Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CC#N>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:5][CH2:4]1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 60 °C

Procedure:
A solution of 4-(aminomethyl)piperidine (7.00 g, 61.3 mmol) in CH3CN (100 mL) was treated sequentially with K2CO3 (3.02 g) and 4-chlorobenzyl chloride (3.52 g, 21.8 mmol). The reaction mixture was heated to 60° C. for 16 h, cooled to 25° C. and concentrated. The residue was partitioned between CH2Cl2 (75 mL) and water (50 mL), and was washed with water (2×50 mL) and brine (1×50 mL). The organic phase was dried (MgSO4) and concentrated. Chromatography (SiO2, 4% H2O-iPrOH) afforded4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (3.58 g, 69%).
Reaction SMILES: Cl.[N:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[C:4]([C:11](=[NH:13])[NH2:12])[CH:3]=1.CN(C)/[CH:16]=[C:17](\[N+:23]([O-:25])=[O:24])/[C:18](OCC)=[O:19].C(N(CC)CC)C>C(O)C>[N+:23]([C:17]1[C:18]([OH:19])=[N:13][C:11]([C:4]2[CH:3]=[N:2][N:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:5]=23)=[N:12][CH:16]=1)([O-:25])=[O:24]
Reactant: N=C(N)c1cnn2ccncc12
Reactant: CCOC(=O)/C(=C/N(C)C)[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(-c2cnn3ccncc23)nc1O
Temperature: 90 °C
Reaction time: 22 h
Yield: 48.9 %

Procedure:
A mixture of crude pyrazolo[1,5-a]pyrazine-3-carboximidamide hydrochloride (Preparation 24c, 4.88 g), (Z)-ethyl 3-(dimethylamino)-2-nitroacrylate (8.04 g, 42.7 mmol) and triethylamine (6.25 mL, 44.8 mmol) in ethanol (165 mL) was stirred and heated to 90° C. in a sealed tube. After 22 hours, the reaction mixture was cooled and the precipitate was filtered, washed with ethanol and diethyl ether and dried to give the title compound (3.12 g, 66%) as a yellow solid.
Reaction SMILES: C(Cl)Cl.[CH:4](OC=C)=[CH2:5].[N+:9]([C:12]([N+:16]([O-:18])=[O:17])([CH3:15])[CH2:13][OH:14])([O-:11])=[O:10].FC(F)(F)C(O)=O>C(Cl)(Cl)(Cl)Cl.O>[CH:4]([O:14][CH2:13][C:12]([N+:16]([O-:18])=[O:17])([N+:9]([O-:11])=[O:10])[CH3:15])=[CH2:5]
Reactant: C=COC=C
Reactant: CC(CO)([N+](=O)[O-])[N+](=O)[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: C=COCC(C)([N+](=O)[O-])[N+](=O)[O-]
Yield: 58.8 %

Procedure:
A 50 ml single necked, round bottom flask was charged with 20 ml methylene chloride, 0.50 g (7.14 mmole) divinyl ether, 1.07 g (7.14 mmole) 2,2-dinitropropanol (VIII), and 0.1 g red mercuric oxide. The solution was stirred, using a Teflon coated magnetic bar while 100 μl trifluoroacetic acid was added. The reaction flask was then fitted with a water cooled reflux condenser and drying tube filled with Drierite desiccant. The reaction was stirred under reflux (~37° C.) for 16 hours. The methylene chloride solvent was removed in vacuo, leaving a slightly yellow, clear oil. The oil was taken up in 2 ml carbon tetrachloride and placed onto 7.8 g neutral alumina (pH 6.9) packed with carbon tetrachloride into a 15 ml "course" glass sintered funnel. The carbon tetrachloride was removed in vacuo, leaving 0.74 g of crude 2,2-dinitropropyl vinyl ether (IX) which was shown by nuclear resonance spectrometry to be 92 percent pure.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]([OH:11])=O.CCN(C(C)C)C(C)C.[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:9](=[O:11])[CH2:8][O:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Cc1ccccc1OCC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1OCC(=O)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a stirred mixture of 2-(o-tolyloxy)acetic acid (100 mg, 0.60 mmol) in DCM (5 mL) was added DIEA (116 mg, 0.90 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (124 mg, 0.60 mmol) and Bop-Cl (183 mg, 0.72 mmol). The mixture was stirred at 25° C. for 16 hours then quenched by addition of water (20 mL). The resulting mixture was extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the product (79 mg, Yield 37%). 1H NMR (400 MHz, MeOD) δ 7.14-7.01 (m, 6H), 6.95-6.82 (m, 2H), 4.55 (s, 2H), 4.04-4.01 (m, 1H), 3.72-3.63 (m, 2H), 3.55-3.46 (m, 1H), 3.42-3.34 (m, 1H), 2.93-2.84 (m, 2H), 2.83-2.74 (m, 2H), 2.57 (d, J=6.3 Hz, 2H), 2.27 (s, 3H). LCMS (m/z): 355.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:9]O)[CH:5]=[N:6][C:7]=1[CH3:8].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH2:9][Cl:15])[C:3]=1[O:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: COc1c(CO)cnc(C)c1Cl
Solvent: ClC(Cl)Cl
Product: COc1c(CCl)cnc(C)c1Cl
Reaction time: 3 h

Procedure:
The above (5-chloro-4-methoxy-6-methylpyridin-3-yl)methanol (520 mg) was dissolved in 20 ml of chloroform, and thionyl chloride (0.38 ml) was then added to the solution under cooling on ice. The resulting mixture was stirred at the same temperature as above for 3 hours. Thereafter, the reaction solution was concentrated, and ethyl acetate was then added to the concentrate. The resulting mixture was washed with saturated sodium bicarbonate solution, water, and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away. The residue was purified by silica gel chromatography (ethyl acetate-hexane), so as to obtain the title compound (550 mg) as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH3:29])=[CH:23][C:22]=2[CH2:30][C:31]([O:33]C)=[O:32])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH3:29])=[CH:23][C:22]=2[CH2:30][C:31]([OH:33])=[O:32])=[CH:17][CH:16]=1
Reactant: CCCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)O)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a mixture of methyl 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-propylphenyl]acetate (0.70 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.60 g, 91%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-propylphenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 116-117° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([I:17])[CH:9]=1>CS(C)=O.CCOCC.C(OCC)(=O)C>[I:17][C:10]1[CH:9]=[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(I)cc(N2CCOCC2)c1
Temperature: 120 °C

Procedure:
Morpholine (2.53 mL, 28.1 mmol) was added to a solution of 1-fluoro-3-iodo-5-nitrobenzene (3 g, 11.2 mmol) in DMSO (22.5 mL) under nitrogen. The reaction was heated at 120° C. for 2 hours, then cooled to room temperature and diluted with a mixture of ether and ethyl acetate. The organic layer was washed with water (2×) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexanes) to afford 4-(3-iodo-5-nitrophenyl)morpholine as deep yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([O:27]CC)=[O:26])[C:4]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:2].O.O.[OH-].[Li+]>O1CCCC1>[C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([OH:27])=[O:26])[C:4]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:2]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c(C2CCCCC2)n1CC(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
To a solution of ethyl 2-(3-cyano-2-cyclohexyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (485 mg, 0.975 mmol) in tetrahydrofuran (2.9 mL), and water (0.98 mL), was added solid lithium hydroxide monohydrate (40.9 mg, 0.975 mmol). The reaction was stirred at room temperature for 45 minutes, after which analysis by LCMS indicated that the reaction was not complete. After 20 more minutes, an additional equivalent of lithium hydroxide monohydrate (40.9 mg) was added, and the reaction was stirred at room temperature for an additional 20 minutes, after which it was determined to be complete by LCMS analysis. Concentration of the reaction mixture, followed by acidification with aqueous 3M hydrochloric acid solution (0.65 mL), extraction with dichloromethane (1×50 mL), then ethyl acetate (2×50 mL), drying (sodium sulfate), filtering and concentration afforded 2-(3-cyano-2-cyclohexyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid (442 mg, 0.941 mmol, 97% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.96 (d, 1H), 7.43 (app. t, 1H), 7.32 (dd, 1H), 7.04 (d, 1H), 4.57 (s, 2H), 4.29 (s, 2H), 3.33-3.36 (m, 4H), 2.50 (m, 1H), 1.93-1.96 (m, 7H), 1.70-1.88 (m, 8H), 1.28-1.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:14][N:15]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[N:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:18]3[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: Cn1cc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Reaction time: 6 h

Procedure:
Dissolve 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (3.43 g, 17.3 mmol) in tetrahydrofuran (100 mL). Add 1-methyl-1H-pyrazole-4-carbaldehyde (2.244 g, 20.38 mmol) in dry tetrahydrofuran (5 mL), stir for 10 min. at room temperature, add sodium triacetoxyborohydride (4.32 g, 20.4 mmol) and subject the reaction to ultrasound stirring for 6 hr. at room temperature. Add saturated aqueous sodium hydrogen carbonate (100 mL) then 2 N sodium hydroxide (10 mL) to the mixture and extract with DCM (2×200 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify (silica gel chromatography, eluting with 0:100 to 8:92 methanol:DCM), to give the title preparation as a crystalline solid (5.21 g, 92%). MS (ES): m/z=293.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>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.CO.C1(C)C=CC=CC=1>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1nnc(I)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1nnc(-c2ccccn2)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Temperature: 65 °C
Yield: 49.7 %

Procedure:
A mixture of 4-iodo-1-methoxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.128 g, 0.27 mmol), K2CO3 (0.075 g, 0.54 mmol), water (0.5 mL), toluene (3 mL), methanol (3 mL), 3-pyridineboronic acid (0.04 g, 0.325 mmol), Pd(PPh3)4 (0.094 g, 0.081 mmol) was heated to 65° C. for 2 hour. The reaction was cooled, filtered through celite, rinsed with methanol and concentrated. The residue was taken up in EtOAc, washed with sat. aq. NaHCO3 and dried (Na2SO4). Column chromatography (Hex/EtOAc) afforded 1-methoxy-4-pyridin-2-yl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (57 mg), m/z 425.01
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[NH2:12])=[O:6])[CH3:3].C([O-])(=O)C.[Na+].[CH:18](=O)[CH2:19][CH:20]([CH3:22])[CH3:21].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:12][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N
Reactant: CC(C)CC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
(1R,2S)-2-Amino-cyclopentanecarboxylic acid ethyl ester hydrochloride (0.81 g, 4.18 mmol) was dissolved in methanol (40 mL). Sodium acetate (0.69 g, 8.36 mmol) was added followed by 4 Å powdered molecular sieve (0.81 g). Isovaleraldehyde (0.36 g, 4.18 mmol) was then added followed by sodium cyanoborohydride (0.6 g, 10.45 mmol). The reaction mixture stirred at 25° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, (1R,2S)-2-(3-methyl-butylamino)-cyclopentanecarboxylic acid ethyl ester (0.58 g, 2.55 mmol, 61%), as a clear oil. LC-MS (ESI) calcd for C13H25NO2 227.19, found 228.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[OH:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].S(Cl)(Cl)=O.[CH2:34](Cl)[Cl:35]>>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[O:9][CH2:34][Cl:35])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: ClCCl
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Solvent: O=S(Cl)Cl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCCl
Temperature: 70 °C

Procedure:
A solution of 18.5 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate, 50 ml of methylene chloride and 50 ml of thionyl chloride was stirred at 20° to 25° C. for 2 hours and was then evaporated to dryness. The residue was admixed with 1.38 g of paraformaldehyde and 0.15 g of zinc chloride and the suspension was heated at 70° C. for 21/2 hours. After treatment, the product was chromatographed over silica gel and eluted with an 8-2 hexane-ethyl acetate mixture to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-chloromethoxy-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: C([C:4]1[C:5](O)=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([NH:9]C1NN=NN=1)=[O:8])(=O)C.[N+]([O-])(O)=O.O>S(=O)(=O)(O)O>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:15]=[CH:16][CH:17]=[CH:4][CH:5]=1
Reactant: CC(=O)c1cccc(C(=O)Nc2nnn[nH]2)c1O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
3-Acetyl-2-hydroxy-N-(tetrazol-5-yl)benzamide (6.0 g) was dissolved in concentrated sulphuric acid (30 ml). The solution was then cooled to 0° C. and, with stirring, was treated with concentrated nitric acid (density 1.42; 1.62 ml) at such a rate that the temperature did not exceed 10° C. The mixture was left to stand at between 0° and 5° C. for 20 hours, and was then poured into a mixture of ice and water (300 ml). The precipitated solid was collected, washed with water, and recrystallized from 98% w/w formic acid to give 3-acetyl-2-hydroxy-5-nitro-N-tetrazol-5-yl)benzamide, m.p. 255° C. (with decomposition).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:14][C:13]=2[N+:31]([O-])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>[Fe]>[NH2:31][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[CH:16]=[CH:17][C:12]=1[S:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(Sc2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)c1ccc(Sc2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2N)cc1
Yield: 70 %

Procedure:
The product from Example 242b was reduced with Fe and NH4Cl following the procedure from Example 9E to give the title compound (206 mg, 70%).
Reaction SMILES: [Mg].[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.BrC1CC1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1C#N>C(O)(=O)C.O>[CH:5]1([C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])=[O:2])[CH2:3][CH2:4]1
Reactant: N#Cc1ccccc1F
Reactant: C1CCOC1
Agent: BrC1CC1
Agent: [Mg]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccccc1F)C1CC1
Yield: 29.4 %

Procedure:
To a stirred mixture of 10 parts of magnesium and 72 parts of tetrahydrofuran there were added portionwise 50 parts of bromocyclopropane, keeping the temperature below 10° C. At reflux temperature, there was added a solution of 50 parts of 2-fluorobenzenecarbonitrile in 72 parts of tetrahydrofuran. Stirring at reflux temperature was continued until completion of the reaction. The reaction mixture was cooled on ice (0°-5° C.) and decomposed with a mixture of ice, water and acetic acid. The product was extracted with trichloromethane (3×) and the combined extracts were washed with water (2×), dried, filtered and evaporated. The residue was distilled (1.33 Pa; 78°-105° C.) (2×), yielding 19.8 parts (29.4%) of cyclopropyl (2-fluorophenyl)methanone; bp. 100°-103° C. (at 1.3 Pa) (interm. 17).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8]([NH:11]C(C)(C)C)(=[O:10])=[O:9])#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8]([NH2:11])(=[O:10])=[O:9])#[N:2]
Reactant: CC(C)(C)NS(=O)(=O)c1sccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccsc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Ten grams of 3-cyano-N-(1,1-dimethylethyl)thiophene-2-sulfonamide was dissolved in 500 mL of trifluoroacetic acid and stirred overnight at room temperature. After removal of the solvent by evaporation, the residue was dissolved in ethyl acetate and washed with four portions of 100 mL of water followed by saturated sodium chloride. After drying over magnesium sulfate, the solvent was evaporated in vacuo to yield 6.42 g of white solid, m.p. 152°-155°. It showed peaks by Nuclear Magnetic Resonance consistent for the desired structure.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[OH-].[Na+]>>[CH3:35][C:21]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)[S:24][C:20]=1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], (6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with NaOH to obtain (6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:13]2[S:12][CH:11]=[N:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: CNc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(F)cc1)c1cncs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.0 g (40 mmol) of 4-fluoro-N-methylaniline and 3.6 mL (40 mmol) of 2-bromothiazole were added to a suspension of 1.9 g (81 mmol) of NaH in 100 mL of DMF, and the suspension was stirred overnight at rt. The reaction mixture was concentrated onto 20 g of silica in vacuo and the residue purified by flash chromatography eluting with a linear gradient of 20% EtOAc in hexane to 100% EtOAc to deliver the desired compound. MS (M+H)+ 209.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[N:16]([CH3:21])[C:15](=[O:22])[CH:14]=1>>[NH2:16][C:15]1[C:14]([C:13]#[N:12])=[C:7]([C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH3:11])[C:14]2[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:13]=2[N:12]=1
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: COc1ccc(F)cc1C=O
Product: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
7-amino-5-(5-fluoro-2-methoxyphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (70a) was prepared by the reaction of 5-fluoro-2-methoxybenzaldehyde and 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, according to procedures described in the synthesis of Compound 56. MS [m+H] calc'd C17H15FN5O3 356; found 356.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][CH2:14]O)[N:9]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:8]=2[CH:28]=1)([O-:3])=[O:2].S(Cl)([Cl:31])=O.O>ClCCl>[Cl:31][CH2:14][CH2:13][CH:10]1[N:9]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:8]2[CH:28]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11]1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1cccc(C(F)(F)F)c1)N1c2cc([N+](=O)[O-])ccc2OCC1CCO
Solvent: O
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1c2cc([N+](=O)[O-])ccc2OCC1CCCl

Procedure:
To 5.37 g (0.0135 mol) of (±)-6-nitro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-3-ethanol dissolved in 80 ml of dichloromethane are added dropwise 4.85 ml (0.0675 mol) of thionyl chloride and the mixture is stirred, while being kept warm in a bath of hot water, for 5 h 30.