Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[O:16]=[C:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=[O:26]>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=[C:22]([N:18]2[CH2:19][CH2:20][CH2:21][C:17]2=[O:16])[CH:23]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(N2CCCC2=O)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-(2-oxo-pyrrolidin-1-yl)-5-trifluoromethyl-benzoic acid (Selena Chemicals Inc.) after a reaction time of 120 hours. The product was purified by preparative HPLC (Phenomenex Gemini® column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2). Light brown solid (2%). MS (ESI): m/z=454.17 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.CCCCCC.C(OCC)(=O)C>ClCCl.O>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: OCc1ccccc1
Reactant: O=C(O)CC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: O=C(CC1CCOCC1)OCc1ccccc1
Reaction time: 12 h
Yield: 32.5 %

Procedure:
To a solution of 2-(tetrahydropyran-4-yl)acetic acid (325 mg, 2.26 mmol) in anhydrous dichloromethane (10 mL) were added benzyl alcohol (439 mg, 2.94 mmol), 1-ethyl-3-(3-dimethylammoniumpropyl)carbodiimide hydrochloride (564 mg, 2.94 mmol) and triethylamine (297 mg, 2.94 mmol) at room temperature, and the mixture was stirred for 12 h. The reaction mixture was diluted with water (1 mL) to separate the phases, and the organic layer was further washed with water (1 mL) and brine (1 mL). The organic layer was concentrated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 7:1) to give 172 mg of the title compound as oil (yield: 32%).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([OH:9])=O)[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OC)=O.[NH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[NH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[C:28]2=[O:36].C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl.C(#N)C>[C:1]([NH:4][CH:5]([CH3:6])[C:7]([NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[NH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[C:28]2=[O:36])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](C)C(=O)O
Reactant: Nc1cccc2c(=O)c(C(=O)O)c[nH]c12
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)NC(C)C(=O)Nc1cccc2c(=O)c(C(=O)O)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A mixture of 3.93 g (30 mmol) of N-acetyl-L-alanine, 3.3 ml (30 mmol) of N-methyl morpholine, 2.33 ml (30 mmol) of methyl chloroformate, and 80 ml of acetonitrile is stirred at -10° to -20° for 30 minutes. A mixture of 4.08 g (20 mmol) of 8-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 8.4 ml (60 mmol) of triethylamine, 7.6 ml (60 mmol) of chlorotrimethylsilane, and 100 ml of dichloromethane was stirred at room temperature for 40 minutes and then cooled to -20°. The cold mixed anhydride is added to the cold silylated quinoline and stirred for 4 hours with cooling and overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is treated with acetonitrile and 1N hydrochloric acid. The solid is filtered to give 3.03 g of 8-[[2-(acetylamino)-1-oxopropyl]amino]-1,4-dihydro-4 -oxo-3-quinolinecarboxylic acid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[CH:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:26]([Cl:34])[CH:25]=2)[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(OCC)(=O)C>[Cl:34][C:26]1[CH:25]=[C:24]([CH:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:35])[CH:29]=[CH:28][C:27]=1[S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ccn(CCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
In a flask containing N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (150 mg, 0.26 mmol) was added ethanol (5 mL) and concentrated hydrochloric acid (three drops) and was stirred at 25° C. for 30 minutes. It was then diluted with ethyl acetate (50 mL) and washed with water (1×20 mL) and saturated aqueous brine solution (1×20 mL). The organic layer was then dried over sodium sulfate and absorbed onto silica gel (2 g) and purified on Biotage Flash purification system (40S column, silica gel, 5% methanol/ethyl acetate) which afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (107 mg, 89%) as a white foam: ES-HRMS m/e calcd for C20H26N3O5SCl (M+H)+ 456.1355, observed 456.1354; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.27 (m, 2H, CH2), 1.29-1.42 (m, 1H, CH of CH2), 1.49-1.70 (m, 3H, CH of CH2 and CH2), 2.00-2.14 (m, 1H, CH), 3.20 (m, 2H, OCH2), 3.34 (s, 3H, SO2CH3), 3.67 (q, J=5.5 Hz, 2H, OCH2), 3.75-3.86 (m, 2H, OCH2), 3.95-4.08 (m, 3H, CH and NCH2), 4.83 (t, J=5.3 Hz, 1H, OH), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.54 (d, J=2.3 Hz, 1H, Ar), 7.60 (dd, Jo=8.2 Hz, Jm=1.6 Hz, 1H, Ar), 7.71 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.81 (s, 1H, NH).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[O:3][C:2]2=[O:10].C(N(CC)CC)C.Cl.[CH2:19]([NH:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:29]1([CH2:28][O:27][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([C@@H:5]2[CH2:6][CH2:7][C@H:1]([C:2]([OH:3])=[O:10])[CH2:8]2)=[O:9])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(CNOCc2ccccc2)cc1
Reactant: O=C1OC(=O)C2CCC1C2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1CC[C@@H](C(=O)N(Cc2ccccc2)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
552 mg of 3-Oxabicyclo[3.2.1]octane-2,4-dione (3.94 mmol, prepared according to the procedure described in Chem. Lett., p 93, (1994)) is added to a rapidly stirring solution of triethylamine (0.55 mL, 3.94 mmol) and N-benzyl-O-benzylhydroxylamine hydrochloride (983 mg, 3.94 mmol) in CH2Cl2 in a flame dried flask under nitrogen. After stirring at ambient temperature for 3 days, the reaction is quenched with aqueous citric acid (1M). Extraction into CH2Cl2 (3×50 mL), followed by drying over MgSO4, yielded a pale yellow oil, 1.51 g. Recrystallization in ethyl acetate/hexane provided the product as a white crystalline solid, 1.32 g (95%). mp. 118°-120° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:25]=[N:26][N:27](COC)[CH:28]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:32][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[CH:14]=[C:15]([F:16])[C:10]=1[S:7]([NH:6][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)(=[O:8])=[O:9]
Reactant: COCn1cc([C@@H]2CCCC[C@H]2Oc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)c(F)c2)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@@H]2CCCC[C@H]2c2cn[nH]c2)cc1F
Yield: 86 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 147e by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-4-({(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (62.2 mg, 0.0988 mmol) prepared in Example 169d, triethylsilane (0.080 mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol (6.0 mL) and 6 M hydrochloric acid (2.0 mL), to yield the title compound (37.0 mg, 85%) as a colorless solid.
Reaction SMILES: [Na:1].N1C(N)=C2C(N(C([C@@H]([C@H](CO)OCP(O)(O)=O)O)=O)C=N2)=NC=1.[N:25]1([C:33]([C@@H:35]([C@H:37]([CH2:50][OH:51])[O:38][CH2:39][P:40]([O:46]C(C)C)([O:42]C(C)C)=[O:41])[OH:36])=[O:34])[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]1=[O:27]>>[Na:1].[N:25]1([C:33]([C@@H:35]([C@H:37]([CH2:50][OH:51])[O:38][CH2:39][P:40]([OH:42])([OH:46])=[O:41])[OH:36])=[O:34])[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: CC(C)OP(=O)(CO[C@@H](CO)[C@@H](O)C(=O)n1ccc(=O)[nH]c1=O)OC(C)C
Agent: Nc1ncnc2c1ncn2C(=O)[C@H](O)[C@H](CO)OCP(=O)(O)O
Agent: [Na]
Product: O=C([C@H](O)[C@H](CO)OCP(=O)(O)O)n1ccc(=O)[nH]c1=O
Yield: 49 %

Procedure:
This compound was prepared as described for 3a using 17 (200 mg, 0.53 mmol) as a starting material and TBMSBr (200 mL, 2.1 mmol). Compound 3c (93 mg, 0.26 mmol) was obtained as a colorless solid, in 49% yield, which was characterized as follows:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=3)[C:15](O)=[O:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.B>O1CCCC1>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:13]=[C:14]([CH2:15][OH:16])[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[N:20]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-6-(trifluoromethyl)isonicotinic acid (490.0 mg, 1.411 mmol) was dissolved in tetrahydrofuran (17.5 mL) and cooled to 0° C. 1.0 M Borane in THF (4.23 mL, 4.23 mmol) was then added and stirred at 0° C. for 10 min and at 25° C. for 16 hours when LCMS analysis showed the absence of starting material. The reaction was quenched with 1N NaOH and water, and extracted with EtOAc. The EtOAc extract was evaporated in vacuo and the residue was used in the next reaction without further purification. MS (ES): 334 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[N:12]([CH2:22][CH2:23][CH3:24])[C:13]3[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.[Ni]>[NH:12]1[CH:13]=[CH:14][N:15]=[C:11]1[CH2:10][NH:21][CH2:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:12]([CH2:22][CH2:23][CH3:24])[C:13]=2[CH:19]=1
Reactant: CCCn1c(CCCCN2CCCCC2)nc2ccc(C#N)cc21
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(CCCCN2CCCCC2)nc2ccc(CNCc3ncc[nH]3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 151 %

Procedure:
The compound (451.8 mg) obtained in Example 61-3 was dissolved in ethanol (18.1 ml) and added with a 1 mol/l sodium hydroxide aqueous solution (4.52 ml) and Raney nickel. The whole was stirred at room temperature for 20 hours under a hydrogen atmosphere. The reaction solution was filtrated through Celite and the filtrate was concentrated under reduced pressure. The residue was added with water and the whole was subjected to separation/extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was again dissolved in methanol (22.1 ml) and added with 2-imidazole carboxaldehyde (194.0 mg) and trimethyl orthoformate (0.442 ml). The whole was stirred at room temperature for 1.5 hours. Subsequently, the solution was added with sodium borohydride (152.8 mg) under ice-cooling and the whole was stirred at room temperature for additional 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was added with water and the whole was subjected to separation/extraction with chloroform. The organic layer washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (429.5 mg) as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[C:10]1[CH:11]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(Nc2ccccc2)c1
Temperature: 100 °C

Procedure:
To a mixture of dimethyl bromoterephthalate (4.5 g, 16.0 mmol), aniline (2.2 mL, 24.0 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (922 mg, 1.48 mmol), and toluene (50 mL) was added cesium carbonate (7.53 g, 23.1 mmol), followed by palladium(II) acetate (0.22 g, 1.0 mmol). The mixture was heated to 100° C. for 24 h. HPLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with diethyl ether and filtered under reduced pressure through a pad of Celite. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography using a 1:10 mixture of EtOAc and hexane to give 4.58 (97%) of 1A as a bright yellow solid. HPLC retention time=3.74 min. (Condition A) and LC/MS M++1=286+. 1H-NMR (400 MHz, CDCl3): δ 9.50 (bs, 1H), 8.01 (d, J=8.30, 1H), 7.91 (d, J=1.50, 1H), 7.32-7.40 (m, 4H), 7.25 (m, 1H), 7.13 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]([C:20](=O)[CH:21]([CH3:23])[CH3:22])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38].C(O)(=O)C(C)(C)C>C1(C)C=CC=CC=1>[CH2:37]([O:36][CH:35]([O:39][CH2:40][CH3:41])[CH2:34][CH2:33][N:32]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[C:20]1[CH:21]([CH3:22])[CH3:23])[CH3:38]
Reactant: CCOC(CCN)OCC
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: Cc1ccccc1
Product: CCOC(CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C)OCC
Yield: 81.2 %

Procedure:
To a nitrogen purged flask equipped with a mechanical stirrer is added 130 kg (311 mol) of (±)4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers, 540 L of heptanes and 60 L of toluene, 59 kg (400 mol) of 3-amino-1,1-diethoxypropane, and 22.3 kg (218 mol) of pivalic acid. The mixture is stirred and heated to reflux, removing water with a Dean Stark trap. The mixture is refluxed 32 hours and slowly cooled to 60°-65° C., diluted with 500 L of 2-propanol-water (3:2), seeded, and cooled to 20°-25° C. The product is isolated by filtration, washed with 300 L of 2-propanol, and dried in vacuo to yield 133.5 kg of 1-(3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide; mp 125.1°-127.7° C. after recrystallization from ethanol.
Reaction SMILES: Cl[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].[NH3:24].C(OCC)(=O)C.O>O1CCCC1>[NH2:24][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12]
Reactant: N
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Cl)C2CCC(C2)C1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(N)C2CCC(C2)C1=O
Reaction time: 0.5 h
Yield: 86 %

Procedure:
1.0 g (0.0029 mol) of 4-chloro-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one are dissolved in 10 ml of tetrahydrofuran and, at 25° C., treated with 2.0 ml of aqueous ammonia (30%). After 0.5 hours at 25° C., the reaction mixture is added to ethyl acetate and water, the organic phase is washed twice with water, dried with sodium sulfate and evaporated and the residue is triturated with a little ethyl acetate. Filtration gives 0.81 g (86% of theory) of 4-amino-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[3.2.1]oct-3en-2-one in the form of white crystals (m.p. 262-263° C). 1H NMR (CDCl3, ppm): 10.62 br s 1H; 8.223 br s 1H; 7.41, d, J=8.1 Hz, 1H; 7.35, d, J=8.1 Hz, 1H; 3.03, br t, J=4.8 Hz, 1H; 2.70, br t, J=4.8 Hz, 1H; 2.41, s, 3H; 1.97-2.14, m, 3H; 1.77-1.812, m, 1H; 1.47-1.70, m, 2H.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=2)=[N:15][CH:16]=1.[I-].[I-].[Sm+2]>O1CCCC1>[F:8][C:2]([F:9])([C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][N:15]=2)=[CH:22][CH:21]=1)([OH:25])[CH3:24])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC(=O)c1ccc(-c2ccc(F)cn2)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [I-]
Agent: [Sm+2]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(C)(O)c1ccc(-c2ccc(F)cn2)cc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
A solution of ethyl bromo(difluoro)acetate (0.53 mL, 4.1 mmol) and 1-[4-(5-fluoropyridin-2-yl)phenyl]ethanone (800 mg, 3.7 mmol) in tetrahydrofuran (40 mL) was added to a 0.1 M solution of samarium diiodide in tetrahydrofuran (82 mL, 8.2 mmol) at ambient temperature. After stirring at ambient temperature for 3 min, the reaction was cooled and quenched with 1N aqueous hydrochloric acid. Volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded ethyl 2,2-difluoro-3-[4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanoate.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH2:22](Br)[CH:23]=[CH2:24]>>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH2:24][CH:23]=[CH2:22])[N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCOc2ccc(C3=NNC(=O)CC3)cc21
Reactant: C=CCBr
Product: C=CCN1N=C(c2ccc3c(c2)N(S(C)(=O)=O)CCO3)CCC1=O

Procedure:
6-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one was reacted with allyl bromide instead of methyl iodide, following the procedure of Example 9. The title compound was recovered, yield 2.03 g, mp 153°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C=C(C(OC)=O)C=C(C=1)C(OC)=O.[CH3:29][NH:30][CH3:31].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:30]([CH3:31])[CH3:29])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(C=O)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(CN(C)C)c1
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a solution of methyl 3-bromo-5-formylbenzoate (1.8 g, 7.4 mmol, prepared as described in WO2003/048111 starting from dimethyl 5-bromoisophthalate (Alfa Aesar) in methylene chloride (20 mL) was added a solution of 2.0M dimethylamine in tetrahydrofuran (7.4 mL, 15 mmol) and the reaction was stirred for 15 min. Sodium triacetoxyborohydride (4.7 g, 22 mmol) was then added and the resulting mixture was stirred overnight. Saturated sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate. The organic extract was washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford product as a light yellow oil (1.87 g, 93%). 1H NMR (400 MHz, CDCl3) δ 8.08-8.03 (m, 1H), 7.90-7.87 (m, 1H), 7.70-7.67 (m, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 2.24 (s, 6H); LCMS (M+H)+: 272.0, 274.0.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[S:17](N)(N)(=[O:19])=[O:18]>COCCOCCOC>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]1[CH2:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][S:17]1(=[O:19])=[O:18]
Reactant: NS(N)(=O)=O
Reactant: Nc1ccccc1CNc1ccccc1F
Solvent: COCCOCCOC
Product: O=S1(=O)Nc2ccccc2CN1c1ccccc1F
Yield: 53.9 %

Procedure:
A solution of N-(2-aminobenzyl)-2-fluoroaniline (4.3 g, 20 mmol) in diglyme (50 mL) was treated with sulfamide (2.5 g, 26 mmol) and heated to reflux for 0.5 h. The reaction mixture was evaporated and the oily residue purified by flash chromatography (SiO2, 10-100% ethyl acetate/hexanes) to provide 3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (3.0 g) as a tan solid:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[OH-:15].[K+].Cl>O>[Cl:1][C:2]1[NH:3][C:4](=[O:15])[C:5]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Clc1nc(Cl)c2ccn(C3CC3)c2n1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c(Cl)nc2c1ccn2C1CC1
Temperature: 100 °C
Yield: 95.9 %

Procedure:
A mixture of 2,4-dichloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (68 mg, 298 μmol) in a 2N aqueous potassium hydroxide solution (1.67 ml, 3.34 mmol) was heated to 100° C. overnight. At this time, the reaction was cooled to room temperature. The reaction was diluted with water (−50 mL) and then neutralized by the addition of a 2N aqueous hydrochloric acid solution. The product was extracted into a 10% methanol/methylene chloride solution (3×25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-7-cyclopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a light yellow solid (59.9 mg, 95.8%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-1.17 (m, 4H) 3.50 (s, 1H) 6.42 (d, J=3.39 Hz, 1H) 7.07 (br. s., 1H) 12.87 (br. s., 1H). LC-MS calcd. for C9H9ClN3O [(M+H)+] 210, obsd. 209.9.