Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.4 %

Procedure:
A mixture of ethyl 2-[1-benzyl-6-(4-trifluoromethoxyphenyl)-1H-indol-3-yl]-2-oxoacetate (1.27 g, 2.72 mmol), potassium hydroxide (0.539 g, 9.61 mmol) in THF (12 mL) and water (12 mL) was stirred at room temperature for 3.5 hours. The mixture was poured into excess water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was dried under vacuum at 92° C. for 15 hours to yield the title compound (0.985 g, 82%) as a yellow solid. A sample crystallized from isopropanol gave a solid, mp: 202-204° C. (dec.). Mass spectrum (+APCI, [M+H]+) m/z 440; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.7 (s, 1H), 8.25 (d, 1H, J=8.3 Hz), 7.95 (t, 1H, J=0.73 Hz), 7.8-7.85 (m, 2H), 7.65 (dd, 1H, J=8.3 Hz and 1.5 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.25-7.4 (m, 5H), and 5.65 ppm (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:24]1>O1CCOCC1.O.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>[CH:14]1([C:11]2[O:10][C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([CH2:29][N:26]5[CH2:27][CH2:28][O:23][CH2:24][CH2:25]5)[CH:31]=4)[CH:3]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: OB(O)c1cccc(CN2CCOCC2)c1
Reactant: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cccc(CN3CCOCC3)c2)cc1-c1nnc(C2CC2)o1
Temperature: 100 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a solution of 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (400 mg; 1.42 mmol) in dioxane (10 mL) and water (6 mL) were added K2CO3 (587 mg; 4.26 mmol), (3-(morpholinomethyl)phenyl)boronic acid (348 mg; 1.56 mmol) in a sealed tube. The reaction mixture was degassed with argon for 30 min, then added Pd(PPh3)4 (82.0 mg; 0.07 mmol) to the reaction mixture. The reaction mixture was stirred for 18 h at 100° C. The reaction mixture was diluted with water (50 mL) extracted with ethyl acetate (2×50 mL) and organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel and eluted with 100% ethyl acetate, which is further purified by washing with 30% chloroform in hexane to afford 90 mg (Yield: 16.7%) of the title compound, as a yellow colour solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=O)=[CH:6][N:7](C)C)C.Cl.[C:20]([NH:24]N)([CH3:23])([CH3:22])[CH3:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:3][C:4]([C:5]1[CH:6]=[N:7][N:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=1[C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:18]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(C)on1
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cnn(C(C)(C)C)c1-c1cc(C)on1
Temperature: 90 °C
Yield: 101.7 %

Procedure:
A solution of 3-dimethylamino-2-(5-methyl-isoxazole-3-carbonyl)-acrylic acid ethyl ester (27.53 mmol) in absolute ethanol (41.7 mL) was treated with tert-butylhydrazine hydrochloride (3.57 g, 28.63 mmol) and sodium acetate (2.80 g, 34.13 mmol). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C. The reaction was diluted with water (200 mL) and was then extracted with dichloromethane (3×150 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-tert-butyl-5-(5-methyl-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid methyl ester (7.37 g, 96%) as a black solid. The material was used without further purification.
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:1]([C:13]1[CH:14]=[C:15]2[C:16]([N:17]=[C:26]3[C:25](=[C:23]2[OH:22])[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C1CCCCC1
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCc1ccc2nc3c(c(O)c2c1)CCCC3
Reaction time: 72 h

Procedure:
4-Dodecylaniline (15.7 g) was dissolved in 100 mL of benzene and then 2-ethoxycarbonylcyclohexane (10.2 g) was added, followed by 0.20 g of p-toluenesulfonic acid. The reaction mixture was stirred for three days and then refluxed for 2 hours with the separation of H2O. The benzene was evaporated from this mixture, which was then dissolved in 100 mL of phenyl ether and refluxed for 45 minutes. At the end of this time the reaction mixture was allowed to cool and the precipitated product was filtered off. This crude product was purified by flash chromatography (20% ethyl acetate/CH2Cl2) and then recrystallized from 1,2-dichloroethane/methanol to give 1.31 g, mp 225°-226°.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]2[O:16][C:15]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:14][C:13]=2[C:24]=1[CH3:25])(C(C)(C)C)(C)C.C(O)(=O)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:8][C:9]1[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]2[O:16][C:15]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:14][C:13]=2[C:24]=1[CH3:25]
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(C)(c1ccccc1)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)SC(C)(c1ccccc1)O2

Procedure:
3.0 g of 5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2-phenyl-1,3-benzoxathiole were dissolved in 30 ml of tetrahydrofuran. Under a stream of nitrogen, 4.5 g of acetic acid and 12.9 g of tetrabutylammonium fluoride trihydrate were then added to the mixture. The reaction mixture was then allowed to react for 2 hours at room temperature. At the end of this time, the reaction mixture was poured into water, and the resulting precipitate was extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The resulting crude oily substance was subjected to silica gel column chromatography. The title compound was obtained from the portion eluted with a 1:1 by volume mixture of cyclohexane and benzene. It melted at 80°-81° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:54](=[O:62])[NH:55][S:56]([CH:59]([CH3:61])[CH3:60])(=[O:58])=[O:57])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45](O)=[O:46])=[CH:42][C:41]4[CH:48]=[C:49]([O:52][CH3:53])[CH:50]=[CH:51][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:63][N:64]1[CH2:73][CH2:72][C:67]2([NH:71][CH2:70][CH2:69][CH2:68]2)[CH2:66][CH2:65]1>CN(C=O)C.CO>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:54]([NH:55][S:56]([CH:59]([CH3:61])[CH3:60])(=[O:57])=[O:58])=[O:62])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]([N:71]4[C:67]5([CH2:66][CH2:65][N:64]([CH3:63])[CH2:73][CH2:72]5)[CH2:68][CH2:69][CH2:70]4)=[O:46])=[CH:42][C:41]4[CH:48]=[C:49]([O:52][CH3:53])[CH:50]=[CH:51][C:40]=4[C:39]=23)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CN1CCC2(CCCN2)CC1
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(C(=O)N1CCCC13CCN(C)CC3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
HATU (30 mg, 0.079 mmol) was added to a stirring solution of 13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (34 mg, 0.063 mmol) and 8-methyl-1,8-diazaspiro[4.5]decane (24 mg, 0.16 mmol) in DMF (0.5 mL) and TEA (100 μL, 0.72 mmol) and the reaction mixture was stirred at rt for 1 h (complete by LCMS). The reaction mixture was diluted with MeOH, filtered and purified by preparative HPLC (CH3CN/H2O w/10 mM NH4OAc) to yield 13-cyclohexyl-N-(isopropylsulfonyl)-3-methoxy-6-((8-methyl-1,8-diazaspiro[4.5]dec-1-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (19.7 mg, 0.029 mmol, 46% yield) as a yellow solid. 1HNMR (300 MHz, CD3OD) δ ppm 1.10-2.20 (m, 22H), 2.76 (s, 3H), 2.67-3.49 (m, 9H), 3.91 (s, 3H), 3.86-4.00 (m, 1H), 4.27-4.45 (m, 1H), 5.07-5.20 (m, 1H), 6.91 (s, 1H), 7.03 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.73 (dd, J=8.4, 1.5 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 8.26 (br s, 1H). LC-MS retention time: 2.64 min; m/z 671 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[CH3:13])[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: Cc1ccc(OCCCCCl)cc1C
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: Cc1ccc(OCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1C

Procedure:
Prepared by Procedure G and Scheme B1 using 4-(4-chlorobutoxy)-1,2-dimethylbenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 423.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@@:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:17][CH2:18][OH:19])[O:13][C:12]2=[O:27])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1B(O)O>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>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@@:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:17][CH2:18][OH:19])[O:13][C:12]2=[O:27])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Yield: 25.9 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxy ethyl)-1,3-oxazinan-2-one (60 mg, 0.14 mmol), 2,4-difluorophenylboronic acid (26 mg, 0.17 mmol) and Pd(PPh3)4 (16 mg, 0.01 mmol) in dioxane (5 mL) was added a solution of CsCO3 (2 M, 1 mL) at 0° C. Then the reaction mixture was refluxed overnight under nitrogen. The reaction mixture was washed with water and then extract with CH2Cl2 twice. The combined organic phases were dried over Na2SO4, filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (17 mg, 26%). 1H NMR (CD3OD): 0.96 (m, 3H), 2.01 (m, 2H), 2.12 (m, 2H), 2.30 (m, 2H), 2.48 (m, 1H), 3.10 (m, 1H), 3.33 (m, 1H), 3.65 (m, 1H), 5.38 (m, 1H), 7.02 (m, 4H), 7.08 (m, 2H), 7.28 (m, 4H), 7.42 (m, 1H). 443-114-3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26]([CH2:28]Br)=[O:27]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][C:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[O:27])=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.50 g) in 5 mL of dimethylformamide was treated with 60% sodium hydride (0.112 g) and after 20 minutes, bromomethyl 2-naphthyl ketone (0.70 g) was added. The reaction mixture was stirred 3 hours at room temperature, was quenched with 0.1 mL of acetic acid and was diluted with ethyl acetate (75 mL). The mixture was washed with water (1 x 25 mL) and brine (1×25 mL), dried (MgSO4) and chromatographed over 100 g of silica gel, eluting with dichoromethane-ethyl acetate (50:1) to give 0.62 g of 4-[2-(2-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester, mp 120°-121° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.C(N(C(C)C)C(C)C)C.C1N=CN([C:39](N2C=NC=C2)=[O:40])C=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:39](=[O:40])[NH:14][N:13]=3)[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4n[nH]c(=O)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 3-iodo-1-tosyl-1H-indole-5-carbohydrazide (2.00 g, 4.39 mmol) in DMF (10 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (1.68 mL, 9.66 mmol) and CDI (0.784 g, 4.83 mmol). The reaction was stirred at RT for 30 min, followed by 65° C. in an oil bath for 15 min. It was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluted with 20-70% EtOAc in Hex) to afford 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (1.7 g, 80%) as an off white crystalline solid. MS (ESI, pos. ion) m/z: 482.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[CH3:26][O:27][CH2:28][CH:29]1[CH2:31][O:30]1>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH3:25])[N:22]([CH2:31][CH:29]([OH:30])[CH2:28][O:27][CH3:26])[N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: COCC1CO1
Reactant: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)n[nH]1
Solvent: CN(C)C=O
Product: COCC(O)Cn1nc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)cc1C

Procedure:
A mixture of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-methyl-1H-pyrazol-3-yl)-benzamide (0.36 g, 1 mmol) and 2-methoxymethyl-oxirane (0.8 mL) was stirred in N,N-dimethylformamide (1.0 mL) at 90° C. for 12 h. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography, followed by trituration (1:1:1 diethyl ether-dichloromethane-ethyl acetate) to afford the title compound (0.08 g). LCMS (m/z) 450.1 M+1
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:35]=[N:34]C2CCNCC=2C=1.C(C(CCC)C(Cl)=O)CC>>[NH:34]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:11][C:4]=2[CH:3]=1)[NH2:35]
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: CCCC(CCC)C(=O)N1CCc2nnc(Cl)cc2C1
Agent: CCCC(CCC)C(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Product: CCCC(CCC)C(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 3-chloro-5,6,7,8-tetrahydro-6-(2-n-propylvaleroyl)pyrido[4,3-c]pyridazine, required as starting material, is produced in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 2-n-propylvaleroyl chloride. The organic phase is concentrated, and the crude product is extracted from the resulting solid residue with a Soxhlet extraction apparatus, and is recrystallized from cyclohexane. M.P. 94°-95°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)(OC)O[CH2:11][CH:12]=[CH2:13]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH:12]=[CH2:11])=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)OC
Reactant: Oc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCOc1ccc(Cl)cc1
Temperature: 70 °C
Yield: 97.3 %

Procedure:
A mixture of 4-chlorophenol (1.28 g, 10 mmoles), allyl methyl carbonate (1.40 g, 12 mmoles), palladium acetate (11 mg, 0.05 mmole) and triphenyl phosphine (40 mg, 0.15 mmole) is heated at 70° C. for 2.5 hours. After removal of volatiles, the residue is subjected to bulb-to-bulb distillation (110° C., 4 mm Hg) to give 1.64 g, 97 percent of allyl 4-chlorophenyl ether.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>C1COCC1.CO.C(OCC)(=O)C>[C:35]([O:34][C:32]([NH:31][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:39])=[O:2])=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)C(Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoic acid methyl ester (125 mg, 0.24 mmol) in THF (2 mL) and methanol (2 mL) was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring at room temperature for 1 h the solution was acidified with 10% HCl to pH 2 and diluted with ethyl acetate (25 mL). After being seperated, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. Purification by flash column chromatography (2-5% methanol in dichloromethane) provided 2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoic acid (80 mg, 67%) as white solid. 1H NMR (CDCl3), 7.98 (d, J=9 Hz, 2H), 7.93 (d, J=8 Hz, 2H), 7.74 (d, J=9, 2H), 7.59 (m, 4H), 7.41 (m, 5H), 5.01 (d, J=8 Hz, 1H), 4.66 (m, 1H), 3.30 (m, 2H), 1.47 (s, 9H). LCMS 408 (M+−100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][CH2:9][C:8]=2[CH:20]=1)([O-])=O.CO>>[N:14]1([CH:11]2[CH2:10][CH2:9][C:8]3[CH:20]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[CH2:13][CH2:12]2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCOCC1)CC2
Solvent: CO
Product: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reaction time: 10 h

Procedure:
Into a Parr pressure reactor was added 4-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine (200 mg, 0.0007 mol) in methanol (6 mL, 0.1 mol). The reaction was placed under 40 psi for 10 h. HPLC indicated no starting material remaining. The reaction mixture was filtered through celite. The celite was further washed with methanol and DMF. The filtrated was concentrated in vacuo to a tannish-brown solid which was confirmed as product by both 1HNMR and LCMS. Material was carried on without further purification to give 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine. 1HNMR (400 MHz, CDCl3) δ 6.89 (d, 1H, J=7.8 Hz), 6.49 (s, 1H), 6.45 (d, 1H, J=7.8 Hz), 3.70 (broad s, 4H), 3.52 (broad s, 1H), 2.68-2.77 (m, 2H), 2.56 (broad s, 4H), 2.05 (m, 2H), 1.59 (broad s, 2H), 1.39 (m, 2H), 1.22 (m, 2H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1CCl
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1CSc1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.5 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone, and thereto were added 1.2 g of anhydrous potassium carbonate and 1.0 g of α-chloro-o-xylene. The resulting mixture was heated to 80° to 110° C. under stirring for 2 hours. After allowed to cool to room temperature, the mixture was incorporated with 100 ml of water and then stirred. The precipitated solid was filtered off, washed with water, dried and recrystallized from ethanol to give white needle-like crystals having the following physical properties (yield: 72.7%):