Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[C:7]#[N:8])=[O:4]>CO.C1COCC1>[OH:4][CH2:3][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c(C=O)cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c(CO)cccc1[N+](=O)[O-]

Procedure:
Sodium borohydride (92.0 mg, 2.43 mmol) was added to a solution of 2-formyl-6-nitrobenzonitrile (Example 207e) (0.86 g, 4.88 mmol) in MeOH (38 mL) and THF (38 mL) at −8° C., and was stirred at that temperature for no more than 30 min. The reaction was quenched with HCl (6 M, 4.88 mL), followed by addition of water (50 mL), and brine (50 mL). The mixture was extracted with EtOAc, the combined extract was dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography on silica using the solvent gradient CH2Cl2→CH2Cl2/MeOH (8:2) to give the title compound in amount of 0.32 g, (37%), which was used immediately in the next step. 1H NMR (400 MHz, DMSO-d6) δ 4.77 (d, J=5.6 Hz, 2H), 5.87 (t, J=5.6 Hz, 1H), 7.97 (t, J=8.0 Hz, 1H), 8.07 (dd, J=0.4, 8.0 Hz, 1H), 8.28 (dd, J=0.8, 8.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1.[Cl:21]CCl.CO>>[Cl:21][C:5]1[CH:4]=[C:3]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[CH:2]=[CH:7][C:6]=1[NH2:8]
Reactant: CC1CCN(CCNc2ccc([N+](=O)[O-])cc2Cl)CC1
Reactant: ClCCl
Solvent: CO
Product: CC1CCN(CCNc2ccc(N)c(Cl)c2)CC1

Procedure:
Prepared analogously to Example 3.1.b. from (2-chloro-4-nitrophenyl)-[2-(4-methylpiperidin-1-yl)ethyl]amine. Yield: 7 g (89.3% of theory); C14H22ClN3 (M=267.80); calc.: molecular ion peak (M+H)+: 268/270; found: molecular ion peak (M+H)+: 268/270; Rf value: 0.6 (Alox, dichloromethane/methanol (49:1)).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[CH2:3]1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[O:13]=[C:4]1[N:5]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:2](=[O:1])[CH2:3]1
Reactant: O=C1CC(=O)Nc2ccccc2N1
Reactant: BrCC1CC1
Product: O=C1CC(=O)N(CC2CC2)c2ccccc2N1CC1CC1

Procedure:
2,4-Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared following General Procedure 8-M using the product from Example 8-P, Step A and (bromomethyl)cyclopropane (Lancaster). Purification was by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to straight EtOAc), then recrystalization from EtOAc/hexanes.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:28][C:29]([F:45])([F:44])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH:40]=[CH:39][N:38]=[C:37]1[C:41]([OH:43])=O>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:41]([C:37]3[N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:29]([F:28])([F:45])[F:44])[CH:40]=[CH:39][N:38]=3)=[O:43])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1nccn1-c1ccccc1C(F)(F)F
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3nccn3-c3ccccc3C(F)(F)F)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 1-[2-(trifluoromethyl)phenyl]-1H-imidazole-2-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [Mg].[C:2]1([CH2:8][CH2:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl[Si](C)(C)C.Cl>C1COCC1>[OH:14][C:10]([CH2:9][CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:11][CH2:12][CH3:13])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCl
Reactant: CCCC(=O)CCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Reaction time: 2 h
Yield: 72.3 %

Procedure:
Magnesium (13.6 g, 0.559 mole) was suspended in THF (50 mL), and thereto was added a mixture of 1-phenyl-3-hexanone (20.09 g, 0.114 mole), ethyl chloroacetate (34.8 g, 0.284 mole) and chlorotrimethylsilane (15.4 g, 0.142 mole) at 20° C.-30° C. over 180 min in a thin stream. The mixture was stirred at 20° C.-30° C. for 2 hr and treated with diluted hydrochloric acid to give a THF solution containing ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate (21.8 g, yield: 72.3%; quantified by absolute calibration curve method (external standard method) using HPLC).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=[N:11]O)[NH:4][C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1.[OH-].[NH4+]>>[F:1][C:2]([F:14])([F:13])[C:3]1[N:4]=[C:5]2[CH:10]=[N:9][CH:8]=[CH:7][N:6]2[N:11]=1
Reactant: ON=C(Nc1cnccn1)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: FC(F)(F)c1nc2cnccn2n1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
A mixture of 2,2,2-trifluoro-N′-hydroxy-N-pyrazin-2-ylethanimidamide (10.5 g, 50.97 mmol, from Step B) and polyphosphoric acid (80 mL) was heated to 150° C. with stirring for 18 h. The solution was added to ice and neutralized by addition of ammonium hydroxide. The dark aqueous solution was extracted three times with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography (50% then 100% ethyl acetate/hexane) afforded the title compound as a yellow solid. 1H-NMR (500 MHz, CDCl3): δ 8.42 (d, 1H, J=4.6 Hz), 8.67 (dd, 1H, J=1.4 and 4.6 Hz), 9.47 (d, 1H, J=1.4 Hz). LC/MS 189 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C(N(C(C)C)CC)(C)C.Cl[CH:20]([CH3:29])[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O>C(Cl)Cl>[CH2:20]([C:21]1[N:1]=[C:2]2[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[N:4][N:3]2[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:29]
Reactant: CCOC(=O)CC(=O)C(C)Cl
Reactant: Cc1cc(C)c(N)nn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(CC)nc2c(C)cc(C)nn12
Temperature: 75 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a suspension of 0.598 g (4.86 mmol) of 3-amino-4,6-dimethylpyridazine in 10 mL of CH2Cl2 in a high pressure vessel was added 0.941 g (1.27 mL; 7.28 mmol) of diisopropylethylamine and 1.301 g (7.28 mmol) of ethyl a-chloropropionylacetate. The reaction mixture was equipped with a magnetic stir bar, tightly sealed, then heated and stirred in an oil bath at 75° C. for 16 hours. The flask was then cooled to room temperature, opened and the reaction mixture was evaporated in vacuo. The residue was partitioned between EtOAc and water, and the organic layer was separated. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The residual brown solid was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Combination of the purified fractions and evaporation in vacuo afforded 0.874 g (73%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[C:16]3[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:14]=[CH:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=1)[CH3:2].C1C2C=CC3C(=CC([CH:40]=[O:41])=C4C=3C=CC=C4)C=2C=CC=1>C1COCC1>[CH2:1]([O:3][C:4]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH:40]=[O:41])[CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Solvent: C1CCOC1
Product: CCOc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Yield: 64 %

Procedure:
6-Ethoxychrysene (Cambridge Chemical, Inc., 48 g, 0.176 mol) was formylated according to the procedure outlined in 1A, except that CH2Cl2 (1L) was used as the reaction solvent. After isolation, the crude material was chromatographed on a plug of SiO2 (500 g) using CH2Cl2 as the eluting solvent to give (after removal of solvent and drying) 33.7 g (64%) of 12-ethoxychrysene-6-carbaldehyde mp 173.5°-176°, (C,H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[O:15][CH:16]=[N:17][N:18]=1)=[CH:8]2)(=[O:4])=[O:3].[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C)C=O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:10]2[C:11]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=3)[CH:8]=[C:9]2[C:14]2[O:15][CH:16]=[N:17][N:18]=2)=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3nnco3)cc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1nnco1)n2Cc1ccc(F)cc1
Reaction time: 0.08 h

Procedure:
To a solution of the crude product (200 mg) of 5-methansulfonyl-2-([1,3,4]oxadiazol-2-yl)-1H-indole in N,N-dimethylformamide (8 ml), 60% sodium hydride (40 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 5 minutes, followed by addition of 4-fluorobenzyl bromide (215 mg), and the mixture was stirred for 3 hours. To the reaction solution was then added water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain 67 mg of the desired product as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][CH:11]([CH2:18][CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:10][CH:11]([CH:12]([C:1]([OH:3])([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][CH3:19]
Reactant: CCOC(=O)CC(C)CC
Reactant: CC(=O)c1ccccc1
Product: CCOC(=O)C(C(C)CC)C(C)(O)c1ccccc1
Yield: 35.9 %

Procedure:
The reaction of acetophenone (12 grams, 0.1 mole) with the enolate of ethyl 3-methylvalerate (14.4 grams, 0.1 mole) is carried out in the manner described in Example I. Distillation yields 9.5 grams (36%) of the pure product, b.p. 75°-80° C. (air bath temperature) at 0.05 mm Hg. I.R., N.M.R. and M.S. data confirm the above structure.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[Cl:24][C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:31]([C:26]4[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:32])[CH:11]=[N:10][CH:9]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: O=C(O)c1ncccc1Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)ccc21
Agent: Cl
Product: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)c4ncccc4Cl)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 42) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as a light yellow viscous oil. MS: 437.4 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([CH2:9]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:8].[CH:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])=[O:21]>CO>[O:21]1[C:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[CH:9][N:7]=[CH:8]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1cccc(-c2cnco2)c1
Yield: 40.5 %

Procedure:
MeOH (28 mL) was added to a round bottom flask containing K2CO3 (4.22 gm, 30.50 mmol), 1-(isocyanomethylsulfonyl)-4-methylbenzene (3.28 gm, 16.78 mmol), and 3-formylbenzonitrile (2.00 gm, 15.25 mmol). The reaction mixture was refluxed for 2 h. After this time, the mixture was concentrated under reduced pressure. The remaining residue was dissolved in water (50 ml). The aqueous solution was extract with EtOAc (50 ml). The EtOAc layer was washed with saturated aqueous NaCl (30 ml), dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, 3-(oxazol-5-yl)benzonitrile, (1.05 gm, 6.17 mmol, 41% yield) as a yellow solid. Anal. Calcd. for C10H6N2O m/z 170.1, found: 171.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>O>[CH3:32][O:31][C:27]1[CH:26]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[C:28]=1[O:29][CH3:30])[C:23]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:3]1)=[O:24]
Reactant: OC1CCN(CCc2c[nH]c3ccccc23)C1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)OC2CCN(CCc3c[nH]c4ccccc34)C2)cc(OC)c1OC
Reaction time: 24 h

Procedure:
A mixture of 3 g. (0.013 mole) of 3-[2-(3-hydroxypyrrolidinyl)ethyl]indole, 3 g. (0.013 mole) of 3,4,5-trimethoxybenzoyl chloride and 5 g. (0.05 mole) of sodium carbonate in 40 ml. of chloroform was stirred under anhydrous conditions for 24 hours. Then 0.3 g. of additional acid chloride was added and the mixture stirred another 24 hours. The mixture was treated with 50 ml. of water, stirred for 1 hour and the chloroform layer separated and dried over magnesium sulfate. Evaporation of the chloroform on a rotating evaporator gave an oil which would not crystallize.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]O)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>C(Cl)Cl>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][Cl:21])=[CH:5][CH:4]=1
Reactant: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The alcohol 2.2 (15 g, 59.5 mmol) was dissolved in anhydrous DCM (100 mL). Thionyl chloride (10 mL) was slowly added dropwise to the above solution. The resulting mixture was stirred at room temperature for 24 hours. The organic solvent was removed under vacuo. The residue was chromatographed (SiO2 gel 60, eluted with 20% DCM in hexanes). Fractions containing the desired product 2.3 were combined and concentrated to a white solid (14.0 g). 1H NMR (400 MHz) (CDCl3) δ 7.73 (4H, s); 7.65 (1H, s); 7.58 (1H, s); 7.52-7.28 (2H, m); 4.69 (2H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[N:10]=1)=O)C.[NH3:14]>>[C:11]([C:9]1[N:10]=[C:6]([C:4]([NH2:14])=[O:3])[S:7][CH:8]=1)(=[O:13])[CH3:12]
Reactant: N
Reactant: CCOC(=O)c1nc(C(C)=O)cs1
Product: CC(=O)c1csc(C(N)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-acetyl-2-thiazolecarboxylic acid ethyl ester (2.5 g) in 28% aqueous ammonia solution (40 ml) was stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration to afford 4-acetyl-2-thiazolecarboxamide (1.76 g).
Reaction SMILES: [Cl:1][C:2]([Cl:9])=[CH:3][C:4](=[O:8])[CH:5]([CH3:7])[CH3:6].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C(O)(C)C>[Cl:1][C:2]([Cl:9])=[CH:3][CH:4]([OH:8])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C(=O)C=C(Cl)Cl
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: CC(C)C(O)C=C(Cl)Cl

Procedure:
reducing 1,1-dichloro-4-methyl-1-penten-3-one with aluminum isopropoxide and isopropanol to produce 1,1-dichloro-3-hydroxy-4-methyl-1-pentene,
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:17]23)[CH:22]=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][NH:13][C:14]2[CH:15]=[C:16]3[C:20]4=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]4[C@H:18]4[CH2:27][CH2:28][NH:29][CH2:30][C@@H:17]34)[CH:22]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1cnc2ccccc2c1
Product: c1ccc2ncc(CNc3cc4c5c(c3)[C@@H]3CNCC[C@@H]3N5CCSC4)cc2c1

Procedure:
Using 3-quinolinecarboxaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 164. LRMS (ES)+: 403.4 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1.O>O1CCCC1>[Si:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][N:26]=2)=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1

Procedure:
2-hydroxyethyl-4-(4-tert-butyldimethylsilyloxybutyl)benzene (0.3 g, 0.97 mmol) is dissolved in dry tetrahydrofuran and to it is added sodium hydride (24 mg, 1 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloroquinazoline (0.164 g, 1 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:14][CH2:13]2)[C:5]=1[C:6]#[N:7])([O-])=O.[H][H]>[Pd].C(Cl)Cl.C(O)C>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14]2)[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(C2CC2)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c(N)cccc1C1CC1
Reaction time: 48 h
Yield: 39 %

Procedure:
A slurry of palladium on carbon (10%; 0.025 g) in DCM (5 mL) was added to a solution of 2-nitro-6-cyclopropylbenzonitrile (Intermediate 11, 0.25 g) in ethanol (15 mL) under nitrogen. The nitrogen atmosphere was exchanged for hydrogen and the mixture was stirred for 48 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a colorless oil (0.082 g).
Reaction SMILES: OC1C=CC(/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C4C=CC=CC=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40](CC)CBr)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:37][CH:38]=1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Reactant: CCC(CBr)Oc1ccc(F)cc1
Product: Fc1ccc(OCCCCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-(4-fluorophenyl)oxybutyl bromide to produce the above.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[CH3:16])([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[CH3:16]
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(N)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 43.8 %

Procedure:
1.0 gram of 2,4,6-trinitrotoluene was dissolved in 22 ml of glacial acetic acid. With vigorous stirring, 0.82 g of iron powder (400 mesh) was added in small portions over two hours. The red reaction suspension was diluted to 50 ml with water giving a bright yellow precipitate. Filtration gave 0.38 grams of 2-amino-4,6-dinitrotoluene of sufficient spectral and chromatographic purity for use in the subsequent synthesis without recrystallization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[S:30](=O)(=[O:33])([OH:32])[OH:31]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc(S(=O)(=O)O)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (5 g), acetic anhydride (4.3 ml) and sulfuric acid (0.97 ml) in dichloromethane (47 ml) was stirred at ambient temperature overnight. The mixture was concentrated to give a crude blue oil of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-sulfonic acid (10.5 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:26]([CH:29]1[CH2:31][CH:30]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:27]=[O:28].O>CN(C=O)C>[C:32]1([CH:30]2[CH2:31][CH:29]2[NH:26][C:27]([NH:1][C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)=[O:28])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NC1CC1c1ccccc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)NC1CC1c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethyl-phenyl)methanone (123 mg, 0.35 mmol) in DMF (20.0 mL) was added (2-isocyanatocyclopropyl)benzene (111 mg, 0.7 mmol). The mixture was stirred at 60° C. overnight. After cooling, the mixture was poured into water (120 mL). The white solid, which precipitated, was filtered off and dried in vacuum to give the title product (162 mg) as a white solid in 90% yield. 1H NMR (300 MHz, CDCl3) δ 8.01-7.97, 7.73, 7.60, 7.55, 7.32, 7.22-7.10, 7.06, 4.00-3.95, 3.87-3.86, 3.62-3.52, 3.43-3.41, 3.25-3.22, 2.85-2.82, 2.14-2.10, 0.91-0.86. MS (ES+) m/z 511.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14]C=O)=[CH:9][CH:8]=2)=[N:3]1.[OH-].[Na+].O>CO>[CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccc(COC=O)cc2)=N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)COC(c2ccc(CO)cc2)=N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
4-(4,4-Dimethyloxazolin-2-yl)-1-(formyloxymethyl)benzene (37 mg) was dissolved in methanol (0.4 ml), added with 1 N aqueous sodium hydroxide (0.18 ml) and stirred at room temperature for 20 minutes. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=1:2) to obtain 17.7 mg of the title compound. Yield: 54%.