Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([F:1])[CH:3]=4)=[N:13][C:14]=23)=[O:27])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.18) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 620.3 [(M+H+]; mp 221° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH3:14])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:15][N:16]([CH2:18]N(C)C)[CH3:17].C(Cl)(=O)C>ClCCl>[CH3:15][N:16]([CH2:18][C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH3:14])[C:2]=2[Cl:1])[NH:6][CH:5]=1)[CH3:17]
Reactant: CCCOc1ccc2[nH]ccc2c1Cl
Reactant: CN(C)CN(C)C
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCCOc1ccc2[nH]cc(CN(C)C)c2c1Cl
Yield: 78.8 %

Procedure:
Treatment of 4-chloro-5-n-propyloxyindole (5.10 g, 24.3 mmol) with bis (dimethylamino)methane (BDAM) (3.34 g, 32.7 mmol) and acetyl chloride (2.57 g, 32.7 mmol) in dichloromethane by the method described in 1 (c) gave 3-dimethylaminomethyl-4-chloro-5-n-propyloxyindole (5.11 g) as a sticky solid.
Reaction SMILES: [ClH:1].[CH:2]1([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[CH:23]=[C:22]([N+:24]([O-])=O)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[O:27][CH3:28])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(O)C.[Pd]>[ClH:1].[NH2:24][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([O:27][CH3:28])=[C:14]([C:12]([NH:11][CH2:10][CH2:9][NH:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:13])[CH:23]=1
Reactant: COc1c(C(=O)NCCNC2CCCCC2)cc([N+](=O)[O-])c2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1c(C(=O)NCCNC2CCCCC2)cc(N)c2ccccc12
Yield: 85.2 %

Procedure:
A solution of N-[2-(cyclohexylamino)ethyl]-1-methoxy-4-nitro naphthalene-2-carboxamide hydrochloride (0.38 g, 0.001 m) in ethanol (100 ml) was hydrogenated at 60 psi using 5% Pd/C as catalyst for 18 hours. The catalyst was removed by filtration and the solvent removed in vacuo. The product was crystallised from ethanol/ether to give 0.3 g of 4-amino-N-[2-(cyclohexylamino)ethyl]-1-methoxy naphthalene-2-carboxamide hydrochloride, m.p. 250°-252° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([C:13]#[N:14])=[CH:5]2.[CH3:15][O-:16].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:16][CH3:15])[C:6]([C:13]#[N:14])=[CH:5]2
Reactant: N#Cc1cc2cc(Br)ccc2nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2ccc(Br)cc2cc1C#N

Procedure:
A solution of 6-bromo-2-chloro-3-cyano-quinoline (1.2 g) in methanol (30 cm3) was heated under reflux for 16 hours with sodium methoxide [made from sodium (0.116 g) and methanol (20 cm3)]. The mixture was cooled to 0° and the solid filtered to afford 6-bromo-3-cyano-2-methoxyquinoline, m.p. 172°-174°, (0.60 g).
Reaction SMILES: Cl.N1CCCC1.[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:37][CH2:38][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1
Reactant: ClCCN1CCCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCCC1
Temperature: 100 °C
Yield: 9.5 %

Procedure:
1-2-Chloroethyl)pyrrolidine hydrochloride (200 mg, 1.2 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (403 mg, 1.26 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (650 mg, 4.7 mmol) in DMF (4 ml). The mixture was heated to 100° C. and further portions of 1-(2-chloroethyl)pyrrolidine hydrochloride (800 mg in total) were added periodically over 4 hours while the reaction mixture was maintained at 100° C. The reaction was then allowed to cool and volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water, separated and the organic phase passed through phase separating paper. Column chromatography eluting with methylene chloride/methanol (95/5) gave 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (50 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:29])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH:63]1[CH2:68][CH2:67][CH:66]([N:69]2[C:77]3[C:72](=[N:73][CH:74]=[CH:75][CH:76]=3)[NH:71][C:70]2=[O:78])[CH2:65][CH2:64]1>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:63]4[CH2:64][CH2:65][CH:66]([N:69]5[C:77]6[C:72](=[N:73][CH:74]=[CH:75][CH:76]=6)[NH:71][C:70]5=[O:78])[CH2:67][CH2:68]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:29])[C:5]=2[NH:4][N:3]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
(S)-2-(1,4-dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (74 mg, 0.168 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). N,N-Diisopropylethylamine (120 μl, 0.689 mmol) was added to the mixture followed successively by TBTU (58 mg, 0.181 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (58 mg, 0.199 mmol). Reaction stirred at room temperature for 5 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (water-acetonitrile-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 71% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.86 (s, 1H) 11.55 (s, 1H) 7.90 (s, 1H) 7.84 (d, J=7.63 Hz, 0.6H) 7.59 (d, J=8.24 Hz, 0.4H) 7.33 (s, 1H) 6.84-7.06 (m, 1 H) 5.22-5.36 (m, 2H) 4.40-4.64 (m, 2H) 4.16 (t, J=14.65 Hz, 1H) 3.80-4.02 (m, 2H) 3.12-3.29(m,3H) 2.95-3.09(m, 1H) 2.84-2.96(m, 1H) 2.62-2.78(m, 1 H) 2.53-2.60 (m, 1H) 2.39-2.49 (m, 1H) 2.01-2.33 (m, 5H) 1.62-1.98 (m, 4H) 1.09-1.22 (m, 6H). High resolution MS m/e (M+H)+=639.2393.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2C(OCC2C=CC=CC=2)=O)=[N:5][N:4]=[N:3]1.Br>>[CH3:1][N:2]1[C:6]([C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][NH:8]2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1[C@H]1C[C@@H](c2cc(=O)[nH]o2)CCN1C(=O)OCc1ccccc1
Agent: Br
Product: Cn1nnnc1[C@H]1C[C@@H](c2cc(=O)[nH]o2)CCN1
Yield: 66.6 %

Procedure:
(2R,4S)-Benzyl 2-(1-methyl-1H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.231 g, 0.60 mmol) was dissolved in hydrogen bromide (33% in HOAc, 5.26 mL, 30.05 mmol) and allowed to react for 1 h. The mixture was evaporated and the residue was partitioned between water and EtOAc. The aqueous phase was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 0-10% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. The compounds were detected by UV at 220 nm. Product fractions (which contained DMSO) were collected and the acetonitrile was evaporated. The aqueous phase was freeze dried. Most of the DMSO was left so the residue was dissolved in 2 mL of MeOH and loaded onto a 2 g SCX-2 column and the column washed with MeOH. The amine was liberated by running 10 mL of 10% triethylamine in MeOH through it. The solvent was evaporated and the residue was freeze dried from water to yield 5-((2R,4S)-2-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl)isoxazol-3(2H)-one (100 mg, 67%). 1H NMR (400 MHz, dmso) δ 1.47 (dq, 1H), 1.70-1.81 (m, 1H), 1.87 (d, 1H), 2.12 (d, 1H), 2.74 (dt, 1H), 2.92-3.02 (m, 1H), 3.04-3.13 (m, 1H), 4.09 (s, 3H), 4.18 (dd, 1H), 5.78 (s, 1H). HRMS Calcd for [(2×C10H14N6O2)+H]+: 501.2435. Found: 501.2418.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:35](=[O:42])[CH:36]=[C:37]([CH2:40][OH:41])[O:38][CH:39]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:35](=[O:42])[CH:36]=[C:37]([CH2:40][OH:41])[O:38][CH:39]=1)=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: O=c1cc(CO)occ1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CO)cc1=O
Reaction time: 0.17 h
Yield: 31 %

Procedure:
4-Hydroxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (0.86 g, 3.02 mmol) was dissolved in DMF (10 mL). Cs2CO3 (0.98 g, 3.02 mmol) was added at RT and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (0.86 g, 3.02 mmol) in DMF (5 mL) was added via syringe. This mixture was stirred at 50° C. for 22 h. Water (10 mL) was added and the mixture extracted with EtOAc (2×50 mL), washed with water (3×50 mL), brine (3×50 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=90:10. 4-[5-(6-Hydroxymethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester 13 was obtained (0.43 g, 31% yield) as a pale yellow foam.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][CH:23]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[O:37])[N:7]([CH3:38])[C:6]1=[O:39])[CH:2]([CH3:4])[CH3:3].Br[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[N:42]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.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>[CH3:47][C:45]1[CH:44]=[C:43]([CH3:48])[N:42]=[C:41]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:12]3[C:13]([NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:9]4[C:10]([N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6](=[O:39])[N:7]([CH3:38])[C:8]4=[O:37])=[N:11]3)=[CH:27][CH:26]=2)[CH:46]=1
Reactant: Cc1cc(C)nc(Br)c1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc21
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: C1COCCO1
Product: Cc1cc(C)nc(-c2ccc(Cn3nc4c(c3Nc3ccccc3)c(=O)n(C)c(=O)n4CC(C)C)cc2)c1
Temperature: 100 °C

Procedure:
A mixture of 7-isobutyl-5-methyl-3-(phenylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (41 mg, 0.077 mmol), 2-bromo-4,6-dimethylpyridine (14.3 mg, 0.077), tetrakis(triphenylphosphine)palladium(0) (3 mg), and 1M NaHCO3 aqueous solution (116 uL) in dioxane (350 μL) was heated at 100° C. for 4 hours, and then cooled to room temperature. The mixture was filtered through a 0.45 μm microfilter, and then purified by a semi-preparative HPLC to give pure product as a white powder. MS (ESI) m/z 509.2 [M+H]+
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1([OH:18])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH3:2]
Reactant: CCOCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOCC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(ethoxymethyl)-4-hydroxypiperidine-1-carboxylate (9C, 1 eq.) in DCM was added TFA (10 eq.). The mixture was stirred at r.t. for 0.5 hr, when TLC showed that s.m. was consumed. The mixture was concentrated to give the crude product which was used to the next step without further purification. LC-MS: m/z 160.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O>CC(O)=O.CCO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(F)ccc1Br

Procedure:
To a solution of 1-bromo-4-fluoro-2-nitrobenzene (5.0 g, 22.7 mmol) in HOAc/EtOH (20 mL/20 mL) was added iron powder in one portion at room temperature. The mixture was bubbled with N2 for 5 min, and then refluxed for 2 hrs. Partial of the solvents were removed on rotary vacuum, then the residue was partitioned between aqueous NaOH (10N, 200 mL) and Et2O (200 mL). After separation, the organic phase was washed with H2O (50 mL), brine (50 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product, as an light tan oil (quantitative yield), which was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δppm 4.15 (s, 1 H), 6.34 (td, J=8.44, 2.77 Hz, 1 H), 6.46 (dd, J=10.20, 2.90 Hz, 1 H), 7.31 (dd, J=8.81, 5.79 Hz, 1 H); Mass spec. 189.94 (MH+), Calc. for C6H5BrFN 188.96
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[N:28][CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[N:28][CH:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnnc3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnnc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-methyl-2-[3-oxo-3-(3-pyridazin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M44) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (59 mg).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[C:27]=[O:28].Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:27]([NH:26][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:30]=4)=[O:28])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cccc(Oc5ccccc5)c4)ccc3C2=O)C(=O)N1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
TEA (0.20 g, 2.00 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.00 mmol) and 1-isocyanato-3-phenoxy-benzene (0.212 g, 1.00 mmol) in acetonitrile (10 mL) under nitrogen at RT. After 3 hrs, 1N HCl (10 mL) was added, and the mixture was stirred for 10 min. The solids were isolated by filtration, and washed with water (20 mL) and acetonitrile (10 mL). The crude product was dissolved in a minimal amount of DMF and the product was precipitated by slow addition of water (˜30 mL). The solids were collected by filtration, washed with Et2O, and dried in vacuo for 18 hrs to give the product as a white solid (422 mg, 87%): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 35/65, CH2CN/0.1% H3PO4, 3.76 min (99.3%); mp: 224-226 0C; 1H NMR (DMSO-d6) δ 1.99 (s, 4H, CH, CH3), 2.29-2.46 (m, 1H, CH), 2.55-2.66 (m, 1H, CH), 2.80-3.01 (m, 1H, CH), 4.18-4.56 (m, 4H, CH2, CH2), 5.10 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.71 (t, J=5.9 Hz, 1H, NH), 7.23-7.36 (m, 1H, Ar), 7.36-7.48 (m, 2H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.55 (s, 1H, NH), 9.75 (s, 1H, NH), 10.67-11.27 (m, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 23.82, 31.18, 42.77, 47.12, 51.56, 118.12, 119.57, 121.85, 122.91, 126.88, 130.26, 133.18, 135.70, 142.36, 144.94, 155.29, 167.67, 167.95, 170.98, 172.85; LCMS: MH+=485; Anal. Calcd. for C27H24N4O5: C, 66.93; H, 4.99; N, 11.56. Found: C, 67.03; H, 4.72; N, 11.41.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[Ca+2].[C:30](Cl)(Cl)=[S:31]>O.C(Cl)Cl>[N:13]([C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[C:30]=[S:31]
Reactant: S=C(Cl)Cl
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 42, (726 mg, 1.79 mmol) and CaCO3 (716 mg, 7.16 mmol) in H2O (2 mL) is added CCL4 (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2Cl2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue which is purified over silica (CH2Cl2) to afford 480 mg (73%) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=8.7 Hz, 2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 7.15 (d, J=0.9 Hz, 1H), 5.40-5.95 (m, 1H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.46 (dd, J=13.8 and 6.0 Hz).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CC(C)([O-])C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][N:21]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:19]=2)=[CH:14][CH:13]=1.O>CS(C)=O>[F:26][C:23]([F:24])([F:25])[C:20]1[NH:21][N:22]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:2][CH2:1][CH2:3][NH2:4])=[CH:13][CH:14]=2)[CH:19]=1
Reactant: NCCO
Reactant: Fc1ccc(-c2cc(C(F)(F)F)n[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NCCOc1ccc(-c2cc(C(F)(F)F)[nH]n2)cc1
Temperature: 65 °C
Yield: 34.3 %

Procedure:
In a flame-dried, round-bottomed flask, ethanolamine (836 mg, 13.7 mmol) was dissolved in dimethylsulfoxide (2.7 ml), and potassium tert-butoxide (95%, 1.54 g, 13.7 mmol) was added to the solution. This mixture was stirred at about 65° C. for about ten minutes, and then 5-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole (630 mg, 2.74 mmol) was added. The dark-colored solution was heated to about 85° C. for about eighteen hours, and was then allowed to cool to room temperature. Water was added, and the resulting tan-colored solid was collected by filtration. This crude product was purified by column chromatography (5% methanol/dichloromethane to 20% methanol/dichloromethane) to afford the product as a white solid (255 mg, 25% yield). LRMS ([M+H]+)=272.2.
Reaction SMILES: [F:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:13][C:12](=[O:14])[C:11](=[O:15])[CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[C:3]=1[O:18][CH3:19])([CH3:17])[CH3:16])[CH3:26]
Reactant: CCO
Reactant: COc1c(C(C)(C)CC(=O)C(=O)O)ccc(C)c1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(C)c(F)c1OC
Yield: 83.7 %

Procedure:
6.04 g (22.52 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 140 ml of ethanol, mixed with 2.5 ml of sulfuric acid, and refluxed for six hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with 300 ml of saturated sodium bicarbonate solution. It is extracted three times with ethyl acetate. The combined organic extracts are washed once with saturated sodium bicarbonate solution and once with brine. After drying, and after the desiccant is filtered off and the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 5.58 g (83.7%) of the desired compound is isolated.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[CH:4][C:3]=1[N+:23]([O-])=O.CO>C(OCC)(=O)C.[Pd]>[NH2:20][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH2:23])[CH:4]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: O=[N+]([O-])c1cc(CCCCCc2ccc(O)c([N+](=O)[O-])c2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(CCCCCc2ccc(O)c(N)c2)ccc1O
Reaction time: 4 h
Yield: 93.5 %

Procedure:
A mixture of 1,5-bis(4-hydroxy-3-nitrophenyl)pentane of Example 10 (6.6 g), ethyl acetate (150 ml), methanol (50 ml) and 300 mg of palladium/carbon (5%) was hydrogenated on a Parr hydrogenator for 4 hours. Then it was diluted with 100 ml of ethyl acetate, filtered and concentrated to give 5.1 g of an off-white solid. NMR and TLC confirmed the structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14]>>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC1(C)CCNc2ccccc21
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(C)(C)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirred solution of 15 g (0.93 mol) of 4,4-dimethyl-1,2,3,4-tetrahydroquinoline in 50 ml of pryidine, at 0° C., was added, dropwise, 14.5 g (0.185 mol) of acetyl chloride over a 30 minute period. Stirring was continued at 0° C. for 1 hour, and then the reaction mixture was poured onto 200 g of ice. The resulting mixture was extracted with ether. The combined organic extracts were washed successively with 1N hydrochloric acid and saturated sodium bicarbonate and then they were dried using magnesium sulfate. Evaporation of the ether solution in vacuo afforded 18.8 g (99% yield) of the title compound as a yellow oil.