Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:9]([C:11]2[CH:36]=[CH:35][C:14]([O:15][C:16]3[N:21]=[CH:20][C:19]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH:37]([C:39]1[S:40][CH:41]=[CH:42][N:43]=1)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[S:40]1[CH:41]=[CH:42][N:43]=[C:39]1[CH2:37][N:6]1[CH2:7][CH2:8][N:3]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[N:21]=[CH:20][C:19]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)=[CH:35][CH:36]=2)=[O:10])[CH2:4][CH2:5]1
Reactant: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCNCC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCN(Cc4nccs4)CC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-{6-[4-(piperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethyl-benzamide dihydrochloride (400 mg, 0.74 mmol) in 1,2-dichloroethane (20 mL) were added 2-formylthiazole (125 mg, 1.10 mmol) and triethylamine (0.21 mL, 1.50 mmol). After the resulting solution was stirred at room temperature for 30 minutes, sodium triacetyloxy borohydride (312 mg, 1.47 mmol) was added under ice cooling. The reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. Acetic acid (0.085 mL, 1.48 mmol) was added to the reaction mixture, and stirred at room temperature for 17 hours. The reaction mixture was poured into ice water, and extracted with chloroform. The chloroform layer was washed with a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. A significant part of the solvent was evaporated. The white precipitate was then filtered off and washed with ethyl acetate, to thereby yield 293 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2o1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)oc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
A solution of 6-nitrobenzo[d]oxazol-2(3H)-one (0.500 g, 2.78 mmol) in DMF (10 ml) was cooled to 0° C. NaH (60% w/w dispersion in mineral oil, 0.133 g, 3.33 mmol) was added, and the reaction was allowed to warm to room temperature and stirred for 15 minutes. The mixture was cooled to 0° C., methyl 2-bromoacetate (0.309 ml, 3.33 mmol) was added, and the reaction was warmed to room temperature and stirred for 4 hours. The mixture was partitioned between ethyl acetate and 1N HCl. The organic phase was washed several times with brine and dried over sodium sulfate. The solvent was removed, and the crude was purified by trituration with diethyl ether (50 ml) affording methyl 2-(6-nitro-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.570 g, 2.260 mmol, 81% yield). MS/ESI+ 252.9 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:23][NH:22][C:10](=[O:11])[C:9]=2[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CC1(O)OC(=O)C(c2cccs2)=C1c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(=O)c(-c2cccs2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A mixture of 3.35 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(2-thienyl)-2(5H)-furanone, 0.70 g of hydrazine monohydrate and 30 ml of 1-butanol was heated under reflux for 7 hours. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure to obtain 1.46 g of 5-(4-chloro-phenyl)-6-methyl-4-(2-thienyl)-2H-pyridazin-3-one.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.[OH-].[Li+].Cl>C1COCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:5]([CH2:4][C:3]([OH:19])=[O:2])=[CH:6][N:7]=[CH:8]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: COC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1

Procedure:
A solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester (4.44 g, 17.4 mmol) in THF (100 ml) and 1M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1M HCl (17.4 ml) was added and the THF was removed by evaporation in vacuo. The aqueous solution was lyophilized to afford the title compound containing lithium chloride as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].Br[CH2:13][CH2:14][CH2:15][OH:16].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[OH:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCCCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.0 g, 33.29 mmol) in DMF (30 mL) were added 3-bromo propan-1-ol (5.56 g, 39.95 mmol) and Cs2CO3 (16.24 g, 50.0 mmol). Then, the reaction mixture was stirred at room temperature for 48 hours. Then, water was added and the products were extracted with ethyl acetate (2×250 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 5.38 g (77%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([N:8]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]3)[P:9]2([CH3:24])=[O:23])[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:36](Br)[CH:37]=[CH2:38].[CH3:40][C:41]([CH2:43]C)=O>>[CH2:36]([N:16]1[C:17]([CH3:19])([CH3:20])[CH2:18][CH:13]([N:10]2[CH2:11][CH2:12][N:8]([CH:6]3[CH2:7][C:2]([CH3:27])([CH3:1])[N:3]([CH2:43][CH:41]=[CH2:40])[C:4]([CH3:26])([CH3:25])[CH2:5]3)[P:9]2([CH3:24])=[O:23])[CH2:14][C:15]1([CH3:22])[CH3:21])[CH:37]=[CH2:38]
Reactant: CCC(C)=O
Reactant: CC1(C)CC(N2CCN(C3CC(C)(C)NC(C)(C)C3)P2(C)=O)CC(C)(C)N1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: C=CCN1C(C)(C)CC(N2CCN(C3CC(C)(C)N(CC=C)C(C)(C)C3)P2(C)=O)CC1(C)C
Reaction time: 18 h

Procedure:
A mixture of 19.9 g (0.05 mole) of 1,3-bis-(2,2,6,6-tetramethylpiperid-4-yl)-2-methyl-2-oxo-1,3,2-diazaphospholane (compound 1), 16.6 g of potassium carbonate, 0.3 g of finely powdered potassium iodide, 24.2 g of allyl bromide and 80 ml of ethyl methyl ketone is stirred for 18 hours at reflux temperature. The mixture is then filtered, the filtrate is freed from the solvent in vacuo and the residual crystalline crude product is recrystallised from acetonitrile, yielding pure 1,3-bis(1-allyl-2,2,6,6-tetramethylpiperid-4-yl)-2-methyl-2-oxo-1,3,2-diazaphospholane (compound 13) with a melting point of 168°-169° C.
Reaction SMILES: [Br:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.[C:11]1([CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C:19](O)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][O:10][C:19](=[O:20])[CH2:18][CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][CH2:4]1
Reactant: OC[C@H]1CC[C@H](CBr)CC1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Product: O=C(CC(c1ccccc1)c1ccccc1)OC[C@H]1CC[C@H](CBr)CC1

Procedure:
From 4-bromomethyl[trans]cyclohexylmethanol and 3,3-diphenylpropionic acid. Yield: 60% (oil).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16].C(OCC)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reaction time: 1 h

Procedure:
The 2,6-dichloropurine (5.00 g, 26.46 mmol) was suspended in 55 ml of dry DMF at room temperature and treated with sodium hydride, 60% dispersion (1.21 g, 31.75 mmol) added in portions. After stirring for 1 hr, 2-iodopropane (4.5 ml, 44.98 mmol) was added and the reaction stirred for 2 days. The reaction was poured into diethyl ether and washed once with saturated sodium bicarbonate solution and once with water. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was chromatographed over silica gel eluting with 10% acetone in dichloromethane solution to give the desired N-9 alkylation product as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[S:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccsc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccsc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3-thiophenecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.Cl[C:11]([O:13][CH3:14])=[O:12]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[O:13][CH3:14])=[C:4]([I:9])[CH:3]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(Br)cc1I
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(Br)cc1I
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To solution of 4-bromo-2-iodoaniline (18.50 g, 62.08 mmol) in pyridine (120 mL) at −10° C. was added methyl chloroformate (7.50 mL, 97.46 mmol) over 30 min via syringe pump. Reaction was allowed to warm to room temperature and was diluted with H2O (450 mL). Solid which was formed was collected by filtration, washed with H2O and dried in dessicator. Methyl 4-bromo-2-iodophenylcarbamate (21.59 g, 98%) was obtained as colorless solid.
Reaction SMILES: [C:1]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[CH2:23]=O>C(O)C>[N:17]1([CH2:23][CH:2]([CH2:3][CH3:4])[C:1]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:7]=2)=[O:5])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: C=O
Reactant: CCCC(=O)c1cc(-c2ccccc2)no1
Solvent: CCO
Product: CCC(CN1CCCCC1)C(=O)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Added to 320 ml of ethyl alcohol were 160 g (0.74 mol) of 5-butyryl-3-phenylisoxazole and 103 ml of piperidine, followed by the dropwise addition of 96 ml (1.18 mol) of a 37% aqueous solution of formaldehyde under ice cooling over 30 minutes. After the reaction mixture was stirred for 1.5 hours at room temperature, the solvent was distilled off. The residue was dissolved in 800 ml of ethyl ether. The resultant solution was washed with water and the organic layer then dried over anhydrous magnesium sulfate. The solvent was distilled off, whereby the target compound, 5-(2-piperidinomethylbutyryl)-3-phenylisoxazole was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCc2c(Br)cc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc(Br)c2c(c1)C(=O)NC2
Yield: 100 %

Procedure:
A mixture of Example 104B (103 mg, 0.45 mmol), Cs2CO3 (164 mg, 0.5 mmol) and t-butyl bromoacetate (0.075 mL, 0.5 mmol) in DMF (2.2 mL) was stirred overnight at room temperature, diluted with water, and filtered. The filter cake was dried to give 154 mg (45%) of the desired product. MS (ESI(+)) m/e 342,344 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:10][C:7]=1[CH:8]=O.[S:27]=[C:28]1[NH:32][C:31](=[O:33])[CH2:30][S:29]1>C1C=CC=CC=1>[Br:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:10][C:7]=1[CH:8]=[C:30]1[S:29][C:28](=[S:27])[NH:32][C:31]1=[O:33]
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1OCc1ccccc1Br
Reactant: O=C1CSC(=S)N1
Solvent: c1ccccc1
Product: O=C1NC(=S)SC1=Cc1ccc(OCCN2CCOCC2)cc1OCc1ccccc1Br

Procedure:
2-(2-Bromobenzyloxy)-4-(2-morpholin-4-yl-ethoxy)benzaldehyde (43 mg, 0.102 mmol) obtained in step 4 was dissolved in benzene and reacted with 2-thioxothiazolidin-4-one in the same manner as in step 2 of Example 1 to afford the object compound (yellowish solid, 25 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:27]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH2:11][N:37]2[CH2:38][CH2:39][CH:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:26]([CH3:25])=[O:27])[CH2:35][CH2:36]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)c1ccccc1C1CCNCC1
Product: CCN1C(=O)c2ccccc2C1C(CCN1CCC(c2ccccc2S(C)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 98.6 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.24 g) and 4-(2-methylsulfinylphenyl)piperidine (0.224 g) were coupled using conditions similar to those described Example 1 to give the title compound (0.198 g); mp 150° C. (dec); MS: m/z=571(M+1); NMR (CD3OD): 1.3 (m,3), 2.0 (m,6), 2.6 (m,1), 3.3 (m,12), 5.05 (m,1), 7.28 (m,11). Analysis for C31H34Cl2N2O2S.1.0 HCl.0.9 H2O: Calculated: C, 59.83; H, 5.96; N, 74.50; Found: C, 59.55; H, 5.76; N, 4.89.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[CH:11]=[CH:12]C2C=CC=CC=2)=[C:5]([CH3:20])[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1.O>CCCCCC>[OH:2][C:3]1[CH:8]=[C:7]2[C:6](=[C:5]([CH3:20])[CH:4]=1)[NH:9][C:10](=[O:19])[CH:11]=[CH:12]2
Reactant: COc1ccc(NC(=O)C=Cc2ccccc2)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: Cc1cc(O)cc2ccc(=O)[nH]c12
Temperature: 125 °C
Reaction time: 1 h

Procedure:
To N-(4-methoxy-2-methylphenyl)cinnamamide (28.33 g, 0.106M), aluminum chloride (70.5 g, 529 mmol) and chlorobenzene (175 ml) were added, and the mixture was stirred in a bath of 125° C. for 1 hour. Thereafter, the mixture was cooled and poured into ice--water, to which n-hexane was added. The insoluble matter was collected by filtration, and washed with chloroform. As a result, 15.0 of 6-hydroxy-8-methylcarbostyril was obtained as brown crystals (80.8%).
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=O.[NH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][NH2:15].N1[C:20]2C=CC=C[C:19]=2N=N1.C(C=O)=O.[BH4-].[Na+]>O.CO>[CH3:4][C:2]12[CH:1]3[N:6]4[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][N:12]1[CH2:11][CH2:10][N:9]2[CH2:8][CH2:7]4
Reactant: NCCNCCNCCN
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(=O)C=O
Agent: O=CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC12C3N4CCN3CCN1CCN2CC4
Temperature: 2 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A 40% strength solution of 61.53 g of pyruvaldehyde in water (341.8 mmol) in 20 ml of water is added by slow dropwise addition INto a solution of 50 g (341.8 mmol) of triethylenetetraamine in 800 ml of distilled water cooled to 2° C. On completion of addition, the reaction mixture is adjusted to ambient temperature and 81.36 g (683.6 mmol) of benzotriazole are added in a single portion. A solution of glyoxal (40% in water) (341.8 mmol) in 200 ml of methanol is then added by slow dropwise addition. After 2 h of stirring at ambient temperature, 25.85 g (683.6 mmol) of NaBH4 are added in small portions. After 2 h of stirring at ambient temperature, the methanol is evaporated and 50 g of KOH pellets are added to the residue. The solution is then extracted with three 1.5 l portions of chloroform. After drying over MgSO4 and evaporation of the solvents, (IIb) is isolated in the form of an orange oil (28.50 g; yield=40%).
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].S(=O)(=O)(O)O.[Cl:14][CH:15]=[CH:16]Cl.C([O-])([O-])=[O:19].[K+].[K+]>O>[Cl:14][CH:15]([CH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[CH:16]=[O:19]
Reactant: O=C([O-])[O-]
Reactant: ClC=CCl
Reactant: O=C1CCCN1CO
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=CC(Cl)CN1CCCC1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
In a 250 ml, three-necked flask fitted with a magnetic stirrer, 1-(hydroxymethyl)pyrrolidin-2-one x82 (15 g, 0.13 mol) is cooled to −10° C. Cold concentrated sulfuric acid (150 ml) is added dropwise. At this temperature, 1,2-dichloroethene (46.73 g, 0.482 mol) is added while the temperature is kept below 0° C. At the end of the addition the mixture is stirred at 40° C. for 2 h. Water is added and the pH is adjusted with K2CO3. The aqueous phase is extracted with CH2Cl2, the combined organic phases are dried over MgSO4, filtered and concentrated. The crude 2-chloro-3-(2-oxopyrrolidin-1-yl)propanal x83 is used in the next step without any further purification.
Reaction SMILES: [O-:1][CH2:2]C.[Na+].C[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[CH2:15]([O:17][CH2:18][C:19](OCC)=[O:20])[CH3:16]>C(O)C>[CH2:15]([O:17][CH2:18][C:19](=[O:20])[CH:12]([C:9]1[CH:8]=[CH:7][C:6]([O:1][CH3:2])=[CH:11][CH:10]=1)[C:13]#[N:14])[CH3:16]
Reactant: Cc1ccc(CC#N)cc1
Reactant: CC[O-]
Reactant: CCOCC(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: CCOCC(=O)C(C#N)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Sodium ethoxide (2 eq) is dissolved in ethanol (200 mL) and 4-methylphenylacetonitrile (10.0) and ethyl ethoxyacetate (1.5 eq) are slowly added. The reaction mixture is stirred for 1 hour under reflux. Upon completion of the reaction, ethanol is removed under reduced pressure and water (100 mL) and ethyl acetate are added. The organic layer is removed and the aqueous layer is acidified by adding acetic acid (10 mL) and extracted 3 times with ethyl acetate. The extracted organic layer is collected, washed with water and dehydrated with MgSO4. After concentration under reduced pressure, the produced solid is recrystallized with Hx:EA=20:1 to obtain the target compound (70-95%).
Reaction SMILES: O[C@@H:2]1[CH2:22][C:21]2[C@:16]([CH3:24])([CH:17]=[CH:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@@H:3]1[C@H:4]1[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@H:7]([CH:8]([CH:10]=O)[CH3:9])[CH2:6][CH2:5]1.[CH3:26][C:27]([CH3:32])([CH2:30][OH:31])[CH2:28][OH:29].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:27]1([CH3:32])[CH2:30][O:31][CH:10]([CH:8]([C@@H:7]2[C@:12]3([CH3:25])[C@H:4]([C@H:3]4[C@H:15]([CH2:14][CH2:13]3)[C@:16]3([CH3:24])[C:21](=[CH:20][C:19](=[O:23])[CH:18]=[CH:17]3)[CH:22]=[CH:2]4)[CH2:5][CH2:6]2)[CH3:9])[O:29][CH2:28]1
Reactant: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 30.7 %

Procedure:
In 200 ml of benzene were dissolved 5.00 g (14.6 moles) of 7α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde and 4.56 g (43.8 mmoles) of 2,2-dimethyl-1,3-propanediol, followed by addition of 100 mg of p-toluenesulfonic acid. The mixture was refluxed for 5 hours, with the byproduct water being constantly removed from the reaction system by means of a Dean-Stark trap. The reaction mixture was cooled to room temperature and washed with aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ether-hexane (70:30, v/v) and the extract was combined with the organic layer. This mixture was washed with aqueous sodium chloride solution and dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eleuent: ethyl acetate-hexane=1:10, v/v) to recover 5.53 g of 20-(5,5-dimethyl-1,3 -dioxan-2-yl)pregna-1,4,6-trien-3-one (yield: 92%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:17]2=[CH:18][O:19][N:20]=[C:16]2[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:14]([CH2:28][OH:29])[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:17]2=[CH:18][O:19][N:20]=[C:16]2[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:14]([CH:28]=[O:29])[CH:13]=1
Reactant: OCc1cc(Cl)c2conc2c1-c1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cc(Cl)c2conc2c1-c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
Dimethyl sulfoxide (0.064 mL, 0.90 mmol) was added to oxalyl chloride (0.048 mL, 0.56 mmol) in methylene chloride (2.1 mL) at −78° C. After 10 minutes, [4-chloro-7-(3-fluorophenyl)-2,1-benzisoxazol-6-yl]methanol (0.104 g, 0.374 mmol) in methylene chloride (4.2 mL) was added and the resulting mixture was stirred at −78° C. for 30 minutes. Triethylamine (0.261 mL, 1.87 mmol) was then added and the mixture was stirred for 5 hours at room temperature. After quenching with water, the mixture was extracted with methylene chloride. The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated to dryness. The resulting mixture was purified on silica gel, eluting with 0 to 30% ethyl acetate in hexane, to give the desired product (88 mg, 85%). LCMS calculated for C14H8ClFNO2 (M+H)+: m/z=276.0; Found: 276.1.