Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH:29][CH3:30])([CH2:23][C:24]#[C:25][CH2:26][O:27][CH3:28])[C:19]([O:21]C)=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O=S(Cl)Cl.CI.C([O-])([O-])=O.[Cs+].[Cs+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]([NH:29][CH3:30])([CH2:23][C:24]#[C:25][CH2:26][O:27][CH3:28])[C:19]([OH:21])=[O:20])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CNC(CC#CCOC)(C(=O)OC)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: CI
Product: CNC(CC#CCOC)(C(=O)O)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methyl-amino-6-methoxyhex-4-ynoate: The acid 51 (500 mg, 1.23 mmole) is dissolved in 20 mL of MeOH and treated with 8 mL of SOCl2. The resulting mixture is stirred at RT for 18 hr. and then evaporated. The residual solid is dissolved in 10 mL of dimethylacetamide and treated with methyl iodide (0.092 mL, 1.47 mmole) in the presence of 600 mg of Cs2CO3. The resulting mixture is stirred for 2 hr and then partitioned between EtOAc and H2O. The organic layer is washed with water and then brine, dried over MgSO4, filtered and evaporated to give a yellow oil. The title acid is prepared from compound 52b as described for compound 46f.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH:23](=O)[CH3:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: CC=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
In a 100 mL round-bottomed flask, 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (179 mg, 560 μmol, Eq: 1.00) and acetaldehyde (247 mg, 316 μl, 5.6 mmol, Eq: 10.0) were combined with THF (5.0 ml) to give a light yellow solution. Acetic acid (33.6 mg, 32.0 μl, 560 μmol, Eq: 1.00) was added. The reaction mixture was cooled to 0° C. Sodium triacetoxyborohydride (178 mg, 840 μmol, Eq: 1.5) was added. The reaction mixture stirred at room temperature for 2 h. The reaction was poured into water, and then saturated NaHCO3 was added to the solution until it was basic. The solution was extracted twice with EtOAc, and then the organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a solid. The solid was triturated with ether to give 6-chloro-4-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (121 mg, 62%). LC/MS-ESI observed [M+H]+ 348.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-]>CO.O>[C:21]1([CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:7][CH2:8]2)=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CN1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CN1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
A mixture of [4-(3,3-diphenyl-propionyl)-piperazin-1-yl]-acetic acid ethyl ester (1.17 g, 3.07 mmol) and LiOH (645 mg, 15.35 mmol) in MeOH: H2O (3:1, 40 ml) stirred at room temperature for 2 days. The solvent was then evaporated and residue dissolved in water. Upon acidified with 2N HCl to pH 3, product precipitated in aq. phase, filtered and washed few times with water and dried to give the desired product in 78% yield.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]1[C:13]2[O:12][CH:11]=[CH:10][C:9]=2[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][CH:6]=1.NOS(O)(=O)=O.CN(C)C=O>C(OCC)C>[N+:14]([C:8]1[C:9]2[CH:10]=[CH:11][O:12][C:13]=2[C:5]([CH2:4][C:3]#[N:2])=[CH:6][CH:7]=1)([O-:16])=[O:15]
Reactant: CN(C)C=Cc1ccc([N+](=O)[O-])c2ccoc12
Agent: NOS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#CCc1ccc([N+](=O)[O-])c2ccoc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
Add dimethyl[2-(4-nitrobenzofur-7-yl)vinyl]amine (4.8 g, 20.6 mmol) and hydroxylamine-O-sulfonic acid (4.6 g, 40.6 mmol) to dimethylformamide (45 mL) and stir at room temperature for 15 minutes. Heat at 100° C. under nitrogen for 1 hour, cool to room temperature, dilute with diethyl ether, and wash with water and aqueous saturated sodium chloride. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Chromatography on flash silica using 85% hexane, 15% ethyl acetate gives 2.9 g (64%) of the title compound as a light brown solid. Mass spectrum (ES, m/z) (M−1)=200.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].[BH4-].[Na+].CCO>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:19]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCOC(=O)CN
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
3,4-Dimethoxybenzaldehyde (2.358 g, 14.19 mmol) was dissolved in dry THF (14.19 ml) under nitrogen atmosphere, and a solution of glycine ethyl ester (1.33 g, 12.90 mmol) in dry THF (6.47 ml) was added followed by a solution of tetraisopropoxytitanium (5.73 ml, 19.35 mmol) in dry THF (5.83 ml). The resulting mixture was stirred at RT overnight. NaBH4 (1.366 g, 36.1 mmol) was suspended in abs. EtOH (46.3 ml) and added drop wise to the reaction mixture, stirring for 3 hours. The reaction mixture was treated with water (30 ml) and then filtered through a sintered glass funnel. The filtrate was partitioned between EtOAc and brine and the aqueous phase was extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and the solvent was removed under vacuum affording 2.52 g of crude product. 1.4 g of this product were purified by chromatography on silica gel column (DCM:EtOAc=70:30 to 50:50) affording ethyl 2-(3,4-dimethoxybenzylamino)acetate (0.200 g, 0.790 mmol, MS/ESI+ 254.2 [MH]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].O.[NH2:23][NH2:24].C(OCC)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:16][CH2:17][C:18](=[O:20])[NH:23][N:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)COc1ccc(C(=O)CCC(=O)O)cc1Cl
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1ccc(C2=NNC(=O)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a stirred suspension of 4-[3-chloro-4-(ethoxycarbonylmethoxy)phenyl]-4-oxobutyric acid (9, 21.5 g, 69.2 mmol) in ethanol (200 mL) at 0° C. was added a solution of hydrazine monohydrate (3.4 mL, 69.2 mmol) in ethanol (20 mL). The reaction mixture was then allowed to warm to ambient temperature and stirred at this temperature for 15 minutes before being heated to reflux and stirred at this temperature for 3 hours. Ethyl acetate (40 mL) was added to the hot solution and the mixture was allowed to cool to ambient temperature. The precipitate which formed was filtered off and washed with water (2×100 mL) and cold ethanol (2×100 mL), then dried with suction, then under high vacuum to give 10 as light yellow powder (17.6 g, 82% yield, 99% pure by LCMS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.52 (m, 1H); 7.41 (m, 1H); 6.70 (m, 1H); 4.90 (s, 2H); 4.12 (q, 2H); 2.22 (m, 2H); 1.62 (m, 2H); 1.30 (q, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=3)=[CH:18][C:13]=2[O:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][N:56]([C:59](=[O:70])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[O:52]=[C:51]([N:53]1[CH2:54][CH2:55][N:56]([C:59](=[O:70])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])[CH2:57][CH2:58]1)[CH2:50][NH:49][C:24]([C:21]1[CH:20]=[C:19]([C:17]2[CH:16]=[CH:15][C:14]3[O:10][CH2:11][O:12][C:13]=3[CH:18]=2)[NH:23][N:22]=1)=[O:26]
Reactant: O=C(O)c1cc(-c2ccc3c(c2)OCO3)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccc3c(c2)OCO3)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 95.5 %

Procedure:
DIPEA (77 mg, 0.1 mL, 0.59 mmol) was added to a stirred solution of 5-benzo[1,3]dioxol-5-yl-1H-pyrazole-3-carboxylic acid (60 mg, 0.17 mmol))(prepared by the method as described above) in DMF (2 mL). HOBT (24 mg, 0.17 mmol) and EDCI (34.3 mg, 0.17 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (60 mg, 0.17 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 86 mg (95% yield) of 5-benzo[1,3]dioxol-5-yl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.365%. 1H NMR (DMSO-d6): δ 13.6 (s, 1H), 8.0 (s, 1H), 7.7 (m, 2H), 7.6 (m, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0 (m, 2H), 6.0 (s, 2H), 4.1 (m, 2H), 3.7 (m, 2H), 3.54 (m, 2H), 3.4 (m, 2H), 3.1 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[N:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C.O>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]2[O:18][C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[N:8][C:9]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: Cc1ccsc1C=Nc1cc([N+](=O)[O-])ccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccsc1-c1nc2cc([N+](=O)[O-])ccc2o1
Yield: 41.5 %

Procedure:
2-[[(3-Methyl-2-thienyl)methylene]amino]-4-nitrophenol (13.1 g, 0.05 mole) is heated to reflux in 500 ml of glacial acetic acid and lead tetraacetate (22.2 g, 0.05 mole) is added to the hot mixture. After heating for 10 minutes, the mixture is diluted with 1 liter of water and the precipitated product collected. The crude material is dissolved in chloroform (350 ml) and treated with activated charcoal. The chloroform is evaporated yielding 5.4 g of product, melting point 174°-176° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1>>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:55])([CH3:57])[CH3:56])=[O:52])[CH2:47][CH2:46]3)[CH:10]=2)[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(O)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2ccccc2)CC1
Reaction time: 19 h
Yield: 51 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 6-hydroxy-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 19 h, and being recrystallized with EtOAc to give the title compound (51%).
Reaction SMILES: [C-:1]#[N:2].[K+].[I-].[Na+].[CH3:6][O:7][C:8]1[C:13]([CH2:14]Cl)=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.O>CS(C)=O>[CH3:6][O:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1c(CCl)cccc1Oc1ccccc1C
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(CC#N)cccc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Powdered potassium cyanide (12.50 g) and sodium iodide (28.80 g) were added to a solution of o-tolyl 2-methoxy-3-chloromethylphenyl ether (47.50 g) in dimethylsulfoxide (100 ml) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water 3 times, dried over magnesium sulfate and then evaporated to give only 2-[2-methoxy-3-(o-tolyloxy)phenyl]acetonitrile (44.0 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][N:27]=3)[CH:15]=[CH:14][C:13]1=2.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(CO)cn3)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C=O)cn3)ccc21
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in 25 ml of methylene chloride is placed in a 4-necked flask equipped with a stirrer, a thermometer and two pressure-equalizing addition funnels fitted with drying tubes. The solution is cooled to -60° C. and then treated dropwise with a solution of 1.875 g (24 mmol) of dimethyl sulfoxide (distilled from calcium hydride) in 5 ml of methylene chloride over a five minute period. The reaction mixture is then stirred at -60° C. for an additional 10 minutes. A solution of 3.195 g (10 mmol) of 2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-hydroxymethylpyridine in 10 ml of methylene chloride is then added to the reaction mixture over a period of 5 minutes. The mixture is stirred for a further 15 minutes and is then treated with 5.06 g (50 mmol) of triethylamine. The cooling bath is then removed and the mixture is allowed to warm to room temperature. Thirty ml of water is then added to the mixture and stirring is continued for a further 10 mintues. The organic layer is then separated and the aqueous layer is extracted with 20 ml of methylene chloride. The organic layers are then combined and washed successively with dilute HCl, water and dilute Na2CO3 solution and then dried (MgSO4). The solution is then filtered and concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][OH:24]>ClCCl>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: Cc1cccc(Nc2ccccc2CO)c1C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cccc(Nc2ccccc2C=O)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A suspension of pyridinium chlorochromate (47.5 g, 0.22 mol) and neutral alumina (170 g) in dichloromethane (600 ml) is stirred for 30 minutes at room temperature. 2-[(2,3-dimethylphenyl) amino]benzyl alcohol (25 g, 0.11 mol) is added and the reaction mixture is stirred at room temperature overnight. The suspension is filtered through a pad of silica gel (1000 g) and the product is eluted with dichloromethane (2500 ml). The combined filtrate and eluant are evaporated and the residue is recrystallized from cold methanol/water to give 2-[(2,3-dimethylphenyl)amino] benzaldehyde (11.95 g, 48%). Recrystallization from hexane at 0° C. gives analytical material; mp 45-47° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C.O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]4[N:11]=[CH:12][C:13]([F:16])=[CH:14][N:15]=4)[CH2:9][C@@H:4]3[CH2:3]2)=[CH:21][CH:20]=1
Reactant: O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(CO[C@@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 100 °C
Yield: 8.2 %

Procedure:
A solution of 0.75 g (3.15 mmol) of (7R,8aS)-7-hydroxy-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6) and 0.79 mL (6.3 mmol) of 4-fluorobenzyl bromide in 30 mL of dry DMF was treated with 0.15 g (3.8 mmol) of sodium hydride (60% oil dispersion), and the mixture was heated at 100° C. for 18 hours. The mixture was cool, diluted with water, and extracted with diethyl ether (5×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatograph with 50:50 ethyl acetate:hexane gave 0.090 g (8%) of the title compound. Mp (.HCl) 74-79° C. 13C NMR (base, CDCl3): δ 35.6, 43.9, 48.9, 51.2, 60.4, 60.7, 70.7, 76.7, 115.1, 115.4, 129.35, 129.46, 133.9, 144.9, 145.2, 149.9, 153.2, 158.9, 164.0. HRMS calc'd for C18H20F2N4O (MH+): 347.1683, found: 347.1671.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[CH2:5]2.[H-].[Na+].[CH3:19]I.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[CH:5]2[CH3:19]
Reactant: CC(C)(O)CN1Cc2cc(Br)ccc2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1c2cc(Br)ccc2C(=O)N1CC(C)(C)O
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, 100 mg of 5-bromo-2-(2-hydroxy-2-methyl-propyl)-1-oxo-isoindoline obtained in Example 177-1) was dissolved in tetrahydrofuran, 40 mg of sodium hydride, 0.4 ml of methyl iodide were added and the mixture was heated under reflux for 2 hours. The reaction solution was cooled down to room temperature, water was added, and the products were extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by thin-layer silicagel column chromatography (ethyl acetate) to obtain 7 mg of the above compound as a white solid.
Reaction SMILES: CC[C:3](C1C=CC=CC=1)=[S:4].Br[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14].C[S-].[Na+]>C(O)C>[CH3:3][S:4][CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CCC(=S)c1ccccc1
Agent: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSCC(=O)c1ccc2ccccc2c1

Procedure:
The procedure is as in Example 4 for the preparation of α-methylthioacetophenone, starting with 2-(2-bromoacetyl)naphthalene (12.5 g) and sodium methanethiolate (3.5 g) in ethanol (100 cc). 2-[2-(Methylthio)acetyl]naphthalene (8 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([CH2:16][CH3:17])=[N:6][NH:7][C:8]2=O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=2)[C:5]([CH2:16][CH3:17])=[N:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1n[nH]c(=O)c2cc(OC)cc(OC)c12
Product: CCc1nnc(Cl)c2cc(OC)cc(OC)c12

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 5,7-dimethoxy-4-ethyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[CH2:45][C:46](O)=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[CH2:45][C:46]([NH:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13)=[O:47]
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: O=C(O)Cc1cc(F)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NC(=O)Cc2cc(F)ccc2Br)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 24 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.14 M and 0.40 M in N,N-dimethylacetamide, respectively, 287 μL) and 2-(2-bromo-5-fluorophenyl)acetic acid (0.4 M in N,N-dimethylacetamide, 124 μL), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.21 M in N,N-dimethylacetamide, 287 μL) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C. and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0058 g (24%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.14 (d, J=2.44 Hz, 1H), 7.68 (dd, J=8.85, 5.49 Hz, 1H), 7.65 (s, 1H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.36 (dd, J=9.61, 3.20 Hz, 1H), 7.21 (d, J=8.54 Hz, 1H), 7.14 (td, J=8.54, 3.36 Hz, 1H), 7.04 (s, 1H), 6.82 (m, 2H), 6.49 (m, 2H), 5.02 (d, J=15.87 Hz, 1H), 4.18 (d, J=16.78 Hz, 1H), 4.03 (s, 3H), 3.92 (s, 2H). MS (APCI+) m/z 575.1 (M+H)+.