Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:26][CH:25]=1)=[O:32]
Reactant: CC(C)(C)C(=O)c1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(C(=O)C(C)(C)C)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 1-(4-hydroxy-phenyl)-2,2-dimethyl-propan-1-one via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C23H28O6 [M+H]+: 401.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[H-].[Na+].[CH3:16][Si:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21].C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:20]([CH2:19][CH2:18][Si:17]([CH3:25])([CH3:24])[CH3:16])(=[O:22])=[O:21])[CH:9]=[CH:8]2)=[O:4]
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a solution of 1H-indole-5-carboxylic acid methyl ester (3.6 g, 20.6 mmol) in tetrahydrofuran (180 mL) at 0° C., was added sodium hydride (0.65 g, 21.9 mmol). After 10 min., 2-trimethylsilanylethanesulfonyl chloride (4.4 g, 21.9 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 3 h, acetic acid (1.6 mL, 26.8 mmol) was added and the reaction mixture was concentrated. The crude product was chromatographed (Biotage 40M column, 2.5% ethyl acetate-hexanes) to afford 1-(2-trimethylsilanylethanesulfonyl)-indole-5-carboxylic acid methyl ester (5.43 g) as a white solid.
Reaction SMILES: [CH:1]([Si:9]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([Cl:11])[Cl:10])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:20][SiH:21]([Cl:23])[Cl:22]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:20][Si:21]([Cl:23])([Cl:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][Si:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Si:21]([Cl:23])([Cl:22])[Cl:20])([Cl:11])[Cl:10]
Reactant: Cl[SiH](Cl)Cl
Reactant: CCCCCCC=C[Si](Cl)(Cl)C=CCCCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: Cl[Si](Cl)(Cl)CCCCCCCC[Si](Cl)(Cl)CCCCCCCC[Si](Cl)(Cl)Cl
Temperature: 110 °C
Yield: 94.9 %

Procedure:
To a 100 ml glass ampoule equipped with a magnetic stirring bar was added hexachoroplatinic acid (0.05 ml, 0.090M solution in isopropanol). After the solvent was removed under reduced pressure, bis(octenyl)dichlorosilane (6.02 g, 18.74 mmoles) was introduced into the ampoule in an inert atmosphere enclosure. Subsequently trichlorosilane (29.9 g, 198.6 mmoles) was condensed into the ampoule on the vacuum line. The in vacuo sealed ampoule was placed in an oil bath and heated up slowly to 110° C. at which temperature it was kept for twenty four hours. After opening the ampoule into the vacuum line, a small quantity of noncondensibles was observed. The excess trichlorosilane was distilled off to yield 10.53 g (94.9% yield) of bis (8-trichlorosilyloctyl)dichlorosilane.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.[CH2:29]([N:36](C(OC(C)(C)C)=O)[CH2:37][CH:38]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:49])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:49])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:38][CH2:37][NH:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N(CC=O)Cc1ccccc1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: N[C@@]1(C(=O)O)CN(CCNCc2ccccc2)C[C@@H]1CCCB(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N-benzyl-N-BOC-glycinaldehyde (0.187 g, 0.75 mmol) in anhydrous 1,2-dichloroethane (5 mL) was stirred at room temperature for 30 min, then cooled by ice bath and treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred for 3 h at room temperature. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-1-(2-(benzylamino)ethyl)-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (112 mg, 49%) as a white solid. NMR (D2O) δ 7.30-7.45 (m, 5 H), 4.21 (s, 2 H), 3.94 (d, 1 H, J=12 Hz, 1 H), 3.84 (t, J=9.5 Hz, 1 H), 3.60-3.75 (m, 3 H), 3.30-3.50 (m, 3 H), 2.50-2.65 (m, 1 H), 1.50-1.65 (m, 1 H), 1.10-1.35 m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 350.4; MS (m−H2O+1): 332.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9]C)#[N:2].BrB(Br)Br>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)c(C#N)c2)no1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(O)c(C#N)c2)no1
Reaction time: 2 h

Procedure:
Ethyl 3-(3-cyano-4-methoxyphenyl)-5-isoxazolecarboxylate and tribromoborane were dissolved in a solution of dichloromethane, followed by stirring for 2 hours under ice-cooling. Further, the mixture was stirred at 40° C. for 30 minutes to obtain ethyl 3-(3-cyano-4-hydroxyphenyl)-5-isoxazolecarboxylate. APN: 257.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=S)[CH:6]=[CH:7][CH:8]=1.[NH3:18]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[NH:18])[CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: OCc1cccc(NC(=S)NCC(F)(F)F)c1
Product: N=C(NCC(F)(F)F)Nc1cccc(CO)c1

Procedure:
The above thiourea (1.32 g.) was stirred in 1.6N alcoholic ammonia (50 ml.) with mercuric oxide (3.4 g.) for 17 hours at 20°. The resulting mixture was clarified on the centrifuge and the supernatant was evaporated in vacuo to a syrup which was further dried at 70°/0.1 m.m. to give 1-(3-hydroxymethylphenyl)-3-(2,2,2-trifluoroethyl)guanidine. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethyl silane as internal standard (δ=0) had the following resonances (δ): 6.9 (4H, multiplet); 4.4 (2H, singlet); 3.9 (2H, quartet).
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:17]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:33][CH:32]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)Oc1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCC(C)Oc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Optically active p-(1-methyl-heptyloxy)phenol (50.0 g, 0.22 mol) was dissolved in pyridine (300 ml), followed by dropwise adding to the solution, a solution of p-benzyloxybenzoic acid chloride (50.0 g, 0.20 mol) prepared above in (ii), dissolved in toluene (300 ml), under ice cooling, agitating the mixture for 2 hours while keeping it at about 50°~60° C., allowing it to stand overnight, thereafter adding toluene (1,500 ml) and water (1,000 ml), agitating the mixture, washing the toluene layer with 6N-HCl, then with 2N-NaOH aqueous solution and further with water until the wash water became neutral, distilling off toluene, and recrystallizing the residue from ethanol to obtain optically active p-benzyloxybenzoic acid p-(1-methyl-heptyloxy)phenyl ester (69.0 g).
Reaction SMILES: [CH3:1][OH:2].C[C:4](C)([O-:6])C.[K+].[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24](F)=[CH:25][C:26]=3F)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16].O>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:6][CH3:4])=[CH:25][C:26]=3[O:2][CH3:1])[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: CO
Reactant: Fc1cc(F)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 75 °C
Yield: 69 %

Procedure:
Methanol (6.5 ml) and potassium tert-butoxide (18 g) were added sequentially, each in one portion, to a mixture of N-(3-chloro-4-fluorophenyl)-5,7-difluoroquinazolin-4-amine (13.8 g) in THF (270 ml) at room temperature under a nitrogen atmosphere. The mixture was heated at 75° C. for 18 hours 30 minutes and then cooled to room temperature and concentrated in vacuo to leave a brown solid. The solid was cooled to 0° C. and cold water was added and then the precipitate was filtered and dried to leave N-(3-chloro-4-fluorophenyl)-5,7-dimethoxyquinazolin-4-amine as a light brown solid (10.4 g, 69%); Mass spectrum MH+ 334.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29]
Reactant: NCCc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
1 mL of 2-(2-chlorophenyl)ethylamine and 1.2 mL of triethylamine were dissolved in 50 mL of dichloromethane. To the solution, 1.6 g of 2-nitrobenzenesulfonyl chloride was added at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with saturated saline, and the organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 2.3 g of the title compound as a pale yellow crystalline solid (92%).
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>O1CCCC1.[Ni]>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(N=Cc2ccccc2)c(F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Fc1ccc(NCc2ccccc2)c(F)c1

Procedure:
195.4 g (0.9 mol) of N-benzal-2,4-difluoroaniline are dissolved in 900 ml of tetrahydrofuran in an autoclave. 19 g of Raney nickel and 2 g of acetic acid are added, and the mixture is hydrogenated at 60° to 85° C. and a hydrogen pressure of 100 bar. The end point of the reaction is determined by thin-layer chromatography or gas chromatography. The suspension is filtered and the solution is evaporated on a vacuum rotary evaporator. The residue is distilled in vacuo at 102° C. and 3.6 mbar, to give 125.6 g (64% of theory) of a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[C:7]#[N:8].[Br-].[CH2:12]([Zn+])[CH:13]([CH3:15])[CH3:14]>>[CH3:12][CH:13]([CH3:15])[CH2:14][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1I
Reactant: CC(C)C[Zn+]
Agent: [Br-]
Product: CC(C)Cc1ccc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-iodobenzonitrile (3.25 mmol) was combined with 6.5 mL of 0.5 M solution of iso-butylzinc bromide, the solution was degassed with argon, 100 mg of tetrakis(triphenylphosphine) palladium was added in one portion and the solution was stirred at rt under argon for 48 h. The solvents were removed under reduced pressure and the residual mixture was purified by column chromatography using Biotage 40L cartridge to obtain the title compound: 1H NMR (500 MHZ, CDCl3) δ 0.97 (d, J=8.5, 6H), 2.00 (m, 1H), 2.71 (d, J=7.5, 2H), 7.19 (d, J=8.5, 1H), 7.65 (dd, J=8.5, 2.0, 1H), 7.76 (d, J=2.0, 1H).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.B(F)(F)F.CCOCC.O>C1(C)C=CC=CC=1>[C:6]1([C:1]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:2][CH2:3][CH3:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCC(=O)c1ccccc1
Reactant: C1CCNC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCC=C(c1ccccc1)N1CCCC1
Yield: 77.3 %

Procedure:
In 50 ml of toluene, 4.44 g of n-butyrophenone, 6.40 g of pyrrolidine and 0.43 g of boron trifluoride etherate were dissolved. The mixture was refluxed for 47 hours using a Cope water separator and molecular sieve 4A as the dehydrating agent. After having distilled out the solvent under a reduced pressure, the residue was subjected to a distillation under a reduced pressure to obtain the desired enamine as a pale yellowish oil (yield: 4.66 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH3:42])[CH:32]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH3:42])[CH:32]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2cccc(-c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
A mixture of 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (150 mg, 0.38 mmol), methyl 4-amino-2-methoxybenzoate (70 mg, 0.38 mmol), 1-methyl-1H-imidazole (126 mg, 1.53 mmol) and EDCI (293 mg, 1.53 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with brine (10 mL) and dried over Na2SO4. The residue was concentrated and purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=50:1) to give methyl 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)-2-methoxybenzoate (100 mg, 47%) as brown liquid. LC-MS: [M+H]+, 555.1, tR=1.701 min
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C.[F:24][CH:25]([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([Cl:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:36].[F:37][CH:25]([F:24])[O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([N:6]2[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)F)cc2)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (1.5 g, 7.49 mmol, supplier Aldrich) and N,N-diisopropylethylamine (1.962 mL, 11.23 mmol) in dry DCM (20 mL) was added 4-[(difluoromethyl)oxy]benzenesulfonyl chloride (1.253 mL, 7.86 mmol, supplier Aldrich) dropwise. The solution was stirred at room temperature for 4 h and then left to stand for 16 h. The solution was washed with aqueous sodium bicarbonate (20 mL), 0.5 M HCl (20 mL) and brine (20 mL) before the organic phase was isolated by phase separator. To the solution was added hydrochloric acid (1.872 mL, 7.49 mmol) 4M in dioxane and the reaction stirred at room temperature for 3 h. LCMS showed only partial reaction, so further hydrochloric acid (1.872 mL, 7.49 mmol) 4M in dioxane was added and the reaction stirred for 21 h. The reaction mixture was then concentrated under vacuum to give the title compound (2.448 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O-])=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[Na+].ClC[C:16]([O:18][CH3:19])=[O:17]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:10][C:16]([O:18][CH3:19])=[O:17])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)CCl
Reactant: O=C([O-])c1nc(Cl)c(Cl)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(Cl)c(Cl)cc1Cl
Temperature: 105 °C
Yield: 90 %

Procedure:
Essentially equimolar amounts of sodium 3,5,6-trichloropyridinate and methyl α-chloroacetate in toluene were blended together in the presence of from 2 to 5 mole percent of benzyltriethylammonium chloride and the mixture refluxed at 105°C for 3 hours. The product, methyl α-(3,5,6-trichloropyridyl)acetate, was thus obtained in approximately 90 percent yield.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([CH3:16])[N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[CH:19]=[N:18]1>C(O)C.C([O-])(O)=O.[Na+]>[CH3:16][C:10]1[N:9]=[C:8]([C:3]2[C:2]([NH:26][C:21]3[C:20]4[CH:19]=[N:18][NH:17][C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH:13]=[C:12]([S:14][CH3:15])[N:11]=1
Reactant: CSc1cc(-c2nccnc2Cl)nc(C)n1
Reactant: Nc1cccc2[nH]ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSc1cc(-c2nccnc2Nc2cccc3[nH]ncc23)nc(C)n1
Temperature: 160 °C
Yield: 45.9 %

Procedure:
A glass microwave reaction vessel was charged with 4-(3-chloropyrazin-2-yl)-2-methyl-6-(methylthio)pyrimidine (60 mg, 0.237 mmol) and 1H-indazol-4-amine (63.2 mg, 0.475 mmol, Bionet) in ethanol (2 mL). The reaction mixture was stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 160° C. for 30 min. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a yellow solid. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column eluting with 40% EtOAc/hexanes to provide N-(3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)-1H-indazol-4-amine (38 mg, 46% yield) as yellow solid. 1H NMR (300 MHz, d8-dioxane) δ 12.49 (s, 1H); 11.68 (s, 1H); 10.69 (s, 1H); 8.24 (s, 2H); 8.10 (d, J=7.60 Hz, 1H); 8.02 (s, 1H); 7.23 (t, J=7.97 Hz, 1H); 7.07 (d, J=8.18 Hz, 1H); 2.83 (s, 3H); 2.53 (s, 3H). m/z (ESI, +ve ion) 350 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([OH:22])=[O:21]>CC(C)=O>[CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([O-:22])=[O:21]
Reactant: O=CO
Agent: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Solvent: CC(C)=O
Product: O=C[O-]
Temperature: 45 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of O-desmethylvenlafaxine (39.51 g, 0.150 mol) in acetone (1500 mL) at 55–60° C., under a nitrogen atmosphere, was added a solution of 96% formic acid (13.5 mL, d=1.22, 2.29 molar excess) in acetone (150 mL) over a period of 10 min. The stirred mixture was kept at 55–60° C. for a further 5 min. to complete the dissolution. The warm solution was filtered through a pad of Celite filter aid (prewashed with warm acetone) and the filter pad was washed with warm acetone (150 mL). The filtrate and washings (temperature ˜35° C.) were warmed to 45° C. under a nitrogen atmosphere and seeded with crystals of O-desmethyl-venlafaxine formate. The stirred solution was allowed to cool. Crystallization ensued and was copious after 1 hour (when the temperature had fallen to 30° C.). The slurry of crystals at 27° C. was chilled to −10° C. over a period of half an hour and maintained at −5–−10° C. for 15 min. The crystals were then collected on a filter and washed with chilled (−5 to −10° C.) acetone (2×100 mL). After drying in a vacuum oven at room temperature under oil pump vacuum for 24 hours, the product, O-desmethyl-venlafaxine formate, weighed 38.5 g, (83% yield) and it had mp=148° C.-149.5° C. It was characterized by DSC (sharp endotherm at 152.4° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[OH:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56](O)=[O:57].C(N(CC)CC)C>CN(C=O)C.O>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:14]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:56](=[O:57])[C:55]3[CH:59]=[CH:60][CH:61]=[C:53]([OH:52])[CH:54]=3)=[CH:3][CH:4]=2)[C:9](=[O:10])[N:11]([CH3:13])[CH3:12])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=1
Reactant: O=C(O)c1cccc(O)c1
Reactant: COc1cc(C=C(C(=O)N(C)C)c2ccc(N)cc2)cc(OC)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(C=C(C(=O)N(C)C)c2ccc(NC(=O)c3cccc(O)c3)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-aminophenyl)-3-(3,5-dimethoxyphenyl)-N,N-dimethylacrylamide, 43, (0.59 g, 1.5 mmol), benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP,0.88 g, 2.0 mmol), 3-hydroxybenzoic acid (0.28 g, 2.0 mmol), triethylamine (0.2 g, 2.0 mmol) in DMF (8.0 mL) was stirred for 3 h at room temperature. The reaction mixture was poured in water (50 mL) and solid separated was filtered, dried and purity was checked by HPLC (97.6%).