chromatography, to give 175 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1B(O)O)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:28])[CH3:27]
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOC[C@H]4C)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 36.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 248b (364 mg, 1.0 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (596 mg, 1.5 mmol), K3PO4 (424 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (73 mg, 0.10 mmol), sodium acetate (164 mg, 2.0 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 2.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 50:1) to afford 248c (250 mg, 37%) as yellow oil. MS-ESI: [M+H]+ 681.3
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21]C3CCCCO3)[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]>Cl.CO.CC(=O)OCC.O>[OH:1][CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:39])([F:41])[F:40])[CH:32]=1)[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)CC(O)c1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)CC(O)c1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 0.104 mmol) was dissolved in 2N HCl/MeOH (5 mL). The reaction was stirred at RT for 1 h then diluted with EA (10 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(1-hydroxy-3-methylbutyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 38.5% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.59 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.98-6.92 (m, 3H), 5.62-5.60 (m, 2H), 4.54 (t, J=5.2 Hz, 1H), 4.06-4.01 (m, 2H), 3.60 (s, 3H), 3.46-3.52 (m, 2H), 1.92-1.90 (m, 1H), 1.80-1.72 (m, 3H), 1.24-1.19 (m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H). LCMS: MH+ 498 and TR=3.186 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:15]3[CH2:16][CH2:17][C:18]4[C:23](=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=4)[CH2:14]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: N#Cc1ccc2c(c1)CNCC2
Product: N#Cc1ccc2c(c1)CN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline-7-carbonitrile to provide the title compound in moderate yield.
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]1([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:36]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)#[CH:37]>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[O:35]1)[CH3:33]
Reactant: C#Cc1ccc(C)cc1
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(c2ccc(C)cc2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was added thereto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto. Then 1-ethynyl-4-methylbenzene (174 mg, 1.5 mmol) was put thereinto, followed by stirring at 30° C. for 16 hours, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-p-methylphenyl-1,2-oxaphosphorin 2-oxide (33.2 mg, 34%) which is a title compound.
Reaction SMILES: BrCC1C=CC([N+]([O-])=O)=CC=1CBr.[N+:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][C:20](=[O:26])[NH:21]2)([O-])=O>>[NH2:14][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][C:20](=[O:26])[NH:21]2
Reactant: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Agent: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Product: Nc1cccc2c1CC(=O)N2

Procedure:
Essentially following the procedures described in Intermediate 4, but using 4-nitro-1,3-dihydro-2H-indol-2-one from Step A in place of 5-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, the title compound was obtained. MS: m/z=149(M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1)([O-])=O.[OH-].[NH4+]>O1CCCC1.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:1][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccccc1Cc1nc[nH]n1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccccc1Cc1nc[nH]n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 9.64 g of 3-(o-nitrobenzyl)-1,2,4-triazole in 150 ml of tetrahydrofurane, 220 ml of 1.3M aqueous solution of titanium trichloride is added and the mixture is stirred at room temperature for 24 hours. The mixture is cooled in an ice-water bath and concentrated ammonium hydroxide is added dropwise to bring the pH of the solution to 8; the solution is diluted further with water and extracted 4 times with methylene chloride. The combined extracts are decolorized with charcoal, dried over magnesium sulfate, evaporated to a small volume and diluted with ether to give 3-(o-aminobenzyl)-1,2,4-triazole, m.p. 134°-136°.
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=3)[CH:26]=2)(=[O:31])=[O:32])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a mixture of aqueous sodium hydrogen carbonate (10 ml) solution, 1-tert-butoxycarbonylpiperazine (1.0 g) and ethyl acetate (10 ml), was added 6-chloronaphthalene-2-sulfonylchloride (1.4 g) and the mixture was stirred at room temperature for 1 hour and extracted with dichloromethane. The extract was washed with water, dried and concentrated. The residue was crystallized from diisopropylether to give colorless crystals of 1-(tert-butoxycarbonyl)-4-(6-chloro-naphthalene-2-sulfonyl)piperazine (2.02 g).
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:32])[CH2:14][C@@H:13]1[C:33]([O:35][CH3:36])=[O:34])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:32])[CH2:14][C@@H:13]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Yield: 90.8 %

Procedure:
A solution of methyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 35) (595 mg, 1.19 mmol) in methanol (10 mL) was hydrogenated over palladium on carbon (10%, wet) at normal pressure and room temperature for 30 minutes. It was filtered through a 0.45 μm membrane, washed with methanol and the wash and filtrate were concentrated under reduced pressure to give 395 mg (91%) of the product as a colorless hard foam.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([C:12]2[C:17]3[S:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N+:16]=3[CH2:15][CH2:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].C1(S[C:33]2[S:34][C:35]3[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=3[N+:37]=2[CH2:38][CH3:39])C=CC=CC=1.N1C=CC=CC=1>C(OCC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:38]([N:37]1[C:36]2[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=2[S:34][C:33]1=[C:14]1[CH2:15][N+:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:17]=2[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:13]1)[CH3:39]
Reactant: CC[n+]1c(Sc2ccccc2)sc2ccccc21
Reactant: C1=C(c2ccccc2)c2sc3ccccc3[n+]2CC1
Agent: [I-]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCN1C(=C2C=C(c3ccccc3)c3sc4ccccc4[n+]3C2)Sc2ccccc21
Yield: 35 %

Procedure:
1,2-Dihydro-4-phenylpyrido[2,1-b]benzothiazolium perchlorate (2.0 g., 0.0055 mole), 2-phenylthio-3-ethylbenzothiazolium iodide (2.19 g., 0.0055 mole) and pyridine (30 ml.) are heated to reflux for 3 minutes, the solution is cooled, diethyl ether (30 ml.) is added and the green solution is decanted off from the oily dye. Water is added and the dye solidifies upon cooling. The solid dye is boiled out with isopropyl alcohol. The yield of dye is 1.0 g. (35% yield). The product has a melting point of 120°-128° C with an absorption maximum at 629 nm.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[C:7]([C:11]1[C:19]2[O:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]=2[CH:14]=[C:13]([NH2:22])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>CCOCC>[C:7]([C:11]1[C:19]2[O:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]=2[CH:14]=[C:13]([NH:22][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CCCN=C=O
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Solvent: CCOCC
Product: CCCNC(=O)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
Propylisocyanate (0.21 mL, 2.28 mmol) is added dropwise to a solution of (7-t-butyl-2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-amine (500 mg, 2.28 mmol) and Et2O (5 mL). A solid forms after 10 min and the reaction is quenched with H2O (10 mL) after 40 min. The reaction is extracted with Et2O (3×10 mL) and the organic layers dried (MgSO4) and evaporated to an off-white solid (650 mg). This solid is recrystallized from EtOAc to give a white solid (270 mg, 39%), mp=193°-194° C.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][C:14]1[C:19]([C:20](Cl)=[O:21])=[C:18]([F:23])[C:17]([F:24])=[C:16]([F:25])[C:15]=1[F:26].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1.O>[CH3:13][C:14]1[C:19]([C:20]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:21])=[C:18]([F:23])[C:17]([F:24])=[C:16]([F:25])[C:15]=1[F:26]
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Separately, two drops of carbon tetrachloride are added to a solution of metallic magnesium (0.56 g) in absolute ethanol (0.9 ml). When the reaction starts, a mixture of diethyl malonate (3.6 ml), absolute ethanol (1.6 ml) and anhydrous toluene (6 ml) is added dropwise below 60° C. After stirring at 60° C. for 1 hour, the reaction mixture is cooled to 0° C. and thereto a solution of 6-methyl-2,3,4,5-tetrafluorobenzoyl chloride (5.00 g) prepared above in toluene (5 ml) is added dropwise. After stirring for 30 minutes, a mixture of conc. sulfuric acid (0.4 ml) and water (6 ml) is added and the mixture is extracted with diethyl ether, and the extract is dried over magnesium sulfate and concentrated to give diethyl 6-methyl-2,3,4,5-tetrafluorobenzoylmalonate (8 g) as an yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:16]([C@@H:17]4[C@H:22]([N:23]=2)[CH2:21][CH2:20][O:19][CH2:18]4)=[CH:15][C:14]([O:24][CH2:25][CH3:26])=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:25]([O:24][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:27][CH3:28])[C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)=[N:23][C@H:22]1[C@@H:17]2[CH2:18][O:19][CH2:20][CH2:21]1)[CH3:26]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)OC)cc1)=N[C@@H]1CCOC[C@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCOC[C@H]21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 7.6 mmol of 4((4aR,10aR)-6-Ethoxy-7-methoxy-1,4,4a,10a-tetrahydro-2H-3-oxa-10-aza-phenanthren-9-yl)-benzoic acid methyl ester in 100 ml of dioxan a solution of 7.5 ml of 2 molar sodium hydroxide in water is added and the mixture is stirred for 15 h at RT. A solution of 7.5 ml of 2 molar HCl in water is added and the mixture is stirred for 30 min. After concentration under reduced pressure the solid residue is treated with 100 ml of dichloromethane. After filtering the filtrate is concentrated under reduced pressure yielding the title compound as a grayish solid residue. The title compound is stirred up with diethylether, filtered off and dried under reduced pressure yielding the title compound as white powdery solid. M.p. 203-205° C.