Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)C=O>O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: OCCCOc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a dry 100 mL round bottom flask under nitrogen was added 3-(4-bromophenoxy)propan-1-ol (9.0 g, 39.0 mmol), tert-butyldimethylsilyl chloride (7.0 g, 47.0 mmol), imidizole (3.2 g, 47.0 mmol), and 20 mL of N,N-dimethylformamide. The reaction was allowed to stir at room temperature while being monitored by thin layer chromatography. Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 50 mL of cold water. The product was extracted using 3×25 mL ether. The organic layers were combined and washed with 3×25 mL cold water and 3×25 mL saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate, filtered from drying agent, and the solvent was removed under reduced pressure. The material was purified by filtering through a plug of silica gel eluting with 4:6 dichloromethane:hexane. The solvent was removed under reduced pressure (12.1 g, 89.4%). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.0 Hz, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.76 (t, J=6.0 Hz, 2H), 1.95 (q, J=6.0 Hz, 2H), 0.87 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:5]5[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]5)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: OC1CCNCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCC(O)CC5)n4)cc3)cc12

Procedure:
Using 4-hydroxy-piperidine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.36 (m, 2H); 1.82 (m, 2H); 2.98 (t, 2H, J=7 Hz); 3.34 (m, 2H); 3.55 (m, 2H); 3.76 (bs, 1H); 4.39 (bd, 2H); 4.75 (bs, 1H); 7.20 (m, 2H); 7.48 (m, 2H); 7.92 (d, 2H, J=9 Hz); 8.20 (m, 3H); 8.45 (d, 1H, J=5 Hz); 8.67 (bt, 1H); 12.12 (bs, 1H). MS (ion spray) m/z 467 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]1[C:11]([O:13]CC)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1>[C:17]1([NH:16][C:11]([CH:3]2[C:2](=[O:1])[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]2=3)=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1C(=O)Sc2ccccc21
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)C1C(=O)Sc2ccccc21

Procedure:
470 mg (2.11 mmols) of ethyl 2-oxo-2,3-dihydro-3-benzo[b]thiophene-carboxylate and 206 mg (2.22 mmols) of aniline in 3 ml of xylene are boiled under reflux for 5 hours. After cooling, the product is precipitated by adding hexane (3 ml). After further dilution with 5 ml of ether and stirring, crystalline N-phenyl-2-oxo-2,3-dihydro-3-benzo[b]thiophene-carboxamide with a melting point of 140°-142° is obtained and filtered off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:7]=1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([S:15][C:9]1[N:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[C:12](=[O:13])[CH2:11][N:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(Cl)cc1NC(=S)NCC(N)=O
Solvent: CCO
Product: Cc1ccc(Cl)cc1N1C(=O)CN=C1SCc1ccccc1
Yield: 53.7 %

Procedure:
A mixture of 2-[3-(5-chloro-2-methylphenyl)-thioureido]-acetamide (20.6 g), benzyl chloride (25.0 g), and ethanol (350 mL) was heated at reflux for 2.5 hours. The insolubles were removed by filtration and discarded. The filtrate was concentrated to one-half volume. Diethyl ether (300 mL) was added. The precipitated solid was separated by filtration and discarded. The filtrate was evaporated to dryness. The residue was dissolved in chloroform (300 mL) and washed with water. The organic phase was dried over anhydrous MgSO4, decolorized on carbon then evaporated to dryness. The residue was triturated with diethyl ether to give the title compound (14.2 g) as an off-white solid, m.p. 140°-142° C. Anal. Calcd. for. C17H15Cl N2O S: C, 61.72; H, 4.57; N, 8.47. Found: C, 61.62; H, 4.39; N, 8.37. Mass spectrum (EI, M.+) m/z 330/332. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.46 (m, 1 H), 7.42 (m, 2 H), 7.38 (d, 2 H), 7.22-7.32 (m, 3 H), 4.31-4.48 (m, 4 H), and 2.06 ppm (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10](Cl)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:20]([NH:24][NH2:25])(=O)[CH2:21][CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]([CH2:21][CH3:22])=[N:24][N:25]=2)=[CH:12][CH:13]=1
Reactant: CCC(=O)NN
Reactant: COc1ccc(N=C(Cl)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1nnc(-c2ccc(OC)cc2)n1-c1ccc(OC)cc1
Yield: 72.1 %

Procedure:
Using the procedure of Step B, of Example 4, 3.46 g of the product of Step A, 2.21 g of propionic acid hydrazide, 1.74 ml of triethylamine and 50 ml of toluene were reacted to obtain 2.8 g of 3,4-bis-(4-methoxyphenyl)-5-ethyl-4H-1,2,4-triazole melting at 122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][C@@H:12]([OH:16])[C:13](O)=[O:14])=[O:8])=[CH:5][CH:4]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C([O-])=O.[Na+]>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([N:9]2[CH2:10][CH2:11][C@@H:12]([OH:16])[C:13]2=[O:14])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)NCC[C@@H](O)C(=O)O)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(C(=O)N2CC[C@@H](O)C2=O)cc1

Procedure:
1.05 g of (R)-4-(p-methoxybenzoylamino)-2-hydroxy-butyric acid are boiled at reflux for 48 hours while stirring in 8.5 ml of trifluoroacetic acid anhydride and 0.2 g of sodium trifluoroacetate. After evaporation of the mixture, the residue is shaken twice with toluene and the toluene is then removed by evaporation in vacuo. The residue, containing (R)-1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl-trifluoroacetate, is boiled at reflux for 30 minutes in absolute methanol. After evaporation of the methanol, the residue is boiled in 400 ml of diisopropyl ether, the mixture is decanted, the solution is concentrated to 140 ml and then stirred at room temperature. The solid is filtered off and there is obtained (R)-1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone of melting point 122.5°-123° C.; [α]D20 =+207°; [α]54620 =+256°; [α]36520 =+1172° (c=1.0 in chloroform).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1cc[nH]c1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Product: COc1ccc(N2CCN(C(=O)Cc3cc[nH]c3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using (1H-pyrrol-3-yl)-acetic acid and 3(S)-benzyl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.75 min, [M+1]+ 448. Potency class A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:9].[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C>[CH2:30]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:9])=[O:10])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1

Procedure:
In analogy to example 1, step 2, 2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide was reacted with sodium hydride in N,N-dimethylacetamide at 0° C. followed by reaction with benzyl bromide at r.t. overnight to give N-benzyl-2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 549.3 ([M+NH4]+)
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.C(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and benzaldehyde (13.6 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-(1-Benzyl-piperidin-3-ylmethyl)-N-phenyl-propionamide 7 as a colorless oil (26.6 mg, 88%). LRMS 337.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][C:5]([CH2:9][OH:10])([CH3:8])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[C:20](F)=[CH:21][C:22]([F:32])=[C:23]([CH:31]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:19]1[C:20]([O:10][CH2:9][C:5]2([CH3:8])[CH2:4][CH2:3][C:2]([F:11])([F:1])[CH2:7][CH2:6]2)=[CH:21][C:22]([F:32])=[C:23]([CH:31]=1)[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25]
Reactant: CC1(CO)CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC(F)(F)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
A mixture of (4,4-difluoro-1-methylcyclohexyl)methanol (3.05 g, 18.56 mmol)(PCT Int. Appl., WO2012025857, 2012), cesium carbonate (12.09 g, 37.12 mmol), and tert-butyl 5-chloro-2,4-difluorobenzoate (6.0 g, 24.13 mmol) in dimethylsulfoxide (70 mL) was stirred at 70° C. for 16 hours, cooled to ambient temperature and diluted with ethyl acetate (150 mL); washed with water (2×300 mL), brine (150 mL); dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-5%) afforded the title compound (3.69 g, 51%) as colorless oil: MS (ES+) m/z 393.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:26][CH2:25][CH2:24][NH2:27])=[CH:3][C:4]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]1)=[N:5]2
Reactant: NCCN
Reactant: Clc1cccc2nc(N3CCCc4ccccc4C3)cc(Cl)c12
Solvent: CCOC(C)=O
Product: NCCNc1cc(N2CCCc3ccccc3C2)nc2cccc(Cl)c12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The mixture of 2-(4,5-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine prepared above and ethane-1,2-diamine (2 mL) was heated with stirring in a 10 mL microwave process vial for 2 hours at 150° C. under microwave irradiation. The reaction mixture was diluted with ethyl acetate (20 mL), and then washed with water (20 mL). The organic fraction was dried over sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give 20 mg of product as a white powder. MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD3OD) δ ppm 7.46-7.42 (m, 2 H), 7.27-7.23 (m, 1 H), 7.16-7.11 (m, 3 H), 7.02 (66, J=7.6, 1.2 Hz, 1 H), 5.97 (s, 1 H), 4.79 (s, 2 H), 4.13 (brs, 2 H), 3.38-3.21 (m, 2 H), 3.04-3.02 (m, 2 H), 2.96 (t, J=6.0 Hz, 2 H), 1.91-1.86 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1O[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[N:11][N:12]=1.O.[NH2:26][NH2:27]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1[N:26]([NH2:27])[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: NN
Reactant: COc1cccc(CNc2nnc(-c3c[nH]c4ncccc34)o2)c1
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(CNc2nnc(-c3c[nH]c4ncccc34)n2N)c1
Reaction time: 120 h
Yield: 31.8 %

Procedure:
A mixture of 50 mg of (3-methoxybenzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,3,4-oxadiazol-2-yl]amine (prepared by method 1) and 75 μl of hydrazine hydrate in 1 ml of 2-propanol is stirred at a bath temperature of 100° C.-120° C. for 5 days in a sealed screw-lid vial. The reaction mixture is evaporated and purified by prep. HPLC (RP-18, water/acetonitrile), giving 16.6 mg of N*3*-(3-methoxybenzyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,4-triazole-3,4-diamine (31.8%) MS-FAB (M+H+)=336.4 Rf (polar method): 1.34 min;
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)(Cl)Cl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (170 mg, 0.521 mmol) in chloroform (10 mL) was added triethylamine (0.145 mL, 1.042 mmol) followed by ethyl chloroformate (0.055 mL, 0.573 mmol). The reaction mixture was stirred for 1 hour at room temperature and then it was evaporated to dryness. The oil was partitioned between 3 mL of ethanol and 3 M of 1 M NaOH. After 1 hour, the reaction mixture was concentrated, and 10 mL of ethyl acetate followed by 4 mL of brine were added. The organic layer was separated, dried over MgSO4, filtered and evaporated. The resulting oil was dissolved in 5 mL of 10% AcCN:Et2O and 0.5 mL of 4 M HCl/dioxane was added. The suspension was stirred for 30 min, and then it was filtered. Ethyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (120 mg, 0.336 mmol, 64.6% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.30-7.39 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22 (m, 2H), 4.19 (dd, J=1.26, 13.64 Hz, 2H), 4.13 (q, J=7.16 Hz, 3H), 3.15 (d, J=7.07 Hz, 2H), 3.02 (dt, J=4.14, 7.64 Hz, 1H), 2.86 (d, J=3.28 Hz, 2H), 2.54 (ddd, J=3.66, 6.69, 10.36 Hz, 1H), 1.99 (ddd, J=4.04, 7.52, 11.18 Hz, 1H), 1.82 (d, J=12.13 Hz, 2H), 1.56 (ddd, J=4.29, 6.63, 10.55 Hz, 1H), 1.42 (q, J=6.82 Hz, 1H), 1.27 (t, J=7.07 Hz, 3H), 1.17-1.33 (m, 1H); LC-MS Rt=0.76 min; MS (ESI): 303.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O.O>[CH2:12]([NH:19][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: Brc1cc(Br)c2nonc2c1
Solvent: CS(C)=O
Solvent: O
Product: Brc1cc(NCc2ccccc2)c2nonc2c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 42.7 %

Procedure:
4,6-dibromobenzo[c][1,2,5]oxadiazole 4 (0.9678 g, 3.48 mmol) and benzylamine (1.9 mL, 17.4 mmol) were dissolved in DMSO (10.5 mL) under argon and stirred in a sealed tube for 3 days, after which time, the tube was heated to 60° C. for 12 hours. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), 1 N HCl (aq), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating. The dark solid was recrystallized from EtOH and the dark crystals were collected by filtration and dried to afford 0.4516 g (43% yield) of N-benzyl-6-bromobenzo[c][1,2,5]oxadiazol-4-amine. This material (0.1980 g, 0.651 mmol), benzoylpiperazine hydrochloride (0.1771 g, 0.781 mmol) and Cs2CO3 (0.6353 g, 1.95 mmol) were added to a tube. The tube was evacuated and purged with argon (3×). Toluene (2 mL) and NMP (1.2 mL) were then added to the tube and its contents were degassed for 15 minutes, at which point Pd2(dba)3 (0.0119 g, 0.0130 mmol) and BINAP (0.0162 g, 0.026 mmol) were quickly added, the tube was sealed and heated at 100° C. overnight. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), 1 N HCl(aq), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating. The crude material was purified via chromatography (40% EtOAc/Hexanes) to give 0.188 g (70% yield) of TRV-1256. 1H NMR (500 MHz, CDCl3) δ=7.46-7.43 (m, 5H), 7.39-7.36 (m, 4H), 7.34-7.31 (m, 1H), 6.13 (d, J=1.0 Hz, 1H), 5.88 (s, 1H), 5.32 (t, J=5.5 Hz, 1H), 4.48 (d, J=5.5 Hz, 2H), 3.90 (br s, 2H), 3.58 (br s, 2H), 3.29 (br s, 2H), 3.15 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[NH3:10].O>C1(C)C=CC=CC=1>[C:5](=[O:6])([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])[NH2:10]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)OCC(Cl)(Cl)Cl

Procedure:
Me-PRX (150 g) is dissolved in toluene (450 ml) at room temperature. The mixture is then heated to reflux. At reflux, 2,2,2-trichloroethyl-chloroformate (120 ml) is added dropwise for about 2.5 hours. After about 3 hours at reflux, the reaction mixture is cooled, and ammonia 20% (300 ml) and water (300 ml) is added. The organic phase is separated and washed with water (500 ml), followed by brine (500 ml). The organic phase is then separated, dried over MgSO4, filtered. Toluene is then removed under reduced pressure to give 280.2 g of the 2,2,2-trichloroethyl carbamate of paroxetine. The carbamate is then hydrolyzed according to procedures set forth, for example, in Examples 5-7 to give paroxetine base. Paroxetine base may then be converted into the desired polymorphic form of, e.g., the hydrochloride acid addition salt such as the hemihydrate, anhydrate or solvate form as disclosed herein.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][CH:6]=[C:7]([Cl:12])[C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][N:30]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[CH:42]([CH3:44])[CH3:43])[S:31]1(=[O:33])=[O:32]>CO>[ClH:2].[Cl:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][CH:6]=[C:7]([Cl:12])[C:8]=1[C:9]([O:11][CH2:29][N:30]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[CH:42]([CH3:44])[CH3:43])[S:31]1(=[O:32])=[O:33])=[O:10]
Reactant: CC(C)c1cccc2c1C(=O)N(CCl)S2(=O)=O
Reactant: O=C(O)c1c(Cl)cnc(OCCN2CCOCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CC(C)c1cccc2c1C(=O)N(COC(=O)c1c(Cl)cnc(OCCN3CCOCC3)c1Cl)S2(=O)=O
Temperature: 80 °C
Yield: 16.8 %

Procedure:
A solution of the free base of 3,5-dichloro-2-[2-(4-morpholinyl) ethoxy) pyridine-4-carboxylic acid hydrochloride (3.6 g, 0.01 mol) and cesium carbonate (4.85 g, 0.015 mol) in methanol (50 ml) was stirred for 30 minutes. The methanol was removed in vacuo and the residue was dissolved in DMF (50 ml). 2-Chloromethyl-4-(isopropyl)saccharin (3.0 g, 0.01 mol) was then added and the reaction mixture was heated at 80° C. for 3 hours. The DMF was removed in vacuo, the residue was taken up in methylene chloride and was filtered through charcoal. The solvent was removed in vacuo, the residue was taken up in tert-butyl-methylether and the solution was filtered. The solvent was removed in vacuo and the residue was treated with ethereal HCl. A gum was obtained which was triturated with CH3CN to afford 0.5 g (9%) of 4-(isopropyl]-2-saccharinylmethyl 3.5-dichloro-2-[2-(4-morpholinyl)ethoxy]pyridine-4-carboxylate hydrochloride as a white solid, m.p. 120°-140° C.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>[Zn+2].[I-].[I-]>[CH2:23]([O:22][CH:15]([O:19][CH2:20][CH3:21])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:24]
Reactant: CCOC(OCC)OCC
Reactant: C#CCCCCCCCCCCCC
Agent: [I-]
Agent: [Zn+2]
Product: CCCCCCCCCCCCC#CC(OCC)OCC

Procedure:
Tetradecyne (100 g), (EtO)3CH (200 ml) and ZnI2 (15 g) were heated together (bath temperature 170°-175°) with distillative removal of ethanol (~90 minutes). The reaction mixture was evaporated in vacuo (bath temperature 80°) to remove excess (EtO)3CH. The residue was distributed between CH2Cl2 and water. The CH2Cl2 phase was separated, washed with aqueous NaHCO3, dried (Na2SO4) and evaporated in vacuo to provide a light brown oil. Yield: 135.4 g. This product was shown to be virtually pure by TLC and PMR and it was used as such in subsequent reactions.