Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:23].[C:24](OC)(OC)(OC)[CH2:25][CH2:26][CH2:27][CH3:28].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:25]([C:24]1[N:6]([CH2:5][CH2:4][CH2:3][S:2][CH3:1])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:23]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCC(OC)(OC)OC
Reactant: CSCCCNc1c(N)cnc2cc(-c3ccccc3)ccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCSC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
N4-(3-Methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine (2.75 g, 8.49 mmol), trimethyl orthovalerate (1.7 g, 10 mmol), and pyridine hydrochloride (0.3 g) were dissolved in toluene (28 mL) and heated to reflux for 1.5 h, collecting the volatiles in a Dean-Stark trap. Upon cooling to room temperature, the solvent was removed under vacuum. The resulting solid was slurried in hexanes (100 mL) for 1 h and then collected by filtration to afford 3.0 g of 2-butyl-1-(3-methylsulfanylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:23][CH:24]([CH3:26])[CH3:25])[C:21]=1[Cl:22])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([CH3:18])[CH:9]=1)=[O:6]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:23][CH:24]([CH3:26])[CH3:25])[C:21]=1[Cl:22])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:18])[CH:9]=1)=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)c(OC(C)C)c2)cc1C
Solvent: CO
Product: Cc1cc(NC(=O)c2cc(Cl)c(Cl)c(OC(C)C)c2)ccc1C(=O)O
Temperature: 40 °C
Reaction time: 20 h
Yield: 42 %

Procedure:
4-(3,4-Dichloro-5-isopropoxybenzamido)-2-methylbenzoic acid (AAA-113) (85 mg, 41%) was prepared from methyl 4-(3,4-dichloro-5-isopropoxybenzamido)-2-methylbenzoate (10) (210 mg, 0.530 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that MeOH was added dropwise to obtain a solution and the mixture was stirred at 40° C. for 20 h: m/z 380 [M−H]− (ES−), 1H NMR (400 MHz, DMSO-d6) δ: 12.66 (1H, br s), 10.48 (1H, s), 7.88 (1H, d), 7.81 (1H, d), 7.75-7.66 (2H, m), 7.64 (1H, d), 4.86 (1H, sep), 2.54 (3H, s), 1.35 (6H, d).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:12][NH2:13])=[O:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].S(O)(O)(=O)=O.CS[C:21](=[NH:23])[NH2:22]>CS(C)=O>[C:21]([NH:13][NH:12][C:10]([C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)=[O:11])(=[NH:22])[NH2:23]
Reactant: N=C(N)Nc1nc(C(=O)NN)cs1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Product: N=C(N)NNC(=O)c1csc(NC(=N)N)n1

Procedure:
17.9 g (0.089 mol) of 2 guanidino-4-thiazole carboxylic acid hydrazide was combined with 24.9 g of 2-methyl-2-thiopseudourea sulfate (0.089 mol) and heated rapidly to reflux in 125 ml dimethylsulfoxide. The reactants dissolved and within 5 minutes reflux a heavy precipitate formed. Reflux was continued for a total of 30 minutes. The reaction was cooled and the resulting heavy precipitate was isolated by filtration and washed with a small portion of dimethylsulfoxide followed by washing with isopropyl alcohol and ether. The resulting solid was dried in vacuo to give 34.6 g of 2-guanidino-4-thiazole carboxylic acid 2-amidinohydrazide containing some occluded dimethylsulfoxide.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([CH3:16])[CH:9]=[C:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:5]2=[N:4][C:3]=1[CH3:17].[CH3:18][N:19]1[C:23]([CH3:24])=[C:22](B(O)O)[C:21]([CH3:28])=[N:20]1.C([O-])([O-])=O.[Na+].[Na+].C(COC)OC>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.O.C(O)C>[CH2:12]([CH:11]([C:10]1[C:5]2[N:6]([C:2]([C:22]3[C:21]([CH3:28])=[N:20][N:19]([CH3:18])[C:23]=3[CH3:24])=[C:3]([CH3:17])[N:4]=2)[N:7]=[C:8]([CH3:16])[CH:9]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1nn(C)c(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nn(C)c3C)c(C)nc12
Yield: 6.4 %

Procedure:
3-Iodo-2,6-dimethyl-8-(1-ethyl-propyl)-imidazo[1,2-b]pyridazine (200 mg, 0.582 mmol), 1,3,5-trimethylpyrazole-4-boronic acid (233 mg, 1.53 mmol), Pd(PPh3)4 (13.4 mg, 0.01 mmol) are combined in a microwave pressure tube. Then 0.58 ml of 2N Na2CO3 and 3.0 ml of dimethoxyethane/H20/ethanol (7:3:2) solution is added. The mixture is microwaved at 155° C. for 20 minutes. Water is added and the mixture is extracted four times with ethyl acetate. The combined organics are dried over MgSO4, filtered, then evaporated to a residue which is chromatographed using hexanes, then 1:1 hexanes:ethyl acetate, then 100% ethyl acetate to give the title compound (6.4%) as a yellow oil. 1H-NMR (DMSO-d6): δ6.86 (s, 1H); 3.73 (s, 3H); 3.06-3.10 (m, 1H); 2.41 (s, 3H); 2.22 (s, 3H); 2.03 (s, 3H); 1.93 (s, 3H); 1.74-1.83 (m, 4H); 0.77 (t, J=7.26 Hz, 6H) ppm. MS/ES+=327 (100%, M+2).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2cnn3c(=O)[nH]nc3c2Cl)cc1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc3c2Cl)cc1
Temperature: 55 °C
Yield: 59.6 %

Procedure:
To a stirring suspension of 8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (2.2 g, 8.4 mmol) and 5-(chloromethyl)-2-(trifluoromethyl)pyridine (2.1 g, 11 mmol) in DMF (15 mL) at room temperature under argon was added K2CO3 (1.74 g, 12.6 mmol). The resulting mixture was heated at 55° C. for 2 h. HPLC/MS analysis indicated complete reaction. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (10 mL×2) to obtain a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes/EtOAc/CH2Cl2. Desired product (2.1 g) was obtained as a brown solid. Washing with MeOH (10 mL×2) and drying provided pure title compound, 8-chloro-7-p-tolyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (1.76 g, 56%) as a light yellow solid. MS [M+H]+ 420; HPLC retention time=3.53 min; 1HNMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.13 (s, 1H), 8.00 (d, 1H), 7.70 (d, 1H), 7.30-7.50 (m, 4H), 5.36 (s, 2H), 2.45 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]3[CH:43]=[CH:44][CH:45]=[N:46][C:39]=3[N:38]=[C:37]2[C@H:47]([NH:49][CH2:50][CH2:51][C:52](=[O:54])[CH3:53])[CH3:48])=[CH:32][CH:31]=1)[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]3[CH:43]=[CH:44][CH:45]=[N:46][C:39]=3[N:38]=[C:37]2[C@H:47]([N:49]([CH2:50][CH2:51][C:52](=[O:54])[CH3:53])[C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=2)[CH3:48])=[CH:32][CH:31]=1)[CH3:28]
Reactant: CCOc1ccc(-n2c([C@@H](C)NCCC(C)=O)nc3ncccc3c2=O)cc1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)=O)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
4-fluoro-3-trifluoromethylphenylacetic acid (707 mg, 3.18 mmol) was dissolved in dichloromethane and cooled to 0° C. Oxalyl chloride (278 μL, 3.18 mmol) was added, then after 5 min, dimethylformamide (24.7 μL, 0.32 mmol) was added. The reaction stirred at 0° C. for 30 min and room temperature for 1 h. The solution was added slowly to a mixture of E2 (713 mg, 1.87 mmol) and triethylamine (784 μL, 5.62 mmol) in dichloromethane at −78° C. The reaction stirred for 30 min, then was washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, concentrated in vacuo. Purified by column (2% to 10% methanol in dichloromethane), to yield 859 mg of E3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[CH3:25][S:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([S:26][CH3:25])[CH:28]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: CSc1cccc(N)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(SC)c3)c2cc1OC
Yield: 38.2 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 167.1 mg (1.2 mmol) of 3-(methylthio)aniline to give 134.1 mg (38.2%) of the product as an off white solid, m.p.>250° C., mass (electrospray, m/e): M+H 351.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](OCC)=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1.OC1C=C2C(C=C(C(OCC)=O)C=N2)=NC=1.C([O-])([O-])=O.[Cs+].[Cs+].FC1C=C(C=CC=1F)CBr>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][OH:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1
Reactant: CCOC(=O)c1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Agent: CCOC(=O)c1cnc2cc(O)cnc2c1
Agent: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: OCc1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
Ethyl 7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate. To a solution of ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate (Intermediate 4, 1.0 g, 4.5 mmol) in DMF (20 mL) was added Cs2CO3 (2.2 g, 6.75 mmol), followed by 3,4-difluorobenzyl bromide (0.682 mL, 5.02 mmol). The reaction was stirred at ambient temperature for 72 h. The crude reaction mixture was poured into EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic fractions were washed with brine and concentrated under reduced pressure onto silica. Purification (FCC, SiO2, 0-60%, EtOAc/hexanes) afforded the title compound as a white solid (1.05 g, 64%) 1H NMR (400 MHz, CDCl3) δ 9.48-9.41 (m, 1H), 8.97 (s, 1H), 8.89-8.82 (m, 1H), 7.69 (s, 1H), 7.37-7.29 (m, 1H), 7.25-7.19 (m, 2H), 5.20 (s, 2H), 4.54-4.40 (m, 2H), 1.51-1.41 (m, 3H). [M+H]=345.2.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[NH:4][N:3]=1.IC.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[N:4]([CH3:12])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(N)n[nH]c1N
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1nc(N)c(C#N)c1N
Yield: 16.2 %

Procedure:
3,5-Diamino-4-cyanopyrazole (6.1 g) prepared as in Example 3, iodomethane (3.1 ml), anhydrous potassium carbonate (7.6 g) and acetone (120 ml) were heated under reflux for 18 hours. The mixture was filtered, and the filtrate was concentrated to a viscous oil. Trituration of the oil with water gave a precipitate of 3,5-diamino-4-cyano-1-methylpyrazole (1.1 g), m.p. 194°-196° C.
Reaction SMILES: [Si]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[CH:27]/[S:28]([NH:31][C@H:32]2[CH2:36][CH2:35][N:34]([C@@H:37]([CH3:46])[C:38]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:39])[C:33]2=[O:47])(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[Cl:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:25][C:24]1[CH:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[S:28]([NH:31][C@H:32]2[CH2:36][CH2:35][N:34]([C@@H:37]([CH3:46])[C:38]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[O:39])[C:33]2=[O:47])(=[O:30])=[O:29])=[CH:20][C:19]=1[OH:18]
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)/C=C/c2ccc(Cl)c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)/C=C/c2ccc(Cl)c(O)c2)C1=O
Yield: 83.8 %

Procedure:
To a solution of (E)-2-(3-{[tert-butyl(diphenyl)silyl]oxy}-4-chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide (0.0078 g) in THF (0.3 ml) at −78° C. under nitrogen, tetra n-butylammonium fluoride (1M in THF, 0.014 ml) was added. The mixture was allowed to warm to room tempertaure over 3 days and then concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.0043 g) as a clear film.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.Br[C:26]1[S:27][CH:28]=[CH:29][N:30]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[CH:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(N)cc2)c(F)c1-c1cccc(Cl)c1
Reactant: Brc1nccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cc2ccc(Nc3nccs3)cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 90 °C
Yield: 45 %

Procedure:
(P-443): In an 8 mL vial equipped with a stir bar was placed 4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine (I-35) synthesized above (100 mg, 0.293 mmol), 2-bromothiazole (52.1 μL, 0.585 mmol), 10% aqueous ethanol (1.5 mL) and concentrated hydrochloric acid (48.8 μL, 0.585 mmol). The mixture was heated to 90° C. for 18 hours and then cooled to room temperature. After water (30 mL) and 5% aqueous potassium carbonate (30 mL) were added, the aqueous portion was extracted with ethyl acetate (2×35 mL) and the organic portions were combined, washed brine (30 mL), dried (magnesium sulfate) and concentrated. The crude material was purified by column chromatography utilizing 3% acetone/dichloromethane as the eluent to produce 57 mg of [4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-thiazol-2-yl-amine. (P-443) as white solid in 45% yield. 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 3.94 (s, 2H), 6.62 (d, J=4 Hz, 1H), 6.70 (dd, J=8, 1 Hz, 1H), 7.10 (t, J=9 Hz, 1H), 7.20-7.22 (m, 2H), 7.26-7.40 (m, 8H) ppm; MS (APCI+): 425.0 (M+1), LC-MS: 89%
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)cc1)N1CCCC1
Temperature: -78 °C
Reaction time: 0.07 h
Yield: 35.2 %

Procedure:
The product of Example 48A (3.21 g, 13.3 mmol) was dissolved in CH2Cl2 (30 mL), cooled to −78° C. and treated with BBr3 (8.31 g, 3.26 mmol). The resulting dark red solution was stirred at 25° C. for 4 min, then cooled to −78° C. Methanol (100 mL) was added slowly. The solution was concentrated in vacuo. Toluene was added to the crude and concentrated again. After adding more toluene, the solution was washed with water and concentrated in vacuo. The residue was dissolved in ether and extracted with NaOH (1.0 g) in water (8 mL). The aqueous layer was removed and stirred 15 minutes, then acidified with concentrated HCl. This mixture was extracted with toluene, dried (Na2SO4), filtered, concentrated in vacuo and the residue crystallized from ether and heptane (2:1) to provide the title compound (1.063 g, m.p. 122-125° C.).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:15][S-:16].[Na+]>CO.CN(C=O)C>[CH3:15][S:16][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: C[S-]
Reactant: O=C1Nc2ccccc2OC1CCBr
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CSCCC1Oc2ccccc2NC1=O
Reaction time: 4 h
Yield: 53 %

Procedure:
586 mg of 2-(2-bromoethyl)-1,4-benzoxazin-3-one is mixed in a methanol-DMF mixture with 245 mg of sodium thiomethylate while being stirred. After 4 hours, it is concentrated by evaporation. After column chromatography, the title compound is obtained in a yield of 53%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (71 mg, 71%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C@:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>>[N:24]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][C:6]4[CH2:23][C@:13]5([C:21]6[C:16](=[N:17][CH:18]=[CH:19][CH:20]=6)[NH:15][C:14]5=[O:22])[CH2:12][C:7]=4[CH:8]=3)[N:3]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(Cl)nc3cc1C2
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(N4CCc5ccccc54)nc3cc1C2
Temperature: 200 °C

Procedure:
A mixture of (7S)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (35 mg, 0.109 mmol, described in Intermediate 21) and indoline (324 mg, 2.72 mmol) in CH3 CN (1 mL) was heated at 200° C. in a microwave reactor for 10 min. The mixture was cooled to ambient temperature and the precipitate was isolated by filtration, washed with H2O, and dried to give the title compound. MS: m/z=405 (M+1). HRMS: m/z=405.1715; calculated m/z=405.1710 for C26H21N4O.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]1.[H-].[Na+].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][C:29]#[N:30])=[CH:26][CH:25]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH:28]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)[C:29]#[N:30])=[CH:26][CH:25]=1
Reactant: CC1CN(CCCCCCCCCCCCl)CC(C)O1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1CN(CCCCCCCCCCCC(C#N)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This intermediate (900 mg.) was prepared using the procedure described in Example 2a except using 3.9 g. (0.013 mole) of 4-(11-chloroundecyl)-2,6-dimethylmorpholine, 0.62 g. (0.014 mole) of sodium hydride, 1.97 g. (0.013 mole) of 4-chlorobenzyl cyanide, and 75 ml. of a 2 to 1 mixture of toluene and DMF.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][C:13]([OH:32])=[O:12])[CH2:20][CH2:19]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(CC(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.4 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of [4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-acetic acid tert-butyl ester (1.48 g, 4 mmol) in dichloromethane (10 mL). The reaction was stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue was triturated with diethyl ether. Filtration yielded the product as a white solid (1.25 g, quant.). 1H NMR (400 MHz, DMSO-d6) δ 7.70 (dt, J=9.6, 2.4 Hz, 2H), 7.21 (dt, J=9.6, 2.4 Hz, 2H), 3.86 (m, 5H), 3.09 (m, 8H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:19]=[C:18]([C:28]([O:30]CC)=O)[C:14]=4[NH:15]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:33].CO>>[N:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:19]=[C:18]([C:28]([NH2:33])=[O:30])[C:14]=4[NH:15]3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N
Reactant: CCOC(=O)c1nc(-c2ccccc2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Solvent: CO
Product: NC(=O)c1nc(-c2ccccc2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 135 °C

Procedure:
Ethyl 7-(morpholine-4-carbonyl)-3-phenyl-9H-pyrido[3,4-b]indole-1-carboxylate (15 mg, 0.035 mmol) and 7N NH3/MeOH (1.5 mL, 10.50 mmol) were mixed in a sealed microwave tube and heated in microwave at 135° C. for 3.5 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 401.07 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.83 (s, 1H), 9.07 (s, 1H), 8.43 (m, 4H), 7.89 (s, 1H), 7.84 (s, 1H), 7.53(t, 2H, J=7.6), 7.42 (t, 1H, J=7.3), 7.32 (dd, 1H, J=7.9, 1.5), 3.67-3.43 (bm, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.[CH3:18][C:19](=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH:4]=[C:19]([CH3:18])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1Cl)OCC
Solvent: Cc1ccccc1
Product: CC(=Cc1ccc(Cl)cc1Cl)C(C)(C)C
Yield: 61.7 %

Procedure:
29.7 g (0.1 mol) of diethyl 2,4-dichlorobenzylphosphonate, 10 g (0.1 mol) of pinacolone, 12 g (0.1 mol) of potassium t-butylate and 300 ml of absolute toluene are heated at the boiling point in a nitrogen atmosphere for 20 hours. The solution is cooled, washed with 2 80 ml portions of water, dried over sodium sulphate and freed from the solvent in vacuo. After the residue has been distilled, 15 g (69.7% of theory) of 1-(2,4-dichlorophenyl)-2,3,3-trimethylbut-1-ene of boiling point 85° C. under 0.13 mbar are obtained.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2cccnc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1cnc2c(c1)OCCN2
Yield: 79.5 %

Procedure:
To a suspension of 2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.0 g, 13.3 mmole) in dry THF (40 mL) was added a solution of LiAlH4 in THF (1.0 M, 26.6 mL, 26.6 mmole) slowly at 0° C. After 1 hr the mixture was quenched with 2.0 M NaOH until a solid formed. The mixture was dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (1.44 g, 79%) as a white solid which was sufficiently pure for use in the next step: MS (ES) m/e 137 (M+H)+.