Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[CH:4][CH:3]=1.C([Li])CCC.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCCCCC.O>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:22](=[O:23])[C:21]([F:28])([F:27])[F:20]
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1ccc(F)cc1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of 4.0 g of N-(4-fluorophenyl)-2,2-dimethylpropanamide in 80 mL of dry THF was added dropwise over 30 min 30.8 mL of a 1.6 M solution of n-butyllithium in hexane. After addition was complete, the reaction mixture was stirred an additional 1 h at 0° after which time 5.63 mL of ethyl trifluoroacetate was added quickly dropwise. The cooling bath was removed and the reaction was allowed to proceed at ambient temperature for 40 min. The reaction was quenched by the addition of aqueous ammonium chloride and the reaction mixture was partitioned between ether and water. The ether layer was washed with brine, dried and evaporated to 6.29 g of the title compound as an orange oil. The bulk of this material (6.0 g) was dissloved in ethylene glycol dimethyl ether, 30 mL of 6N HCl was added nd the mixture was heated at reflux for 1.5 h. The cooled reaction mixture was diluted with water, and made basic by the addition of solid sodium carbonate. This was extracted with ether, and the combined extacts were dried and evaporated. The residue was purified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes) affording 2.10 g of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[C:5]1([N:11]=[C:12]=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([NH:11][C:12]([NH:4][CH2:1][C:2]#[CH:3])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: C#CCN
Solvent: Cc1ccccc1
Product: C#CCNC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
25 g (0.45 mol) of propargylamine dissolved in 80 ml of toluene are added dropwise to a suspension of 50 ml (0.45 mol) of phenyl isocyanate in 160 ml of toluene. The mixture is stirred for 1 h 30 min, the precipitate is filtered, washed with a small amount of toluene and then dried in a vacuum oven at 40° C. 70.7 g of product are obtained. (m.p.=133° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].F[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:2]([CH2:3][CH2:4][CH:5]([O:6][C:22]1[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][CH:21]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:1]
Reactant: Fc1cccc2ccccc12
Reactant: CN(C)CCC(O)c1cccs1
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1

Procedure:
In this example, 2-acetylthiophene is used as the starting material for reacting with formaldehyde and dimethylamine to form a Mannich product, namely 3-dimethylamino-1-(2-thienyl)propan-1-one. A hydride reduction is performed on this propanone to form corresponding 3-dimethylamino-1-(2-thienyl)propan-1-ol. The resulting propanol is then reacted with fluoronaphthalene to form N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine. Subsequently, racemic Duloxetine® is obtained by demethylation of this propylamine. In this process, the yield of demethylation is very low, about 41%. In addition, Duloxetine® produced via this route is racemic.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([OH:12])=O)[CH:7]=[CH:6][S:5]2.[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH2:29])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH:29][C:10]([C:9]2[N:8]3[C:4]([S:5][CH:6]=[CH:7]3)=[N:3][C:2]=2[CH3:1])=[O:12])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2CCC[C@@H]21
Reactant: Cc1nc2sccn2c1C(=O)O
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (A. Andreani et al. Eur. J. Med. Chem 1982, 17, 271-274) with (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid tert-butyl ester. LC-MS: tR=0.91 min; [M+H]+=405.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH3:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:18][C@H:19]([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C@H:19]([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21])[C:5]([CH2:9][CH3:10])=[CH:4][N:3]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: CCc1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cnc(Cl)nc1N[C@@H](CO)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
A solution of 882 mg (5.0 mmol) of 2,4-Dichloro-5-ethyl-pyrimidine and 0.75 ml (5.5 mmol) triethylamine in 5 ml of acetonitrile is mixed with 672 mg (6.5 mmol) of (R)-2-Amino-3-methyl-butan-1-ol. The batch is stirred at room temperature for 16 hours and is finally concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 90:10). 742 mg of the product is obtained that still contains considerable amounts of (R)-2-Amino-3-methyl-butan-1-ol. The material is used without further purifications.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[O:22]C)[CH:17]=[O:18])[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:25])([CH3:24])[C:4]1=[O:26])[CH3:2].[S-]CC.[Na+].O>CN(C=O)C>[CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[OH:22])[CH:17]=[O:18])[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:25])([CH3:24])[C:4]1=[O:26])[CH3:2]
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3OC)cc21
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3O)cc21
Temperature: 80 °C

Procedure:
A solution of Compound 2A (240 mg, 0.68 mmol) in 3 mL of dry DMF was treated with sodium thioethoxide (143 mg, 1.7 mmol). The reaction flask was then equipped with a reflux condenser, nitrogen inlet and heated to 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and 5 mL of water is added and the reaction mixture passed through a SPE. The crude compound was eluted with EtOAc. The collected eluant was dried of excess solvent to yield product which was used without further purification in the next step. MS (electrospray): mass calculated for C20H21NO4, 339.15 m/z found 340.1, [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 29.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.125 g, 0.260 mmol) obtained in step 2 and methanesulfonamide (0.123 g, 1.30 mmol), the title compound (0.043 g, 29%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.O>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])=[CH:9][CH:8]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)cc2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(N)n(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)n1
Yield: 93.2 %

Procedure:
To a stirred solution of the benzyl alcohol (66) (640 mg, 2.61 mmol) and imidazole (266 mg, 3.91 mmol) in DMF (5.0 mL) at RT was added TBDMS-Cl (590 mg, 3.91 mmol). After 3 hr the reaction mixture was diluted with water and extracted with Et2O. The organic layer was washed with brine, dried (MgSO4) and then evaporated in vacuo to afford the title compound (Intermediate N) (875 mg, 89%): m/z 360 (M+H)+ (ES+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C=O)C.[Cl:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=2[C:29]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)=[N:30][OH:31])=[CH:23][CH:22]=1>CCOCC>[CH2:7]([O:31][N:30]=[C:29]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)[C:28]1[CH:37]=[CH:38][CH:39]=[CH:40][C:27]=1[O:26][CH2:25][C:24]1[CH:41]=[CH:42][C:21]([Cl:20])=[CH:22][CH:23]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ON=C(c1ccccc1OCc1ccc(Cl)cc1)n1ccnc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccccc2C(=NOCc2ccccc2)n2ccnc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Potassium carbonate (0.21 g), benzyl chloride (0.15 g) and DMF (2 ml) were added to 2-(4-chlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde oxime (0.33 g), and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was extracted with brine (80 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to give 2-(4-chlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde O-benzyloxime (0.38 g) as colorless crystals. mp. 94°-95.5° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:38][S:35]([C:32]1[CH:31]=[CH:30][C:29]([C:21]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:34][CH:33]=1)(=[O:36])=[O:37]
Reactant: COc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cnc2[nH]c(C(=CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 80.8 %

Procedure:
A solution of 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.54 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2 mL, 2 mmol) was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (180 mg, 80.7%) as a white solid: LC/MS m/e calcd for C22H24N2O4S [M+H]+ 413.54, observed 413.1.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])[CH3:3].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.C(N(CC)CC)C>C(O)C.ClCCl>[NH2:20][C:19]1[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:2][CH3:3])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCc1ccccc1NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1-n1ncc(C#N)c1N
Temperature: 60 °C

Procedure:
A solution of 3.0 g (17.0 mmol) of 2-ethylphenylhydrazine hydrochloride and 2.12 g (17.0 mmol) of ethoxymethylenemalononitrile in 36 ml of ethanol is mixed with 7.1 ml (51.1 mmol) of triethylamine and heated at 60° C. until the reaction is complete according to a TLC check (about 30 min). For working up, the solvent is stripped off, and the residue is taken up in dichloromethane, washed with saturated sodium bicarbonate solution and dried over sodium sulphate. Concentration results in a crude product which is purified by column chromatography on silica gel (mobile phase dichloromethane with 0-10% methanol). 3.05 g (83.5% of theory) of the desired product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18]1([C:24]2[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:29]([C:27]2[N:28]=[C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:25][CH:26]=2)=[O:30])[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Product: O=C(Nc1cc(NC(=O)c2csc(-c3ccccc3)n2)ccc1Cl)c1ccccc1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (0.20 mmol) was used in general procedure 2 with 2-phenylthiazole-4-carboxylic acid (0.25 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-2-phenylthiazole-4-carboxamide. MS (Q1) 434.0 (M)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19].Cl>C(OCC)C.O1CCCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])=[O:19]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromoanisole (27.9 g, 145 mmol) in diethyl ether is cooled to -70° C., treated with butyllithium (64.0 mL, 160 mmol), stirred at -70° C. for one hour, treated with 0.5 M zinc chloride in tetrahydrofuran solution (320 mL, 160 mmol), stirred for one hour at -70° C., warmed to about 0° C., and concentrated in vacuo to obtain a yellow-green oil. A solution of the oil in tetrahydrofuran is treated sequentially with tetrakis(triphenylphosphine)palladium(0) (5.00 g, 4.35 mmol) and a solution of 2-chloro-5-nitrobenzoyl chloride (35.0 g, 159 mmol) in tetrahydrofuran, stirred for three days, and poured into 10% hydrochloric acid. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a semi-solid. The solid is triturated with diethyl ether to give the title product as a yellow solid which is identified by NMR spectral analyses.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH-].[Na+]>CC(C)=O.O>[C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc2n(c1)C(C)Nc1ccccc1-2
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2n(c1)C(C)N(C(=O)OCC)c1ccccc1-2

Procedure:
A solution of the product of Example XXXVIII (3.0 g, 0.0117 m) and ethyl chloroformate (12.6 g, 0.117 m) in acetone (50 ml) and H2O (50 ml) was treated with NaOH (0.21 ml aq. 30%) and the mixture refluxed for 1 hr. The acetone was removed in vacuo and the aqueous residue cooled in ice-bath. A solid formed and this was filtered, washed with water, and dried in vacuo. The crude product (3.4 g) was crystallized from methanol (25 ml) to afford the desired product; m.p. 125°-127°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (5.0 g, 27 mmol) and piperidine (2.3 g, 27 mmol) in tetrahydrofuran (50 mL) and N,N-diisopropylethylamine (3.5 g, 27 mmol) was stirred at room temperature for 24 hours. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with a gradient of hexane to yield ethyl acetate/hexane (1:4). The eluent was removed, giving 2,4-dichloro-6-(1-piperidinyl)pyrimidine (3.67 g, 15.8 mmol, 59%, Rf=0.58 in ethyl acetate/hexane, 1:4).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)[C:2]#[CH:3].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: C#CCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: C#CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)cc2CC1

Procedure:
2-[5-Chloro-2-(3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 318b. Product isolated as a yellow solid (26 mg, 13%). m.p.=223-225° C.; LCMS (m/e) 461 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.07 (s, 1H), 8.67 (d, 1H, J=8.5 Hz), 8.11 (s, 1H), 7.58-7.45 (m, 2H), 7.38 (s, 1H), 7.15-7.05 (m, 2H), 6.89 (s, 1H), 6.30-6.15 (m, 1H), 3.46 (s, 2H), 3.05 (d, 3H, J=4.8 Hz), 2.98-2.87 (m, 4H), 2.80-2.70 (m, 4H), 2.24-2.20 (m, 1H), 2.20-2.17 (m, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([CH2:15][NH2:16])[OH:14]>>[C:1]([N:8]1[CH2:11][CH:10]([NH:16][CH2:15][CH2:13][OH:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Product: CC(C)(C)OC(=O)N1CC(NCCO)C1
Yield: 62.3 %

Procedure:
N-Boc-3-azetidinone (1.0 g, 5.84 mmol) was treated with ethanolamine following Procedure 1-Method A to yield N-(N-Boc-azetidin-3-yl)-2-amino-ethanol (0.75 g, 3.46 mmol, 62.3% yield): MS m/e [M+H]+ calcd 217.1, found 217.2.
Reaction SMILES: [C:1]([CH:4]([CH:10]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].Cl.[NH2:28]O.[NH4+].[OH-]>CC(O)=O.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:28]=[C:1]([CH3:2])[C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:21][CH:22]=1
Reactant: NO
Reactant: CCOC(=O)C(C(C)=O)C(CC(=O)c1ccccc1)c1ccc(F)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C
Temperature: 25 °C

Procedure:
A mixture of α-acetyl-β-(4-fluorophenyl)-δ-oxobenzenepentanoic acid, ethyl ester (6.12 gm) and hydroxylamine hydrochloride (3.61 gm, 52 mmol) in glacial HOAc (83 ml) was refluxed for 1 hour. The reaction was cooled to room temperature and poured into an ice cold solution of concentrated NH4OH (115 ml) in H2O (300 ml). The resulting mixture was extracted twice with Et2O and the combined Et2O layers were washed with brine, dried (Na2SO4), filtered and stripped to yield a dark gummy residue. The residue was chromatographed (Flash, Merck SiO2, 8% EtOAc in hexane) to give 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid, ethyl ester which was rechromatographed (8% EtOAc in hexane) to afford pyridine 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid, ethyl ester (1.652 gm, 24% from (E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one) in >90% purity.
Reaction SMILES: [I:1]I.[CH2:3]([NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH:8]=1)[CH3:4].S(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.[OH-].[Na+]>[CH2:3]([NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([I:1])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH:8]=1)[CH3:4]
Reactant: CCNC(=O)c1ccc(C)c(-c2ccc3cn[nH]c3c2)c1
Reactant: II
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(I)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
Iodine (1.35 g) was added to a stirred solution of N-ethyl-3-(1H-indazol-6-yl)-4-methylbenzamide (Intermediate 12, 1.1 g) in 1,4-dioxan (20 ml) and aqueous sodium hydroxide (2M, 20 ml) then stirred at room temperature for 10 min. The reaction mixture was treated with aqueous sodium bisulphite (10%, 25 ml) and aqueous citric acid (10%, 25 ml). The mixture was extracted with ethyl acetate (3×25 ml) and the organic extracts were washed with water (30 ml) dried (Na2SO4) and concentrated under vacuum to give the title-compound (1.54 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:17])([CH3:16])[NH:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[N+:13]([O-])=O.C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>[Cl-].[Cl-].[Cl-].[Ti+3].C(OCC)(=O)C.O.CO>[Cl:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:5][C:4]([CH3:17])([CH3:16])[C:3](=[O:2])[NH:13]2
Reactant: COC(=O)C(C)(C)Nc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)Nc2c(Cl)cccc2NC1=O
Reaction time: 3 h

Procedure:
Aqueous titanium trichloride (20%, 375 ml) is added dropwise over 15 min to a mixture of N-(6-chloro-2-nitrophenyl)-2-methylalanine methyl ester (XI, EXAMPLE 15, 15.7 g), sodium acetate (268 g), methanol (339 ml) and water (174 ml) at 20°-25°. After stirring for 3 hr at 20°-25°, addition of 950 ml of aqueous sodium bicarbonate, extraction with ethyl acetate several times, stirring with magnesium sulfate and concentration gives the title compound; mp 153°-156°; IR (mineral oil) 3369, 2954, 2924, 2856, 1680, 1594, 1489, 1470, 1450, 1381, 1368, 1357, 1300 and 764 cm-1 ; NMR (CDCl3) 8.25, 6.98, 6.70, 6.6-6.7, 4.25 and 1.45 δ; MS (FAB) m/z 210 and 195.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:31])[CH2:18][CH:19]1[C:23]2[CH:24]=[C:25]([F:30])[C:26]([OH:29])=[C:27]([F:28])[C:22]=2[O:21][CH2:20]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:29][C:26]3[C:25]([F:30])=[CH:24][C:23]4[CH:19]([CH2:18][C:17]([OH:31])=[O:16])[CH2:20][O:21][C:22]=4[C:27]=3[F:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)CC1COc2c1cc(F)c(O)c2F
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)CC1COc2c1cc(F)c(OCc1cccnc1SC1CCCC1)c2F
Yield: 0.7 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (19 mg, 0.08 mmol) obtained in Step C of Preparation Example 8 and (5,7-difluoro-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.08 mmol) obtained in Preparation Example 51 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.25 mg, 72%).