Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[C:3]([C:7]1[O:8][C:9]2[C:10](=[C:12]([C:29]#[N:30])[C:13]([CH3:28])=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[N:16]2[CH2:19][CH:18]([NH:20][CH3:21])[CH2:17]2)[N:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:31]([BH3-])#N.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].O.CO>[C:3]([C:7]1[O:8][C:9]2[C:10](=[C:12]([C:29]#[N:30])[C:13]([CH3:28])=[C:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:15]=2[N:16]2[CH2:17][CH:18]([N:20]([CH3:31])[CH3:21])[CH2:19]2)[N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CNC1CN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(C)(C)C)oc23)C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)c(N2CC(N(C)C)C2)c2oc(C(C)(C)C)nc2c1C#N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
Aqueous 36% formaldehyde solution (205 μl, 2.75 mmol) was added to a methanol (4 ml) solution of 2-tert-butyl-5-methyl-7-(3-methylaminoazetidin-1-yl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-73) (103 mg, 275 μmol), followed by cooling at 0° C. Sodium cyanoborohydride (34.6 mg, 550 μmol) and acetic acid (40.9 μl, 715 μmol) were added, followed by stirring at room temperature for 20 minutes. Aqueous 10% sodium carbonate solution and saturated brine were added to the reaction liquid, and this was extracted with ethyl acetate and chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=200:1), again purified by silica gel column chromatography (dichloromethane:ethyl acetate=1:1) to obtain the entitled compound (94 mg, 88%) as a colorless solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)=[O:6].C(OC1C(=O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1>>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]([CH3:36])[CH3:37])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 17.6 %

Procedure:
9-Benzyloxy-6-biphenyl-2-ylmethyl-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-03) (110 mg, 17.54%) was synthesized as a white solid from 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (10-03) (650 mg, 1.3 mmol) following the procedure as described for 9-benzyloxy-6-biphenyl-2-ylmethyl-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-01).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:33][C:34]1[N:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36][CH:35]=1.C(N1CCOCC1)C>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:40]([C:37]3[CH:38]=[N:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[O:41])[CH2:14][C@@H:13]2[CH3:18])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: C[C@H]1CNCCN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(Cl)cc3)[C@@H](C)C2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
To a suspension of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine hydrochloride (Description 4) (105 mg, 0.338 mmol), EDC (71.2 mg, 0.371 mmol), HOBT.H2O (56.9 mg, 0.371 mmol) and 6-methyl-3-pyridinecarboxylic acid (51.0 mg, 0.372 mmol) in DCM (5 ml) was added N-ethylmorpholine (0.090 ml, 0.710 mmol). The reaction was stirred for 18 h at ambient temperature. To the reaction was added water (3 ml) and the organic layer collected via a hydrophobic frit. The organic layer was reduced in volume to approximately 2 ml then loaded onto a silica SP4 chromatography cartridge. The cartridge was eluted with ethyl acetate then a gradient from 0-10% (20% methanol in dichloromethane) in ethyl. Fractions containing the desired product were combined and reduced in vacuo to yield the title compound as a white solid (55 mg).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[CH:3][C:2]=1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][CH2:14][NH:13][C:10]([C:2]3[CH:3]=[C:4]4[N:9]=[CH:8][CH:7]=[CH:6][N:5]4[N:1]=3)=[O:12])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cc2ncccn2n1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc4ncccn4n3)n2)cc1Cl
Yield: 12 %

Procedure:
The title compound was prepared using the method of Example 34 (d) starting from pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.16 g; 0.97 mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.20 g; 0.81 mmol). Yield 12%. 1H-NMR (400 MHz; d6-DMSO): δ 3.75 (q, 2H), 4.41 (t, 2H), 6.96 (d, 1H), 7.03 (s, 1H), 7.19 (m, 1H), 7.86 (d, 1H), 7.97 (m, 2H), 8.06 (s, 1H), 8.64 (m, 1H), 8.71 (m, 1H), 9.09 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1N.N(OCCC(C)C)=O.[CH3:18][S:19]SC>>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[S:19][CH3:18]
Reactant: CSSC
Reactant: Nc1cc(F)ccc1Br
Agent: CC(C)CCON=O
Product: CSc1cc(F)ccc1Br
Temperature: 75 °C
Yield: 76 %

Procedure:
Dissolve 2-bromo-5-fluoroaniline (25 g, 131 mmol) in methyldisulfide (220 mL) and heat to 75° C. under nitrogen. Add isoamyl nitrite (46 mL, 342 mmol) dropwise via an addition funnel trough a reflux condenser (˜1 drop/sec). Large exotherm may occur if addition is too fast. After addition is complete heat the reaction to 95° C. for 1 hour and cool to room temperature and concentrate in vacuo. Purify residue twice via silica gel chromatography eluting with hexanes to yield 22 g of 1-bromo-4-fluoro-2-methylsulfanyl-benzene (76%).
Reaction SMILES: O.[OH:2][C:3]1[C:11]2[N:10]=NN[C:7]=2[CH:6]=CC=1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.Cl.[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([OH:54])=O)=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40].N[C@@H](CC)CO.Cl>C1COCC1.CCCCCCC.C(OCC)(=O)C>[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([NH:10][C@H:11]([CH2:3][OH:2])[CH2:7][CH3:6])=[O:54])=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[C@H](N)CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC[C@@H](CO)NC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
Hydroxybenzotriazole hydrate (43.1 mg, 0.28 mmol), N-ethyldiisopropylamine (241 μL, 1.38 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (54.0 mg, 0.28 mmol) were added at 0° C. to a solution 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) and [S]-(+)-2-amino-1-butanol (32.3 μL, 0.33 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature overnight. Addition of aqueous hydrochloric acid (1 N, 10 mL), extraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=0:1 to 1:0) afforded the title compound (73 mg, 61%) as a brown solid. MS: m/e=434.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[C@:18]1([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][CH2:23][C@H:18]([OH:24])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: C[C@]1(O)CCCNC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O[C@H]1CCCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and (S)-3-methyl-piperidin-3-ol (1.11 g, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated. The resultant residue was purified by flash chromatography (silica, Biotage 50 g column, 50-100% ethyl acetate in cyclohexane) to afford the title compound (0.8 g, 74%). 1H NMR (CDCl3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.14 (m, 2H), 3.85-3.76 (m, 1H), 3.45 (s, 2H), 2.45 (s, 3H), 2.29-2.16 (m, 1H), 1.86-1.70 (m, 1H), 1.67-1.45 (m, 3H) plus 1 exchangeable not observed. LCMS (Method G): RT=1.42 min, M+H+=270.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:22][CH3:23])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2[nH]1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2[nH]1

Procedure:
A 100 ml round-bottomed flask equipped with a magnetic stirrer is charged with 0.3 g (1.3 mmol) of 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Angew Chem Int Ed 2004, 43(34), 4526-4528) and 50 ml of ethanol. This solution is admixed with 0.5 ml of concentrated sulfuric acid. The reaction mixture is then brought to reflux for 18 hours. The cooled solution is concentrated to dryness under reduced pressure. The residue is taken up in dichloromethane (100 ml) and the organic phase is washed successively with normal aqueous sodium hydroxide solution (30 ml), with water (20 ml) and then with saturated aqueous sodium chloride solution. It is dried over sodium sulfate and then concentrated under reduced pressure. This gives 0.29 g (1.12 mmol) of the expected product in the form of a yellow powder.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]3[S:19][CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(O)C>[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]3[S:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1csc(-n2nc(-c3ccccc3)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A 5 M aqueous solution of sodium hydroxide (10 mL, manufactured by Kanto Chemical Co., Inc.) was added to a solution of the compound of Example 1 (579 mg) in ethanol (10 mL, manufactured by Wako Pure Chemical Industries, Ltd.), and the mixture was stirred for 3 hours at room temperature. 5 M hydrochloric acid (10 mL, manufactured by Kanto Chemical Co., Inc.) was added to the mixture to neutralize the mixture, and then the mixture was extracted with ethyl acetate (3×10 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated, to give 477 mg of the title compound. LC-MS: HPLC retention time 5.31 minutes, m/z 322 (M+H), condition A-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]>>[Cl:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:22][CH2:23]2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}methylcarbamate (62 mg, 0.123 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.185 mmol) to afford the crude product (69 mg) as a yellow-green solid.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>C(O)C>[OH:1][C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[N:25]1[CH2:24][CH2:23][N:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:28])([F:29])[F:14])[CH:17]=3)[CH2:27][CH2:26]1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Solvent: CCO
Product: O=C1C(O)=C(N2CCN(c3cccc(C(F)(F)F)c3)CC2)C(=O)c2ccccc21
Reaction time: 20 h
Yield: 29.9 %

Procedure:
A mixture of 1.74 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone and 2.30 g of N-[3-(trifluoromethyl) phenyl]-piperazine in 100 ml of absolute ethanol was stirred for 20 hours, then evaporated. The residue was dissolved in dichloromethane, filtered through hydrous magnesium silicate and then chromatographed on silica gel, eluting with hexane:ethyl acetate (4:1), giving 1.2 g of the desired product, mp 167°-169° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[O:15])[NH:13][C:11](=[O:12])[C:10]2=[CH:16][CH:17]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[O:15])[NH:13][C:11](=[O:12])[C:10]2=[CH:16][CH:17]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
Methanesulfonylchloride (2.6 ml, 0.034 mol) was added dropwise to a stirred suspension of 4-aminophthalimide (5.0 g, 0.031 mol) in pyridine (50 ml). The mixture was stirred for 48 h under N2 at room temperature, after which time the solid formed was isolated by filtration, washing well with H2O and CH2Cl2 and then dried in vacuo to afford the subtitle compound as a colourless solid (5.67 g, 76%). Rf 0.52 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 241 (MH+).
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[Br:13][C:14]1[CH:25]=[CH:24][C:17]([C:18](N(OC)C)=[O:19])=[CH:16][CH:15]=1.Cl>C(OCC)C.CCCCCC>[Br:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([C:12]2[CH:11]=[C:10]3[C:6]([CH:7]=[CH:8][NH:9]3)=[CH:5][CH:4]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(c1ccc(Br)cc1)c1ccc2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
To hexane washed potassium hydride (0.30 g, 1.5 mmol), suspended in anhydrous diethylether (1.5 mL), was added 5-bromoindole (0.241 g, 1.23 mmol) dissolved in diethyl ether (2.0 mL) at 0° C. After 15 min, the mixture was cooled to −78 ° C. and tert-buthyllithium (1.5 mL, 2.55 mmol), pre-cooled to −78° C., was added via cannula. After 10 min 4-bromo-N-methoxy-N-methylbenzamide (0.30 g, 1.2 mmol) in diethylether (2.0 mL), pre-cooled to −78° C., was added. The reaction mixture was kept at −78° C. for 10 min and then allowed to warm up to room temperature and stirred for another hour. HCl (1M, 5 mL) was added and the mixture stirred for 15 min. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over MgSO4, and the solvent was evaporated. The crude product was purified by flash column chromatography on silica using methylene chloride as the eluent affording 176 mg (48% yield) of the title compound as a pale yellow solid: mp 47-49° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (br s, 1 H), 8.01 (s, 1 H), 7.87 (m, 2 H), 7.72 (m, 2 H), 7.68 (dd, J=8.2 Hz, J=1.4 Hz, 1 H), 7.52 (m, 1 H), 7.35 (s, 1 H), 6.74 (m, 1 H); 13C NMR (100.5 MHz, CDCl3) δ 196.5, 138.0, 135.4, 132.0, 131.9, 131.8, 131.4, 128.5, 127.1, 122.4, 120.8, 114.6, 103.6; MS TSP) m/z 300, 302 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[CH:11][CH:12]=1)[C:9]#[N:10].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20].C(N(CC)CC)C>CC(C)=O.CC(C)=O.CCCCC>[C:13]([C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[O:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[NH:1][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=1)#[N:14]
Reactant: N#Cc1ccc(Oc2ccccc2N)cc1C#N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCCCC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Oc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 4-(2-aminophenoxy)phthalonitrile (0.5 g, 2.1 mmol), 3-nitrobenzoylchloride (0.43 g, 2.3 mmol) and triethylamine (0.54 g, 0.74 ml, 5.3 mmol) in acetone (20 ml) was stirred for 2 hours at room temperature. The mixture was evaporated in vacuo. The crude product was dissolved in methylene chloride (25 ml) and water (25 ml) and 1N hydrochloric acid (1 ml) was added. The water phase was extracted with methylene chloride (2×15 ml). The combined organic phase was dried over magnesium sulphate, filtered and evaporated in vacuo giving 700 mg of the crude product. The product was recystallised in acetone/pentane to give white crystals of N-[2-(3,4-dicyanophenoxy)phenyl]-3-nitrobenzamide (yield: 650 mg (81%)). Mp: 176.5-178.1° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][CH2:38][N:39]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[S:40]([CH3:43])(=[O:42])=[O:41])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][CH2:38][N:39]([C:44]1[CH:50]=[CH:49][C:47]([NH:48]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:46][CH:45]=1)[S:40]([CH3:43])(=[O:41])=[O:42])[CH3:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(CCN(c1ccc(N)cc1)S(C)(=O)=O)Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)Cc2ccccc2)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2(N-benzyl-N-methyl-amino)-ethyl)-N-methylsulphonyl-amino)-aniline Rf value: 0.7 (silica gel, methylene chloride/methanol=10:1) C34H34N4O5S
Reaction SMILES: C[O:2][C:3](=[O:40])[C@H:4]([CH2:36][CH2:37][S:38][CH3:39])[NH:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].[OH-].[Li+]>>[CH2:21]([N:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:40])=[O:2])[CH2:36][CH2:37][S:38][CH3:39])=[O:35])=[C:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:9]=1)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CN(Cc2ccccc2)c2cccnc2)cc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Product: CSCC[C@H](NC(=O)c1ccc(CN(Cc2ccccc2)c2cccnc2)cc1-c1ccccc1C)C(=O)O
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a stirred solution of the ester resulting from example 407C (15.51 g, 28 mmol) on methanol (120 mL) at 0° C. was added 1 N aqueous lithium hydroxide (56 mL, 56 mmol, 2 eq). The cooling bath was removed and the mixture was stirred for 2 hours. The solvent was removed in vacuo and the residue diluted with water (400 mL). The solution was carefully acidified to pH 4, and the resultant precipitate collected by filtration to afford the title compound (14.08 g, 100%). 1H NMR (300 MHz, DMSO d6) δ 8.18 (d, 1H), 8.03 (bs, 1H), 7.82 (bs, 1H), 7.48 (d, 1H), 7.30 (m, 6H), 7.19 (m, 2H), 7.10 (m, 4H), 4.84 (s, 2H), 4.79 (s, 2H), 1.96-2.23 (m, 5H), 1.96 (s, 3H), 1.63-1.89 (m, 2H). MS m/e 540 (M+H)+, 522. Anal calcd for C32H33N3O3S (+1.18H2O): C, 68.51; N, 7.31. Found: C, 68.52; H, 6.35; N, 7.49.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1C=O.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[OH:21]
Reactant: COc1ccc(C=O)c(Cl)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(O)c(Cl)c1O
Reaction time: 1 h

Procedure:
Into a reaction flask was introduced 2 g of 2-chloro-3-hydroxy-4-methoxybenzaldehyde in 50 ml methylene dichloride with an excess of m-chloroperbenzoic acid and the reaction refluxed for 2.5 hrs. After removal of the solvent, the solid residue was dissolved in 10 ml methanol and stirred with approximately 10 weight percent aqueous sodium hydroxide (10 ml) for 1 hr. After acidification to pH 1 with dilute HCl, the solution was filtered and the precipitate washed with 10 ml of cold water. The combined filtrate and wash was extracted with ether, the ether washed with 5% NaHCO3 (2×10 ml) and saturated NaCl solution (1×10 ml) and then evaporated to leave a solid which was crystallized from ethyl acetate-hexane mixture to provide the product as white silky needles (1.35 g). mp 69°-70°.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].[C:11](OC)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>C1C=CC=CC=1.O>[O:18]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=1[O-:8]
Reactant: Cc1cccc[n+]1[O-]
Reactant: COC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: O=C(Cc1cccc[n+]1[O-])c1ccccc1
Yield: 82.1 %

Procedure:
A solution of 2-picoline N-oxide (4.4 g, 0.04 mol) in benzene (25 ml) was added to a suspension of sodium hydride (3.2 g of 60% oil dispersion) and methyl benzoate (9.94 ml, 0.08 mol) in dry benzene (100 ml). The reaction mixture was refluxed overnight. Methanol (15 ml) was added to the cooled reaction mixture, followed by water (150 ml). The aqueous layer was separated and extracted with chloroform (2×40 ml). The aqueous layer was acidified with 1N HCl and extracted with chloroform. The combined organic layers were dried (MgSO4) and concentrated to give the subtitle ketone as a solid (7 g), mp 146°-148° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[CH:21]=1>>[CH:1]1([NH:4][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([N:20]3[CH:21]=[C:17]([C:7]4[C:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[N:9][O:10][C:6]=4[CH3:5])[N:18]=[CH:19]3)[CH:23]=2)[CH2:3][CH2:2]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NC3CC3)c2)cn1
Yield: 47 %

Procedure:
As described for Example 71c, cyclopropylamine was converted, using 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (53 mg, 47%) which was obtained as an off-white solid. MS: m/e=385.0 [M+H]+.