Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([O:18]C)=[O:17])[NH:7][C:6]=2[CH:22]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:3]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([OH:18])=[O:17])[NH:7][C:6]=2[CH:22]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(C#Cc4ccccc4F)c(Cl)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Oc2nc3cc(C#Cc4ccccc4F)c(Cl)cc3[nH]2)cc1C(=O)O

Procedure:
A solution of methyl 5-({6-chloro-5-[(2-fluorophenyl)-ethynyl]-1H-benzimidazol-2-yl}oxy)-2-methylbenzoate (910 mg, 2.1 mmol) and 4.2 mL 5 M aqueous NaOH in 15 mL MeOH and 15 mL water was heated at 70° C. for 30 min. Volatiles were removed. The residue was dissolved in water (30 mL), and acidified with 2 N aqueous HCl, the precipitated solid was filtered (rinsing with water) and dried to afford the desired product as a white solid. LC/MS: calculated for C23H14ClFN2O3 420, observed mile 421 (M+H)+ (2.1/4 min). 1H NMR (500 MHz, CD3OD): δ 7.88-7.16 (9H, m), 2.61 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([CH:16]=2)[C:13](O)=[O:14])[CH2:4][CH2:3]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([CH:16]=2)[C:13]([NH:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)=[O:14])[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 5-(4-methyl-1-piperazinyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 40; 50 mg, 0.15 mmol), 3-pyridinamine (14.42 mg, 0.15 mmol), EDC (29.4 mg, 0.15 mmol), HOBT (23.46 mg, 0.15 mmol) and triethylamine (0.02 ml, 0.15 mmol) dissolved in DMF (5 ml) was stirred for 3 h at 40° C. The mixture was then filtered and 10 ml water was added to the filtrate. The mixture was then extracted with ethyl acetate (30 ml) and concentrated. The residue was then purified by reverse phase HPLC using a gradient of acetonitrile and 0.1% aqueous ammonia as the eluent. Evaporation of the product-containing fractions gave the title compound as a white solid. 25 mg.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:30]#[N:31])[CH2:21][C:20](=[O:32])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccco4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-furan-2-yl-phenyl}-carbamic acid tert.-butyl ester (Example K5) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a brown powder (73 mg).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[C:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)=[C:25]([C:35]([NH:37][CH3:38])=[O:36])[C:24]=4[CH:39]=3)[CH:17]=[CH:18][CH:19]=2)=[N:12][N:11]=[N:10]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH2:1]([N:10]1[N:11]=[N:12][C:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)=[C:25]([C:35]([NH:37][CH3:38])=[O:36])[C:24]=4[CH:39]=3)[CH:17]=[CH:18][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(Cc5ccccc5)n4)c3)cc12
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Benzyl bromide (29 μL, 0.242 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.121 mmol) and Na2CO3 (26 mg, 0.242 mmol) in DMF (1.2 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (12 mg, 19%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48-8.56 (1H, m), 8.30-8.35 (1H, m), 8.06 (1H, d, J=7.63 Hz), 7.98-8.03 (2H, m), 7.90-7.93 (2H, m), 7.78-7.83 (1H, m), 7.72-7.77 (1H, m), 7.69 (1H, t, J=7.78 Hz), 7.36-7.46 (7H, m), 6.04 (2H, s), 2.86 (3H, d, J=4.58 Hz). LC-MS retention time: 1.78 min; m/z (MH+): 504. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u 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 2 min, a hold time of 1 min, and an analysis time of 3 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. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=15.69 min, purity=97%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=13.95 min, purity=98%.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[NH2:10][CH2:11][CH2:12]CO.C=O.C(N(CC)CC)C.C(Cl)(=O)C=C>O.C1(C)C=CC=CC=1>[O:9]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:8][C:7]=2[CH:12]=[CH:11][NH:10]1
Reactant: NCCCO
Reactant: COc1ccc(O)cc1
Agent: C=CC(=O)Cl
Agent: C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A 500 mL flask was charged with 4-methoxyphenol (12.4 g, 100 mmol), 3-amino-1-propanol (7.5 g, 100 mmol), and paraformaldehyde (6.4 g, 213 mmol). Toluene (200 g) was added to the flask and the mixture was heated to reflux for one hour, during which time 3.8 mL of water was collected in a Dean-Stark trap. The solution was cooled to 0° C., and triethylamine (23 g, 227 mmol) was added to the flask. This was followed by the drop-wise addition of acryloyl chloride (11 g, 125 mmol). The solution was allowed to stir overnight at room temperature. The product was worked up in a similar fashion as described in previous examples. About 20 g (72% yield) of a low viscosity, orange liquid was recovered.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1([C:11]([OH:13])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]1.[CH3:14]O>>[CH3:5][C:6]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]1
Reactant: CC1(C(=O)O)CCCO1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(C)CCCO1
Yield: 93 %

Procedure:
Thionyl chloride (0.15 mL, 2.1 mmol) is added dropwise at 0° C. to a solution of 2-methyltetrahydro-2-furancarboxylic acid (250 mg, 1.9 mmol) in methanol (2.0 mL). After bringing the reaction mixture to room temperature, it is heated under reflux for 1 h. The solvent is removed under reduced pressure, the crude is dissolved in DCM and filtered through a pad of silica. Removal of the solvent under reduced pressure affords 276.0 mg of methyl 2-methyltetrahydro-2-furancarboxylate that is used in the next step without further purification. Yield: 93%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (3H, s), 1.78-1.85 (1H, m), 1.91-1.99 (2H, m), 2.30-2.37 (1H, m), 3.75 (3H, s), 3.92-4.02 (2H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:32][O:33][CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:32][O:33][CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
Reactant: COC[C@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC[C@H]1CCCN1c1ncnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.01 h

Procedure:
A vial was charged with 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Intermediate KKKK; 0.075 g, 0.157 mmol) and DMF (0.786 ml). (R)-2-(methoxymethyl)pyrrolidine (0.036 ml, 0.314 mmol) was added followed by Hunig's base (0.082 ml, 0.472 mmol). The reaction was stirred for 30 seconds at room temperature. TFA (0.2 ml, 2.60 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was filtered through a frit, concentrated, and purified via Gilson HPLC (5-50% MeCN:H2O w/ 0.1% TFA modifier). The product fractions were passed through an Isolute SCX ion exchange column (pre-wetted with methanol). The column was flushed with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford (R)-4-(2-(methoxymethyl)pyrrolidin-1-yl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as an off-white solid. (ESI) 406.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:9][CH:10]=1)=[O:4].CNN>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:31][CH:32]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][NH2:16])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(OCCCON2C(=O)c3ccccc3C2=O)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: CNN
Product: COC(=O)c1ccc(OCCCON)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 92.1 %

Procedure:
This compound was produced using similar methods as those used in Step 2, example 4, starting with 6-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-propoxy]-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.50 g, 1.00 mmol) and methyl hydrazine (0.087 g, 1.88 mmol). The crude material was purified by flash chromatography through silica gel using ethyl acetate/methylene chloride (2/98 gradient to 8/92) to give 6-(3-aminooxy-propoxy)-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.34 g, 92%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1)[NH2:3].[CH3:14][C:15]1[N:19]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=3)[CH2:25][CH2:24]2)=[O:22])[N:18]=[C:17]([C:36]([F:39])([F:38])[F:37])[CH:16]=1>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:6][N:5]=1)[N:3]=[CH:34][C:32]1[N:33]=[C:29]([CH:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[CH2:20][N:19]3[C:15]([CH3:14])=[CH:16][C:17]([C:36]([F:37])([F:39])[F:38])=[N:18]3)[CH2:28][CH2:27]2)[S:30][CH:31]=1
Reactant: CN(N)c1ccc(C(F)(F)F)cn1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NN(C)c3ccc(C(F)(F)F)cn3)cs2)CC1
Reaction time: 24 h

Procedure:
At room temperature, 2-(1-methylhydrazinyl)-5-(trifluoromethyl)pyridine (58 mg) is added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde (100 mg) in ethanol. The reaction mixture is stirred for 24 hours, and the solvent is then removed under reduced pressure. The residue is purified by column chromatography (silica gel, ethyl acetate:hexane 0%-100% elution gradient). This gives 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde methyl[5-(trifluoromethyl)pyridin-2-yl]hydrazone (79 mg, 56%), (log P(pH2.7)=4.23).
Reaction SMILES: [CH:1]([C@:4]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:7][CH2:8][CH2:9][N:10](C)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]#[N:6])([CH3:3])[CH3:2].ClC(OC=C)=O>ClCCl>[CH:1]([C@:4]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@](C#N)(CCCN(C)CCc1ccccc1)c1ccccc1
Agent: C=COC(=O)Cl
Solvent: ClCCl
Product: CC(C)[C@@](C#N)(CCCNCCc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 17 g (50 mmol) of (S)-2-isopropyl-5-(methylphenethylamino)-2-phenylvaleronitrile in 50 ml of dichloromethane was added dropwise, at 0° C., to a solution of 6 ml (66 mmol) of vinyl chloroformate in 30 ml of dichloromethane. The temperature was then allowed to increase to room temperature, and the mixture was heated for 1 hour at 80° C.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5](S([O-])(=O)=O)[CH:4]=[C:3]([CH3:11])[CH:2]=1.[Na+].[NH2-:14].[Na+].N>>[CH3:12][C:1]1[CH:6]=[CH:5][C:4]([NH2:14])=[C:3]([CH3:11])[CH:2]=1
Reactant: [NH2-]
Reactant: Cc1cc(C)cc(S(=O)(=O)[O-])c1
Agent: N
Agent: [Na+]
Product: Cc1ccc(N)c(C)c1
Yield: 84.4 %

Procedure:
In a 200-ml autoclave were placed 22.9 grams (0.11 mole) of anhydrous sodium 5-m-xylene sulfonate, 9.7 grams (0.24 mole) of sodium amide and 80 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 150° C for 5 hours. The reaction pressure in the autoclave was 135 atm. during the reaction. After the ammonia was removed, 20 ml of water was added to the reaction mixture for hydrolysis. Thereafter the product was treated in the same manner as in Example 1, whereby 11.3 grams of sym. -m-xylidine boiling at 221° to 222° C was obtained. Yield was 84.4%
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][CH:2](Cl)[C:3](Cl)=[O:4].[CH3:7][C:8](=[C:10]([CH3:12])[CH3:11])[CH3:9]>C(C(CC(C)C)=O)C(C)C.[Zn]>[Cl:1][CH:2]1[C:10]([CH3:12])([CH3:11])[C:8]([CH3:9])([CH3:7])[C:3]1=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)=C(C)C
Agent: [Zn]
Solvent: CC(C)CC(=O)CC(C)C
Product: CC1(C)C(=O)C(Cl)C1(C)C

Procedure:
This process is described in U.S. Pat. No. 4,028,418 Gradual addition of dichloroacetyl chloride to a stirred solution of 2,3-dimethyl-2-butene in diisobutyl ketone containing suspended zinc particles resulted in a yield of 2-chloro-3,3,4,4- tetramethylcyclobutanone of 75%, calculated on starting dichloroacetyl chloride of 3.9, a molar ratio of dichloroacetyl chloride to 2,3-dimethyl-2-butene of 1.3, a temperature of 43° C, zinc in the form of turnings having a largest dimension of 0.841 mm and a starting concentration of 2,3-dimethyl-2-butene of 2.4 mol per liter of diisobutyl ketone. Modifying this experiment by reducing the molar ratio of zinc to dichloroacetyl chloride to 1.1 resulted in a decrease in yield to 51%, the theoretical yield still being 77.4% cf. Example VIII of U.S. Pat. No. 4,028,418.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH2:23][CH2:24][SH:25]>FC(F)(F)C(O)=O>[C:7]([S:25][CH2:24][CH2:23][NH2:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCS
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85 %

Procedure:
Triphenylmethanol (22.9 g, 88 mmol) was added to a solution of 2-aminoethanethiol hydrochloride in trifluroacetic acid (TFA, 40 mL). The resulting solution was stirred at room temperature for about 40 min. The TFA was then removed under reduced pressure and the residue was triturated with diethyl ether. The white precipitate that formed was filtered, partitioned with aqueous NaOH (40 mL, 1N), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. The product was obtained as a white solid after solvent evaporation (23.8 g, yield 85%). ESI-MS(m/z): 320 (M+H+). 1H NMR δD (CDCl3): 7.21˜7.43 (m, 15H, phenyl), 2.58 (t, 2H, SCH2), 2.32 (t, 2H, CH2N).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
To a stirring solution of 17 mL (180 mmol) of 4-fluoroaniline in 550 mL of THF at RT is added 26.7 mL (180 mmol, 1.0 equiv) of acetone, 10.3 mL (180 mmol, 1.0 equiv) acetic acid, and 57.22 g (270 mmol, 1.5 equiv) of sodium triacetoxyborohydride. The solution is stirred at RT for 15 h, cooled to 0° C., and then quenched by addition of H2O. The reaction mixture warmed to RT and is poured into EtOAc, the organic layer is separated, washed with brine (1×200 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane 1:1 as eluent afforded 14.9 g (54%) of (4-Fluoro-phenyl)-isopropyl amine. A solution of 6.68 g (43.6 mmol) of (this material in 50 mL of DCM is cooled to 0° C. and 6 mL (43.6 mmol, 1.0 equiv) triethyl amine is added, followed by dropwise addition of 2.27 mL (43.6 mmol, 1.0 equiv) of bromoacetyl bromide. The solution is stirred at RT for 15 h and then poured into DCM (200 mL). The organic layer is separated, washed with saturated aq NaHCO3 (4×50 mL), 1N HCl (6×50 mL), brine (1×50 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane (3:17) as eluent afforded 5.32 g of 2-Bromo-N-(4-fluoro-phenyl)-N-isopropyl-acetamide: 1HNMR (CDCl3, 300 MHz) δ7.26-7.09 (m, 4H), 4.85 (m,1H), 3.51 (s, 2H), 1.05 (d, 6H, J=6.9); low resolution MS(FAB) m/e 274 (MH+).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:14]1[O:16][CH:15]1[CH2:17][OH:18]>[Cl-].C[N+](C)(C)C.C1(C)C(C)=CC=CC=1>[OH:16][CH:15]([CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)[CH2:17][OH:18]
Reactant: Oc1ccc(Cn2cccn2)cc1
Reactant: OCC1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: OCC(O)COc1ccc(Cn2cccn2)cc1

Procedure:
A mixture of 4-(1-pyrazolyl)methylphenol [this was obtained by the same method as described in the square parentheses in Production Example 1] (2 g), glycidol (936 g), dry xylene (10 ml) and a catalytic amount of tetramethylammonium chloride was stirred at 60° C. for 6 hours. The reaction mixture was then subjected to silica gel chromatography, which afforded 941 mg of 2-hydroxy-3-[4-(1-pyrazolyl)methylphenoxy]-propanol.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)N>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccncc1
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccncc1
Yield: 11 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 4-hydrazinopyridine according to the method described for Example 1 in 11% yield. MS: M=316.1 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[BH4-].[Na+]>O.CO>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
To a solution of glycine (8.11 g, 108 mmol) in water (40 ml) were added an aqueous solution of sodium hydroxide (108 mmol, 15 ml) and a solution of 4-bromobenzaldehyde (20 g, 108 mmol) in methanol (240 ml). After 30 minutes stirring at room temperature sodium borohydride (4.09 g, 108 mmol) was added portionwise to this suspension. After 18 h stirring at room temperature the reaction mixture was concentrated under reduced pressure and the resulting aqueous phase was washed with diethyl ether. The aqueous phase was neutralized by the addition of an aqueous solution of 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and diethyl ether. Drying the white solid afforded 2-(4-bromobenzylamino)acetic acid (14.2 g). The product was used in the following step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:13][CH3:14])[CH2:11][OH:12])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:13][CH3:14])[CH2:11][OH:12])=[CH:8][CH:9]=1
Reactant: CCC(CO)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCC(CO)c1ccc(N)cc1
Reaction time: 2 h

Procedure:
A solution was prepared from 12.9 g of 2-(4-nitrophenyl)butanol and 250 ml of absolute ethanol, 0.65 g of 10% palladium on charcoal catalyst was added and the mixture was hydrogenated in a Parr apparatus at about 2.7 atmospheres for 2 hours. The catalyst was removed by filtration and the solvent was evaporated from the filtrate to leave a crude oil which was purified by kugelrohr distillation (115° C. at 0.2 mm pressure) to give 2-(4-aminophenyl)butanol as a clear-white liquid.