Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C[OH:10].OO.[OH-].[Na+]>CCOCC>[CH:7]12[O:8][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]2=[O:10]
Reactant: O=C1C=CCCCC1
Reactant: CO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C1CCCCC2OC12
Reaction time: 1 h
Yield: 80 %

Procedure:
To a 0° C. solution of 50.0 g. (0.454 mmole) of cyclohept-2-en-1-one in 800 ml. of methanol was added 85 ml. of 30% hydrogen peroxide (0.75 mole) followed by the dropwise addition of 15 ml. of 6N sodium hydroxide (0.09 mole). The reaction was stirred for one hour and then added to 400 ml. ether-500 ml. petroleum ether. The ether extract was removed and the aqueous methanol phase extracted with four 500 ml. portions of petroleum ether and three 300 ml. portions of dichloromethane. The combined organic extracts were washed with three 800 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure to an oil (53 g.). The crude oil was purified via vacuum distillation to yield 45.9 g. (80%) of the title compound as an oil. Caution: several forceful detonations have occurred during distillation of the crude product. (In general, however, the crude product is pure enough for further synthetic manipulations and distillation can be avoided.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:23]=[CH:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:30](=[O:31])[CH2:29][CH2:28][C:27]#[C:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:33])([F:34])[F:17])[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Reactant: O=C(O)CCC#Cc1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc2ccc(NC(=O)CCC#Cc3cccc(OC(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
A mixture of (6-amino-indol-1-yl)-acetic acid ethyl ester (100 mg, 0.46 mmol; WO 2003041714 A1), 5-(3-trifluoromethoxy-phenyl)-pent-4-ynoic acid (115 mg, 0.44 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (90 mg, 0.46 mmol) and 4-(dimethylamino)pyridine (57 mg, 0.46 mmol) in dichloromethane (1.5 ml) was stirred for 14 h at ambient temperature. The reaction mixture was diluted with dichloromethane, successively washed with 1 N HCl, brine, 1 N NaOH and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 152 mg (0.33 mmol, 72%) of the title compound as off-white crystals.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[C:7]([C:10](OCC)=[O:11])[N:6]=[CH:5][C:4]=2[C:3]2([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[O:2]1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:10]([C:7]1[N:6]=[CH:5][C:4]2[C:3]3([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]3)[O:2][CH2:1][C:9]=2[CH:8]=1)=[O:11]
Reactant: CCOC(=O)c1cc2c(cn1)C1(CN(C(=O)OC(C)(C)C)C1)OC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=O)ncc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To the stirred solution of 1-tert-butyl 6′-ethyl 1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1,6′-dicarboxylate (0.2 g, 0.60 mmol, 1 eq) in DCM (10 mL) at −78° C. under nitrogen atmosphere was added 25% DIBAL in toluene (0.255 g, 2.56 mL, 1.80 mmol, 3 eq). Resulting reaction mixture was stirred at −78° C. for 1 hour under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by methanol (0.2 mL) followed by addition of saturated solution of sodium potassium tartarate salt (0.5 mL) at −78° C. and extracted with DCM (3×25 mL). Combined organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford the title compound as brown solid (0.15 g, crude). Crude compound was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.19 (d, J=10 Hz, 2H), 4.37 (d, J=10.04 Hz, 2H), 5.16 (s, 2H), 7.85 (s, 1H), 8.89 (s, 1H), 10.12 (s, 1H). LC-MS (m/z): 291.0 (M+H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH2:38]([NH2:40])[CH3:39]>>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:40][CH2:38][CH3:39])[CH:17]=3)[NH:12][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Yield: 43.9 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.361 g, 0.764 mmol) in 2.0 N ethylamine in THF (9 mL, 18 mmol) was stirred at 70° C. for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 10% methanol in chloroform. After drying in vacuo at 68° C. for 20 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-ethyl-amine as a light brown gum (0.116 g, 43.9%) was obtained. This was dissolved in chloroform and methanol, and ethereal hydrochloride was added. Concentrating and drying at 74° C. for 13.5 hours in vacuo yielded the hydrochloride as a buff solid (0.113 g): MP: 248-50° C. (dec). Mass Spectrum (+EI, [M+H]+) m/z 346. 1HNMR (500 MHz, DMSO-d6): δ14.23 (s, 1H), 8.81 (br, 2H), 7.96-7.98 (m, 2H), 7.56-7.68 (m, 4H), 7.40 (d, 1H, J=2.07 Hz), 7.19 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.31 (t, 2H, J=5.00 Hz), 3.35 (br, 2H), 3.00-3.05 (m, 2H), 1.18-1.22 ppm (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-methylpiperidin-4-ol (2.99 mmol, 344.4 mg) was added to a suspension of potassium tert-butoxide in THF (5 mL) and stirred at RT for 30 minutes. 2-fluoro-5-trifluorometyl nitrobenzene (2.39 mmol, 500 mg) was then added and the reaction mixture was stirred an additional 5 h at RT, at which time LC-MS showed complete conversion to the desired product. The reaction mixture was concentrated and the dark brown residue was taken up in methylene chloride (25 mL). This was washed with water (3×20 mL), dried over sodium sulfate, filtered and concentrated to give the crude product as a yellow oil. Crude material (>90% purity) was taken to the next step without further purification LC-MS: 305.1 (M+H)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[O:16])=[CH:5][CH:4]=1.[CH2:17]([C:20]1[NH:21][C:22]2[C:28]([CH3:29])=[CH:27][C:26]([C:30]3[N:34]([CH3:35])C4C=CC=CC=4N=3)=[CH:25][C:23]=2[N:24]=1)[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+].O.[CH3:47][N:48](C)[C:49](=O)C>>[CH2:17]([C:20]1[N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([CH:15]=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[C:23]2[CH:25]=[C:26]([C:30]3[N:34]=[CH:35][N:48]([CH3:49])[CH:47]=3)[CH:27]=[C:28]([CH3:29])[C:22]=2[N:21]=1)[CH2:18][CH3:19]
Reactant: O=Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2cc(-c3nc4ccccc4n3C)cc(C)c2[nH]1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C=O)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A suspension of 4-bromomethyl-2′-formylbiphenyl (I) (1.0 g, 3.6 mmol), 2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2-yl)benzimidazole (1.1 g, 3.6 mmol) and K2CO3 (0.5 g, 3.6 mmol) in 23 ml of N,N-dimethylacetamide is stirred at room temperature under argon atmosphere for 23 hours. Reaction mixture is poured to 160 ml of water and extracted 4 times with 40 ml of ethyl acetate. Combined organic extracts are dried over MgSO4 and evaporated under reduced pressure to obtain crude amorphous product. Yield: 3.03 g.
Reaction SMILES: [N:1]1([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[OH:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>O1CCCC1>[CH3:22][N:23]([CH3:27])[C:24]([O:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:7]=[CH:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:25]
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cnccc1N=CN1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCCC1

Procedure:
A mixture prepared from 4-[[(1-pyrrolidinyl)methylene]amino]-3-pyridinol (3.79 g), triethylamine (4.29 mL), dimethylcarbamyl chloride (2.74 mL) and tetrahydrofuran (130 mL) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. Recrystallization from ethyl acetate and drying under high vacuum and refluxing acetone for 4 hours yielded 3.55 g of crystals, m.p. 99°-100° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])(=[O:4])=[O:3].[CH2:12]([O:14][C:15](=[O:29])[CH:16]([CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17](=O)[CH3:18])[CH3:13].C(N(CC)CC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([C:16]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]([C:7]2[CH:9]=[CH:10][CH:11]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[C:17]=1[CH3:18])=[O:29])[CH3:13]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(S(C)(=O)=O)c2)c1C

Procedure:
3-Methylsulfonylaniline (1.4 mmol, 0.3 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (1.4 mmol, 0.35 g), triethylamine (1.4 mmol, 0.14 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in chloroform, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and the solvents removed under vacuum. The crude material was purified over silica gel to yield the named product as an oil. The structure of the compound was verified by 1H-NMR (CDCl3, ppm): 1.36 t (3H), 2.45 s (3H), 2.82 s (3H), 4.3 q (2H), and 6.8-7.2 m (9H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.C[O:34][C:35](=[O:66])[C@@H:36]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:64])[C:57]4[CH:62]=[CH:61][CH:60]=[N:59][C:58]=4[Cl:63])=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:65])[CH:37]([CH3:39])[CH3:38]>>[Cl:63][C:58]1[N:59]=[CH:60][CH:61]=[CH:62][C:57]=1[C:56]([NH:55][C:52]1[CH:51]=[CH:50][C:49]([C:44]2[CH:43]=[C:42]3[C:47]([CH2:48][N:40]([C@@H:36]([CH:37]([CH3:39])[CH3:38])[C:35]([OH:66])=[O:34])[C:41]3=[O:65])=[CH:46][CH:45]=2)=[CH:54][CH:53]=1)=[O:64]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccnc4Cl)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4cccnc4Cl)cc3)cc2C1=O
Yield: 85 %

Procedure:
The compound of example 209 was prepared analogous to compound of example 98 by hydrolysis of compound of example 208.
Reaction SMILES: [Si]([O:8][C@H:9]([C:40](=[O:42])[NH2:41])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]([CH2:38][CH3:39])C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)(C(C)(C)C)(C)C.Cl.O.CC#N>ClCCl>[CH2:38]([NH:30][CH:27]1[CH2:28][CH2:29][CH:24]([O:23][C:14]2[C:13]3[C:12]4[C@@H:11]([CH2:10][C@H:9]([OH:8])[C:40]([NH2:41])=[O:42])[CH2:22][CH2:21][C:20]=4[S:19][C:18]=3[N:17]=[CH:16][N:15]=2)[CH2:25][CH2:26]1)[CH3:39]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)C(N)=O)CC4)CC1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CCNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Into a 50-mL round-bottom flask was placed a solution of tert-butyl N-(4-[[(3R)-3-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-2-carbamoylethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-ethylcarbamate (160 mg, 0.26 mmol, 1.00 equiv) and hydrogen chloride (conc.) (0.3 mL) in dichloromethane (3 mL). The resulting solution was stirred for 1 h at 0° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-015(Waters)): column: Xbridge Prep C18, 5 um, 19*50 mm; mobile phase: water with 50 mmol NH4HCO3 and CH3CN (10% CH3CN up to 25% in 10 min, up to 95% in 1.5 min, down to 10% in 1.5 min); detector: 254/220 nm. 47.3 mg product was obtained. This resulted in 47.3 mg (45%) of (2S)-3-[(3R)-12-[[4-(ethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2-hydroxypropanamide as a white solid. MS: m/z 405 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.474 (1H, s), 5.24-5.26 (1H, m), 4.08-4.12 (1H, d), 3.53 (1H, m), 3.04-3.28 (1H, m), 2.92-2.95 (1H, m), 2.50-2.71 (4H, m), 2.40-2.47 (2H, m), 2.15-2.23 (2H, m), 1.98-2.07 (2H, m), 1.61-1.96 (3H, m), 1.26-1.34 (2H, m).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[CH2:16][C:17]#[N:18].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[CH2:25][C:26]([NH2:28])=[O:27].[H-].[Na+]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:16]([C:11]1[N:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[C:17]#[N:18].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:25]([C:20]1[N:21]=[CH:22][CH:23]=[CH:24][N:19]=1)[C:26]([NH2:28])=[O:27]
Reactant: N#CCc1ncccn1
Reactant: NC(=O)Cc1ncccn1
Reactant: c1ccc2scnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(=C1Nc2ccccc2S1)c1ncccn1
Product: NC(=O)C(=C1Nc2ccccc2S1)c1ncccn1

Procedure:
In this synthesis, the benzothiazole 10 [L is a leaving group] is coupled with a 2-(pyrimidin-2-yl)acetonitrile 11 or 2-(pyrimidin-2-yl)acetamide 12 in the presence of a strong base, such as sodium hydride, in an aprotic polar solvent, such as tetrahydrofuran, to give a 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetonitrile 6 or 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamide 8. If the compound of formula 6 has been prepared, it is then hydrolyzed to a compound of formula 8, as in Reaction Scheme 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1(C(C)C=O)C=CC=C[CH:26]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO.[Pd]>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][CH2:2][CH2:7][C:6]3[CH:5]=[CH:4][CH:3]=[CH:26][CH:25]=3)[CH2:9]2)=[O:24])=[CH:22][CH:21]=1
Reactant: O=C(NCC1CN(Cc2ccccc2)CCO1)c1ccc(O)cc1
Reactant: CC(C=O)c1ccccc1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCC1CN(CCCc2ccccc2)CCO1)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
A solution of N-(4-benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide (EXAMPLE 202, Step 1) (55 mg) was dissolved in acetic acid (3 mL) and hydrogenated at 1 atm over 10% Pd/C (50 mg) for 18 h. The catalyst was removed by filtration, washed with acetic acid and the filtrate evaporated, to give an oil. A portion of this oil (21 mg) was dissolved in methanol (1 mL) and treated with phenylpropionaldehyde (24 mg) and sodium cyanoborohydride (25 mg). The resulting reaction was stirred for 15 min and the crude reaction mixture purified by preparative reverse phase IPLC to give the 4-Hydroxy-N-[4-(3-phenyl-propyl)-morpholin-2-ylmethyl]-benzamide compound.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[O-:14][C:15]#[N:16].[Na+]>CO.C(O)(=O)C>[NH:1]([C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)[C:15]([NH2:16])=[O:14]
Reactant: N#C[O-]
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)Nc1ccc2c(c1)C(=O)C1(CC1)O2
Temperature: 0 °C
Yield: 169.6 %

Procedure:
To a solution of 5-aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.75 g.) in methanol (10 ml.) and acetic acid (5 ml.) was added dropwise 2 ml. of aqueous solution of sodium cyanate (130 mg.), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added ice-water, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give colorless needles of 5-ureidospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.74 g.).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CN(C)C=O.C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc(=O)c2cc(C#C[Si](C)(C)C)ccc2[nH]1
Temperature: 45 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a solution of 1.0 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.043 g of bis(triphenylphosphine) palladium (II) chloride and 5.8 mg of copper (I) iodide in 5.0 ml of N,N-dimethylformamide and 5.0 ml of triethylamine is added 0.36 g of (trimethylsilyl) acetylene. The resulting reaction mixture is heated at 45° C. for 1 hour and then 65° C. for 5 hours. Upon cooling, the reaction mixture is concentrated in vacuo and the residue purified by flash chromatography on silica gel, eluting with 1:3 ethyl acetate-hexane to yield 0.75 g of the desired product as a white solid. CI MASS SPEC 299(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([OH:23])[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CO.[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C(Cl)Cl>[CH3:26][O:23][C:15]1[CH:14]=[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(-c2cc(O)c3cccnc3c2)cc(OC)c1OC
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-c2cc(OC)c3cccnc3c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 11.5 %

Procedure:
100 mg of 7-(3,4,5-Trimethoxyphenyl)quinolin-5-ol, 42 μL of MeOH and 480 mg of triphenylphosphine was dissolved in 5 mL of DCM. 435 mg of DBAD was added and the mixture stirred for 3 days at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified with HPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 12 mg of Example 3 as solid.
Reaction SMILES: F[C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH-:18].[Na+]>S([O-])([O-])(=O)=O.[Cu+2]>[OH:18][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [OH-]
Reactant: CCCCCCOc1cccc(C(N)=O)c1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCCCCCOc1cccc(C(N)=O)c1O
Temperature: 100 °C
Reaction time: 14 h

Procedure:
A mixture of 2-fluoro-3-Hexoxy-benzamide (0.30 g, 1.2 mmol), copper sulfate (0.10 g, 0.4 mol) copper (0.015 g, 0.2 mmol) and NaOH (2.5 ml) was stirred at 100° C. for 14 hrs. After completion of reaction the reaction mixture was acidified and extracted with EtOAc. The obtained crude compound was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as yellow (0.15 g, 50%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 3.9 (s, 3H), 7.11-7.18 (m, 2H), 7.53-7.58 (m, 1H). MS ES+ (229.0 M+2H adduct). HPLC (Method 7) Rt=11.16 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:41]=[CH:40][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[N:34]([CH3:38])[CH2:35][CH2:36][N:37]=4)=[CH:29][CH:28]=3)[C:17](=[O:39])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[H-].[Na+].CI>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[N:37]([CH3:2])[CH2:36][CH2:35][N+:34]=4[CH3:38])=[CH:29][CH:28]=3)[C:17](=[O:39])[CH2:16]2)=[O:14])=[CH:40][CH:41]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCN=C1c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CC[N+](C)=C1c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg (0.034 mmol) of 4-(4-chlorobenzoyl)-1-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)benzyl]-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin2on trifluoroacetate obtained in Example 125 was dissolved in 3 ml of DMF. 3 mg (0.075 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 30 mg (0.21 mmol) of methyl iodide was added to the reaction mixture, and they were stirred at room temperature for 5 hours. The solvent evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[K+].O>FC(F)(F)C(O)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(C)(C)CN2C(C)=O
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2(C)C
Temperature: 0 °C
Yield: 86.5 %

Procedure:
A solution of 1-acetyl-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indole (2.44 g, 11.13 mmol, see PCT Int. Appl. (2001), WO 2001023374 A1 20010405) in trifluoroacetic acid (50 mL) was stirred at 0° C. and potassium nitrate (1.181 g, 11.68 mmol) was added in one portion. The reaction was maintained at 0° C. for 3 hours and poured into water. The solids were collected via filtration to afford 1-acetyl-3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (2.545 g, 87% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1 H), 7.34 (s, 1 H), 3.91 (s, 3 H), 2.15 (s, 2 H), 1.36 (s, 6 H). Note: proton resonance corresponding to acetyl was extremely broad and/or not evident for a variety of lots.