Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:26])[NH:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:12][N:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Reactant: COCCN
Product: COCCNC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2c(OC)cc(OC)cc12

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with 2-methoxy-ethylamine to give 92 mg of [6,8-dimethoxy-4-(2-methoxy-ethylcarbamoyl)-isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester. H1-NMR (CDCl3): δ, 8.46 (s, 1H), 7.34 (s, 1H), 6.73 (br s, 1H), 6.59 (s, 1H), 6.51 (br s, 1H), 5.03 (d, J=3.9 Hz, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 3.75 (q, J=5.1 Hz, 2H), 3.65 (t, J=5.1 Hz, 2H), 3.43 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[O:19]1[CH2:20][CH2:21][N:16]([S:2]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:17][CH2:18]1
Reactant: COC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Methyl 2-(4-chlorosulfonylphenyl)acetate (2.0 g, 8.04 mmol) was taken in dry DCM (50 mL) under argon atmosphere and cooled to 0-5° C., morpholine (0.77 mL, 8.84 mmol) followed by triethylamine (1.16 mL, 8.84 mmol) was added dropwise to the mixture at 0-5° C. Reaction mixture was then brought to room temperature and stirred for additional 2 hours. Reaction mixture was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography using 14-20% ethyl acetate in hexane as eluent to give Methyl 2-(4-morpholinosulfonylphenyl)acetate (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[B-](F)(F)(F)[F:28].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:25])([F:26])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH:17]([F:28])[CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: F[B-](F)(F)F
Reactant: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1c2ccc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)cc2CC1F
Temperature: 25 °C

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.5 g, 1.24 mmol) in acetonitrile (20 mL), was added Selectfluor® (0.52 g, 1.48 mmol) and the reaction was heated to reflux temperature for 16 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and diluted with DCM. The solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) to afford the title compound as a pale yellow semi solid (0.1 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.80 (m, 1H), 7.48 (m, 2H), 7.32 (m, 2H), 6.65 (d, J=16.0 Hz, 1H), 6.54 (dd, J=16.0, 8.0 Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H); ESIMS m/z 419.06 ([M−H]−); IR (thin film) 1728, 1114, 817 cm−1.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][OH:9].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: OCCc1ccsc1Br
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCCc1ccsc1Br
Yield: 91.4 %

Procedure:
A solution of 2-bromo-3-(2-hydroxyethyl)thiophene (40.0 g, 0.193 mol) in methylene chloride (200 ml) was cooled in ice and methoxyethoxymethyl chloride (41.9 g, 0.336 mol) was added with stirring. After several minutes N,N-diisopropylethylamine (44.3 g, 0.336 mol) was added and the solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in ether (150 ml) and water (75 ml). The ether layer was separated and was washed with saturated NaHCO3 solution and with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature to give 52.1 g of an amber liquid. TLC indicated that the product was pure and NMR confirmed the structure. Field desorption mass spectral analysis gave a molecular ion of M/Z 294. The yield was 91%.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][C:16]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:15]1=2)=O)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].B.C1COCC1.CO>C1COCC1>[CH2:1]([N:3]([CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][O:17][C:16]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:15]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])[CH3:2]
Reactant: CCN(CC(=O)N1CCOc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CCN1CCOc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A yellow solution of tert-butyl ethyl(2-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-2-oxoethyl)carbamate (8.7 g, 23.8 mmol) in anhydrous THF (50 mL) under positive argon pressure was treated with borane-THF complex (1M in THF, 47.6 mL, 47.6 mmol) to give an orange solution. The mixture was refluxed for 20 minutes. It was then cooled in an ice bath and treated dropwise with MeOH (100 mL). The solution stirred for half an hour at room temperature, and the reaction was then concentrated. The residue was subjected to flash chromatography on silica gel using 1:9 EtOAc:hexanes to give an orange solid (7.5 g, 91%). 1H-NMR (DMSO-d6) δ 7.72 (dd, J=2.7, 9.0 Hz, 1H), 7.49-7.47 (m, 1H), 6.85-6.83 (m, 1H), 4.18 (t, J=4.2 Hz, 2H), 3.59-3.53 (m, 2H), 3.37-3.36 (m, 2H), 3.20-3.18 (m, 2H), 1.47 (s, 2H), 1.30 (br s, 9H), 1.02 (t, J=6.9 Hz, 3H); ESI-MS (m/z, %): 374 (MNa+, 86), 352 (MH+, 7.8), 296 (100), 252 (87).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[NH:4][CH2:5][C:6]1[C:7](=O)[NH:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:7]1[C:6]([CH2:5][NH:4][C:3]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=2[Cl:1])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CSc1ncc(CNc2ccc(Cl)cc2Cl)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CSc1ncc(CNc2ccc(Cl)cc2Cl)c(Cl)n1
Temperature: 110 °C
Yield: 87 %

Procedure:
A solution of 1.2 g (3.8 mmol) of 5-[2,4-dichloroanilinomethyl]-2-methylthio-3H-pyrimidin-4-one in 40 ml of phosphorus oxychloride was treated with 0.6 ml (3.7 mmol) of N,N-diethylaniline and the mixture was heated at 110° C. for 1 hour, cooled and evaporated. The residue was cautiously partitioned between 40 ml of ice/water and 30 ml of diethyl ether. The aqueous phase was extracted with a further 30 ml of diethyl ether and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to give 1.1 g (87%) of 4-chloro-5-(2,4-dichloroanilinomethyl)-2-methylthiopyrimidine as an oil which slowly solidified to a white solid. [Mass spectrum (ESI) MH+ =334].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:48]=[CH:47][C:28]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C@:38]5([C:44]([OH:46])=O)[CH2:40][C@H:39]5[CH:41]5[CH2:43][CH2:42]5)=[O:36])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:61][S:62]([NH2:65])(=[O:64])=[O:63].C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:48]=[CH:47][C:28]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C@:38]5([C:44](=[O:46])[NH:65][S:62]([CH3:61])(=[O:64])=[O:63])[CH2:40][C@H:39]5[CH:41]5[CH2:42][CH2:43]5)=[O:36])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(CCCNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)N[C@]1(C(=O)O)C[C@H]1C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)[C@@]1(NC(=O)CCCNC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)C[C@H]1C1CC1
Temperature: 65 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a solution of (1S,2R)-2-(4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)butanamido)bi(cyclopropane)-2-carboxylic acid (15 mg, 0.02 mmol) in THF solution was added CDI (7.0 mg, 0.04 mmol). The mixture was heated at 65° C. for 1 hour. After cooling to room temperature, methanesulfonamide (4.2 mg, 0.04 mmol) and DBU (9.9 ul, 0.07 mmol) were added to the mixture. The reaction mixture was stirred at r.t. for 16 hours. The solvent was evaporated and the residue was purified by preparative HPLC to afford 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(4-((1S,2R)-2-(methylsulfonylcarbamoyl)bi(cyclopropan)-2-ylamino)-4-oxobutyl)benzamide (6.7 mg, 40%) as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 0.34 (m, 2H), 0.57 (q, J=9.20 Hz, 2H), 0.71-0.80 (m, 1H), 1.08-1.13 (m, 1H), 1.18 (ddd, J=9.41, 7.53, 7.40 Hz, 1H), 1.34-1.45 (m, 4H), 1.77 (dd, J=7.53, 5.02 Hz, 1H), 1.85-1.97 (m, 1H), 2.26-2.36 (m, 2H), 2.37 (m, 2H), 3.26 (s, 3H), 3.41-3.51 (m, 1H), 4.00 (s, 2H), 7.23-7.33 (m, 4H), 7.60-7.75 (m, 3H), 7.85 (m, 1H); LC-MS (Condition A), MS m/z 765.1 (M++H).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.ClC(OCC)=O.[N-:16]=[N+:17]=[N-:18].[Na+]>C1COCC1.O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:16]=[N+:17]=[N-:18])=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(=O)c1csc(Br)n1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-bromo-thiazole-4-carboxylic acid (5.33 g, 25.7 mmol) in anhydrous THF (40 mL) at 0° C., under N2, TEA (7.18 mL, 51.5 mmol) was added. After 30 min ethyl chloroformate (2.59 mL, 27.0 mmol) was added dropwise over 10 min. After 25 min a solution of NaN3 (1.76 g, 27.0 mmol) in H2O (12 mL) was added. The mixture was warmed to RT over 1 h then diluted with H2O (100 mL). The precipitate was filtered off and air dried to yield the title compound as a white amorphous solid. MS m/z: 233.2, 235.2 (M+H). Calc'd. for C4HBrN4OS-233.05.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([CH3:17])[N:8]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([C:10]4[C:9]([CH3:17])=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:16][CH:15]=4)=[O:13])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2C)CC1
Yield: 58.3 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylnicotinate (300 mg) described in Preparation Example 37 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (265 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (295 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH3:26][O:27][C:28](=[O:36])[C@H:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[NH2:30].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH:29]([NH:30][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=2)=[CH:20][CH:19]=1)[C:28]([O:27][CH3:26])=[O:36]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC(NC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[NH2:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(OCCO)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:14][CH2:15][C:16]3([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCC1(O)CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCCO
Product: OC1(CNc2ccnc3cc(Cl)ccc23)CCCCC1
Reaction time: 16 h

Procedure:
A solution of 20 g of 4,7-dichloroquinoline 20 g of 1-aminomethyl-1-cyclohexanol hydrochloride and 3 equivalents of triethylamine in 80 ml of 2-ethoxyethanol was stirred at reflux until the reaction was complete. The reaction was complete after 16 hours, and upon dilution of the reaction mixture with water (300 ml), a solid precipitated out which was isolated by filtration. Recrystallization from ethanol gave 16 g of crystalline solid with a melting point of 205°-207° C.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C@@H:24]([NH2:26])[CH3:25]>>[CH3:11][C:8]1([CH3:12])[CH2:7][O:6][C:5]2([CH2:4][CH2:3][C:2]([CH2:15][CH2:16][NH:26][C@H:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:27])[CH3:25])([OH:1])[CH2:14][CH2:13]2)[O:10][CH2:9]1
Reactant: Cc1ccccc1[C@H](C)N
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: Cc1ccccc1[C@H](C)NCCC1(O)CCC2(CC1)OCC(C)(C)CO2
Yield: 37 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-o-tolyl-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 37% of theory; LC (method 8): tR=1.16 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[CH:39]=[C:38]([NH:43][C:44](=[O:46])[CH3:45])[CH:37]=[CH:36]4)(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:48])(=[O:47])[N:20]=1.[OH-].[Na+:50]>O>[C:44]([NH:43][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:30]([NH:29][C:27]1[CH:26]=[CH:25][C:23]3[NH:24][C:19]([C:3]4[C:4](=[O:18])[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]=4[O-:1])=[N:20][S:21](=[O:48])(=[O:47])[C:22]=3[CH:28]=1)(=[O:32])=[O:31])[CH:42]=[CH:41]2)(=[O:46])[CH3:45].[Na+:50]
Reactant: CC(=O)Nc1ccc2cc(S(=O)(=O)Nc3ccc4c(c3)S(=O)(=O)N=C(C3=C(O)c5ccccc5[C@@](C)(CCC(C)C)C3=O)N4)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc2cc(S(=O)(=O)Nc3ccc4c(c3)S(=O)(=O)N=C(C3=C([O-])c5ccccc5[C@@](C)(CCC(C)C)C3=O)N4)ccc2c1
Yield: 99.9 %

Procedure:
A mixture of Example 104A (5.0 mg, 0.0072 mmol) and 0.998 M sodium hydroxide (0.0072 mL, 0.0072 mmol) in water (1 mL) was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo to give the title compound (5.1 mg, quant. yield). 1H NMR (300 MHz, DMSO-d6) δ 0.42 (m, 1H) 0.66 (t, J=6.80 Hz, 6H) 0.75 (m, 1H) 1.26 (m, 1H) 1.36 (s, 3H) 1.73 (m, 1H) 2.10 (m, 4H) 7.21 (d, J=9.93 Hz, 1H) 7.31 (m, J=8.46, 2.21 Hz, 2H) 7.38 (d, J=2.21 Hz, 1H) 7.46 (m, 2H) 7.67 (m, 2H) 8.01 (m, 3H) 8.30 (s, 1H) 8.37 (s, 1H) 10.31 (s, 1H) 10.51 (s, 1H) 15.31 (s, 1H). MS (ESI+) m/z 709.1 (M+H)+, 687.6 (M+H−Na)+, 704.1 (M−Na+NH4)+, (ESI−) m/z 707.1 (M−H)−, 685.0 (M−H−Na)−.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][C:17]([CH3:21])([OH:20])[CH:18]=[CH2:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pt].C(O)C>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[NH:15][CH2:16][C:17]([CH2:18][CH3:19])([CH3:21])[OH:20])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C=CC(C)(O)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: [Pt]
Solvent: CCO
Product: CCC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Yield: 67.4 %

Procedure:
4-[(2-Chloro-3-nitro-4-quinolinyl)amino]-3-methyl-1-butene-3-ol (10.8 g, 0.035 mole, Example 118) was combined with ethanol (300 mL) and 0.5 g 5% platinum on carbon. The mixture was hydrogenated on a Parr apparatus. The reaction mixture was filtered through celite and the filtrate was concentrated to provide an oil. The oil was purified by silica gel column chromatography. An attempt to crystallize the purified oil using ethanol and water produced an oil. The mixture was concentrated under vacuum with toluene then extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate then concentrated under vacuum to provide 6.6 g of the desired product as a solid, m.p. 99-101° C. Analysis: Calculated: %C, 60.1; %H, 6.5; %N, 15.0; Found: %C, 60.0; %H, 6.4; %N, 14.8.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[NH2:12][C:13]1[NH:17][N:16]=[CH:15][CH:14]=1>CO>[CH3:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[N:17]3[N:16]=[CH:15][CH:14]=[C:13]3[NH:12][C:2]=2[N:3]=1
Reactant: Nc1ccn[nH]1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Solvent: CO
Product: Cc1ccc2c(=O)n3nccc3[nH]c2n1
Temperature: 25 °C

Procedure:
17.1 g. of 2-chloro-6-methylpyridine-3-carboxylic acid and 16.6 g. of 5-aminopyrazole are heated together at 180°-190° for 10 minutes. The mixture is cooled to room temperature and treated with methanol. The crystalline 6-methylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is filtered off and recrystallized from dimethylformamide, yield: 11.3 g. (56%); m.p. >300°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:10][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27]
Reactant: O=Cc1cc(F)c(O)c([N+](=O)[O-])c1
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1c(F)cc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 3-fluoro-4-hydroxy-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure of alkylation of substituted 2-nitrophenols gives a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.57 Hz, 3H) 3.66 (s, 3H) 5.27 (qd, J=6.78, 1.64 Hz, 1H) 8.10-8.18 (m, 1H) 8.31-8.38 (m, 1H) 9.95 (d, J=2.02 Hz, 1H). ESI-MS: m/z 272.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[C:10](=[O:21])[CH:9]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:14](=[O:15])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:22]=[CH:23][CH:24]=[C:4]([CH2:3][C:2]([OH:1])([CH3:25])[CH3:26])[CH:5]=4)=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:35]2)[CH2:30][O:29]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
To a solution of (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (prepared as in Example 235, 0.159 g, 0.44 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.129 g, 0.65 mmol), N,N-diisopropylethylamine (0.312 g, 2.41 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.778 g, 1.76 mmol) at 0° C. The mixture was allowed to slowly warm up to room temperature and stirred for 48 h. The solvents were then concentrated in vacuo. The residue was dissolved in ethyl acetate and the mixture formed was washed with aqueous saturated ammonium chloride and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was initially purified by flash column chromatography (silica gel 10% to 100% ethyl acetate/hexanes). Then followed by reverse phase HPLC (C18, 20×150 mm column and 45-100% water/acetonitrile gradient at a flow rate of 30 mL/min) to afford (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.181 g, 76%) as a white solid: HR-ES-MS m/z calculated for C29H40N4O6 [M+H]+ 541.3021, observed 541.3017; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.05 (s, 6H), 1.24 (s, 3H), 1.29 (s, 3H), 1.36-1.64 (m, 2H), 1.63-1.80 (m, 1H), 2.67 (s, 2H), 3.73 (dd, J=8.4, 5.9 Hz, 1H), 4.00 (dd, J=8.4, 6.3 Hz, 1H), 4.03-4.14 (m, 2H), 4.17 (d, J=18.4 Hz, 1H), 4.28-4.37 (m, 1H), 4.36 (s, 1H), 4.55 (d, J=18.4 Hz, 1H), 4.82 (s, 1H), 4.87 (dd, J=10.7, 4.7 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.03-7.17 (m, 3H), 7.24-7.41 (m, 1H), 7.59 (d, J=2.1 Hz, 1H), 10.77 (s, 1H).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[S:30][C:31]([CH3:34])=[N:32][N:33]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:34][C:31]1[S:30][C:29]([NH:28][S:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][CH:4]=[C:5]3[C:16]4[C:8](=[CH:9][CH:10]=[C:11]5[C:15]=4[S:14][CH:13]=[N:12]5)[NH:7][C:6]3=[O:17])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[N:33][N:32]=1
Reactant: Cc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: Cc1nnc(NS(=O)(=O)c2ccc(NC=C3C(=O)Nc4ccc5ncsc5c43)cc2)s1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(5-methyl[1,3,4]thiadiazol-2-yl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (m, 3H), 7.6 (d, 2H), 7.1 (d, 1H); ESI-MS m/z 469 (M−H)−.