Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:40])=[N-]>CO.CCOCC>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:37][CH3:40])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 0.17 h

Procedure:
The resulting crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is dissolved in methanol and a solution of diazomethane in ether is added at 0° C. After 10 minutes, the solution is carefully concentrated and the residue is dried under a high vacuum. The residue is purified by thick layer chromatography (toluene/ethyl acetate, 3:1, silica gel). After eluting the silica gel of the zone at Rf=0.17 with ethyl acetate, and concentrating the solution on a rotary evaporator, 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained; melting point 120° C. (from ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[CH3:33][N:34](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:33]([C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1)#[N:34]
Reactant: CN(C)C=O
Reactant: O=C(NC1=NC2(c3cccc(Br)c3)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(C23CN(c4ncc(F)cn4)CC2CSC(NC(=O)c2ccccc2)=N3)c1
Temperature: 100 °C
Yield: 67 %

Procedure:
To a solution of racemic N-[7a-(3-bromophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (310 mg, 605 μmol) and zinc cyanide (170 mg, 1.42 mmol) in dimethylformamide (6.0 mL) is added tetrakis (triphenylphosphine) palladium (200 mg, 171 μmol). The resulting mixture is heated at 100° C. under N2 for 16.5 hours before being cooled to room temperature, filtered through diatomaceous earth, and washed with ethyl acetate (30 mL). The combined filtrate is washed with semi-saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (30 mL), and chloroform (30 mL). The combined organic layers are dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with a gradient of ethyl acetate/dichloromethane (0 to 30%) to give the title compound (187 mg, 67%). EI/MS (m/e): 459.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:5]2[OH:26].[Cu](C#N)[C:28]#[N:29]>[C-]#N.C([N+](CC)(CC)CC)C.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:28]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:5]2[OH:26])#[N:29]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Reactant: N#C[Cu]C#N
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(C#N)ccc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 5.5 h
Yield: 49 %

Procedure:
1,1-Dimethylethyl N-((6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (297 mg, 700 μmol, prepared in Example 40A-D), dppf (155 mg, 280 μmol), tris(dibenzylideneacetone)dipalladium (64.1 mg, 70.0 μmol), copper cyanide (251 mg, 2800 μmol), and tetraethylammonium cyanide (120 mg, 770 μmol) were mixed in dioxane (6 mL) in a microwave tube under a nitrogen atmosphere. The reaction mixture was then stirred at 75° C. for 5.5 hours. The reaction mixture was returned to room temperature, fused to silica gel, and purified by silica flash chromatography (0-100% DCM/hexane) to give the desired ester as an off-white solid (127 mg). MS (m/e)=315.1 (M+H-tBu)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:40][CH2:41][C@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]=2[CH3:31])=[O:33])[CH2:37][CH2:38]1)([CH3:46])([CH3:48])[CH3:47]
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1([C:11]([F:14])([F:13])[F:12])[O:7][CH:6]([C:8](O)=[O:9])[CH2:5][O:4]1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>>[F:1][C:2]([F:16])([F:15])[C:3]1([C:11]([F:14])([F:13])[F:12])[O:7][CH:6]([C:8]([Cl:25])=[O:9])[CH2:5][O:4]1
Reactant: O=C(O)C1COC(C(F)(F)F)(C(F)(F)F)O1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Cl)C1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
2,2-Bis(trifluoromethyl)-1,3-dioxolan-4-oyl chloride was prepared from 2,2-bis(trifluoromethyl)-4-carboxy-1,3-dioxolane (see U.S. patent application 07/401,668, filed Aug. 30, 1989) (25.4 g, 0.1 mole). To this substrate was added pyridine (3.16 g, 0.04 mole) followed by thionyl chloride (14.3 g, 0.12 mole), with external cooling to maintain the pot at ambient temperature. When the addition was complete, the reaction mixture was heated slowly to 70° C. for 1.5 hour, then at 90° to 100° C. for 0.5 hour. The product was distilled from the reaction mixture, a clear colorless liquid, 22.0 g (81% yield) was obtained. Bp. 50° C./10 mm. 1H-NMR (Neat): δ 5.23 (t, J=7.0 Hz, 1H), 4.73 (m, 2H); 19F NMR (neat): -80.5 (q, J=8.5 Hz, 3F), -81.5 (q, J=8.5 Hz, 3F). Anal. Calc. for C6H3ClF6O3 : C: 26.44, H: 1.11, F: 41.83, Cl: 13.00; Found: C: 26.13, H: 1.11, F: 41.44, Cl: 13.38. ##STR6##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Mg].[Cl:15][CH2:16][Si:17]([CH3:20])([CH3:19])Cl>II>[Cl:15][CH2:16][Si:17]([CH3:20])([CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: II
Agent: [Mg]
Product: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Yield: 57.5 %

Procedure:
In the same apparatus and procedures as Example 2-i) were reacted 18.7 g (80 mmol) of 4-bromobiphenyl, 4.8 g of magnesium and 0.7 g of iodine to prepare 4-phenylphenyl Grignard solution. In the same apparatus and procedures were reacted 10.4 ml (80 mmol) of chloromethyldimethylchlorosilane and the prepared 4-phenylphenyl Grignard solution to treat the reaction product. After separating them by using silica gel column (eluent: hexane), 12 g of chloromethyldimethyl(4-phenylphenyl)silane (92%) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.Cl.[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>C(#N)C.O>[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)[CH2:22][CH2:21]1
Reactant: Cc1nc(NCc2ccccn2)nc(Cl)c1C
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cc1nc(NCc2ccccn2)nc(NC2CCC(F)(F)CC2)c1C
Yield: 41 %

Procedure:
A solution of 4-chloro-5,6-dimethyl-N-(pyridin-2-ylmethyl)pyrimidin-2-amine (200 mg, 0.8 mmol, Example 29, Step C) and (4,4-difluorocyclohexyl)amine hydrochloride (172 mg, 1 mmol) in acetonitrile (5 mL) was refluxed overnight. The reaction mixture was diluted with water (50 mL) and a formed precipitate was collected by filtration. The crude material was purified by HPLC (column: YMC-PACK ODS-AQ C18, 250 mm×20 mm, 10 μm; gradient: 20-50% acetonitrile in 0.02% trifluoroacetic acid/water over fifteen minutes; 50-100% acetonitrile in 0.02% trifluoroacetic acid/water over five minutes; flow rate: 25 mL/min; temperature: 25° C.) to afford 114 mg, 25% of the titled compound as the trifluoroacetic acid salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.45-1.55 (m, 4H), 1.70-1.82 (m, 2H), 1.88 (s, 3H), 1.90-2.00 (m, 2H), 2.25 (s, 3H), 3.90 (bs, 1H), 4.70 (d, J=5.37 Hz, 2H), 7.38 (t, J=6.25 Hz, 1H), 7.47 (d, J=7.52 Hz, 1H), 7.64 (d, J=7.52 Hz, 1H), 7.90 (t, J=7.52 Hz, 1H), 8.46-8.52 (m, 1H), 8.57 (d, J=4.57 Hz, 1H), 12.78 (bs, 1H); MS (ESI) m/z 348.8 (M+1)+. N4-(4,4-Difluorocyclohexyl)-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine trifluoroacetate was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1) to afford 58 mg (68%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40-1.51 (m, 2H), 1.60-1.71 (m, 3H), 1.81 (bs, 4H), 1.90-1.98 (m, 2H), 2.07 (s, 3H), 3.76-3.84 (m, 1H), 4.46 (d, J=5.91 Hz, 2H), 5.84 (d, J=7.25 Hz, 1H), 6.70-6.75 (m, 1H), 7.10-7.22 (m, 1H), 7.24 (d, J=7.79 Hz, 1H), 7.67 (t, J=7.52 Hz, 1H), 8.45 (d, J=4.30 Hz, 1H); MS (ESI) m/z 348.8 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg) in DMF (2.0 ml) was added at 22° C. NaH (55% in oil, 64 mg) and stirring was continued until gas evolution ceased. The suspension was cooled to 0° C. and treated with trifluoroethyl trifluormethane sulphonate (728 mg) and stirring was continued at 22° C. for 2 h. The mixture was partitioned between saturated NaHCO3 and ethyl acetate and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using n-heptane/ethyl acetate (3:1) to give 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg) as a white solid. MS (ISP): m/z=236.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.[NH2:18][C:19]([CH:23]([F:25])[F:24])=[CH:20][C:21]#[N:22]>CC(O)C.C(N(CC)CC)C>[F:24][CH:23]([F:25])[C:19]1[NH:18][C:15]([CH3:16])=[C:12]([C:13]#[N:14])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:20]=1[C:21]#[N:22]
Reactant: N#CC=C(N)C(F)F
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)F)N1

Procedure:
A suspension of 3.42 g (15.2 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A) and 7.27 g (60.7 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (20 ml) and triethylamine (0.21 ml) was stirred at reflux temperature overnight. After cooling, the precipitate was collected by filtration and washed twice with cold 2-propanol. The crude product was purified by silica gel chromatography (tert-butyl methyl ether/ethanol gradient, final mixture 94:6 v/v) to yield 0.36 g (7% of th.) of the racemic title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([OH:30])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>ClCCl>[CH2:38]([NH:40][C:41](=[O:42])[O:30][CH:28]1[CH2:27][N:26]([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:29]1)[CH3:39]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(O)C3)ccc2n1CC1CCC(F)(F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)OC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-ol (100 mg, 0.23 mmol) in 2 mL of dry dichloromethane was added triethylamine (3 uL, 0.023 mmol) and ethyl isocyanate (0.11 mL, 1.4 mmol), respectively. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 100 mg (85%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.00 (t, J=7.23 Hz, 3 H), 1.48-1.57 (m, 2 H), 1.59 (s, 9 H), 1.63-1.83 (m, 4 H), 2.04 (d, J=26.56 Hz, 2 H), 2.18-2.31 (m, 1 H), 3.00 (q, J=7.23 Hz, 2 H), 3.63 (dd, J=9.18, 5.08 Hz, 2H), 4.01-4.09 (m, 2 H), 4.42 (d, J=7.62 Hz, 2 H), 7.70-7.75 (m, 1 H), 7.79-7.84 (m, 1 H), 8.10 (s, 1 H); MS (APPI) (M+H)+=513.3; Anal. Calc. for C24H34F2N4O4S+1.1 TFA: C, 49.32; H, 5.54; N, 8.78. Found: C, 49.31; H, 5.42; N, 8.59.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C(C([O-])=O)=NN=N1)C1C=CC=CC=1.[K+].[CH3:32][C:33]1[CH:38]=[C:37]([C:39]([CH3:41])=[O:40])[C:36]([OH:42])=[C:35]([NH2:43])[CH:34]=1.N1C=CC=CC=1>C(Cl)Cl>[C:39]([C:37]1[C:36]([OH:42])=[C:35]([CH:34]=[C:33]([CH3:32])[CH:38]=1)[NH:43][C:13]([C:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][N:11]=1)=[O:14])(=[O:40])[CH3:41]
Reactant: CC(=O)c1cc(C)cc(N)c1O
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Agent: O=C([O-])c1nnnn1Cc1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Reaction time: 8 h

Procedure:
A solution of crude 1-benzyl-1H-tetrazole-5-carbonyl chloride (prepared from 0.73 g of potassium 1-benzyl-1H-tetrazole-5-carboxylate in the manner hereinbefore described in Reference Example 3) in dry methylene chloride (14 ml) was added to a stirred mixture of 3-amino-2-hydroxy-5-methylacetophenone (0.5 g) and pyridine (0.27 g) in dry methylene chloride (12 ml) at between 5° and 10° C. Stirring was maintained for 2 hours, allowing the temperature to rise to room temperature, and then the mixture was left to stand overnight. A further portion of methylene chloride (20 ml) was then added and the mixture was washed with water. The organic phase was dried over magnesium sulphate, and evaporated in vacuo to give a solid, which was recrystallised from ethanol, to give 3'-acetyl-1-benzyl-2'-hydroxy-5'-methyl-1H-tetrazole-5-carboxanilide (1.0 g), m.p. 183°-184° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C=O.[CH3:17]C(O)=O.[BH4-].[Na+].[NH4+].[Cl-]>C(Cl)Cl.CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:17])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: C=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(Br)cc2)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
A mixture of 1-(4-bromophenyl)piperazine hydrochloride (1.0 g, 3.61 mmol), formaldehyde (37% aqueous, 3 mL, 39.71 mmol), AcOH (0.23 mL, 3.97 mmol) and MeOH (30 mL) was heated at 80° C. under nitrogen. After 1.5 hours, the mixture was cooled to 0° C. in an ice bath. Methylene chloride (5 mL) was added followed by a slow addition of sodium borohydride (1.91 g, 50.54 mmol) under nitrogen. The mixture was stirred for 1 hour and then poured into a seperatory funnel containing a saturated solution of NH4Cl (25 mL) and CH2Cl2 (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The extracts were dried (Na2SO4), filtered and concentrated to to give the sub-title compound (900 mg, 97%) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:14][CH:15]([CH3:34])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]>>[CH3:14][CH:15]([CH3:34])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:5](=[O:6])[C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]([F:13])([F:12])[F:1])[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]
Reactant: CC(C)CCCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CC(C)CCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (4-methylpentyl)amide, the title compound was obtained as a white solid (65.5% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.86, 7.74-7.72, 7.62-7.54, 7.36-7.34, 6.98, 4.08-3.98, 3.92-3.65, 3.47-3.4, 3.35-3.31, 1.62-1.53, 1.28-1.21, 0.86. 13C NMR (75 MHz, CDCl3) δ 167.5, 162.9, 159.9, 145.3, 134.2, 132.3, 129.4, 127.0, 126.7, 126.2, 125.4, 121.7, 112.5, 46.3, 44.5, 44.3, 41.2, 39.6, 35.9, 27.7, 27.4, 22.4. MS (ES+) m/z 464.5 (M+1).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][C@H:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15]
Reactant: CCCOC1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)CCc3ccccc32)CC1
Reaction time: 20 h
Yield: 38.1 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.493 g, 1.5 mmol) and 4-propoxypiperidine (0.430 g, 3.0 mmol) in MeCN (2 mL) and shaken at 60° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, EtOAc/MeOH 4:1) to give the title compound (107LH48) (0.197 g, 38%). 1H NMR (CD3OD) δ 7.26-7.19 (m, 3H), 7.03-6.98 (m, 1H), 3.96 (d, J=7.0 Hz, 2H), 3.40 (t, J=6.7 Hz, 2H), 2.90-2.86 (m, 2H), 2.74-2.71 (m, 1H), 2.65-2.54 (m, 3H), 2.26-1.99 (m, 6H), 1.87-1.84 (m, 2H), 1.59-1.49 (m, 4H), 0.91 (t, J=7.4 Hz, CH3), 0.85 (d, J=6.6 Hz, CH3); 13C NMR (CD3OD) δ 173.0, 140.3, 129.1, 128.4, 128.4, 124.3, 116.8, 76.3, 70.7, 64.5, 53.2, 52.8, 32.9, 32.4, 32.4, 30.3, 26.2, 24.3, 17.1, 11.0.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([CH2:11][C:12]([Br:14])=[CH2:13])[C:6]([O:8]CC)=[O:7])C.[OH-].[Na+]>>[Br:14][C:12](=[CH2:13])[CH2:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:15])=[O:3]
Reactant: C=C(Br)CC(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: C=C(Br)CC(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 63.2 %

Procedure:
A mixture of 10.5 g (0.0376 mol) of 2-(2-bromo-allyl)-malonic acid diethyl ester and 37.6 ml (0.470 mol) of 50% aqueous sodium hydroxide was stirred at room temperature for 4 days. The reaction mixture was extracted with diethyl ether. The isolated aqueous layer was acidified by the addition of concentrated hydrochloric acid and diethyl ether was added. The resulting mixture was transferred to a separatory funnel where the phases were separated. The isolated organic layer dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to yield 5.3 g of 2-(2-bromo-allyl)-malonic acid as a solid which was carried on without purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>>[F:26][C:25]([F:28])([F:27])[S:22]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1)(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc2c(O)ccc(C(=O)N3CCCCC3)c12
Product: Cc1cccc2c(OS(=O)(=O)C(F)(F)F)ccc(C(=O)N3CCCCC3)c12

Procedure:
This compound was prepared by treating (4-hydroxy-8-methylnaphthalen-1-yl)(piperidin-1-yl)methanone (above step-2 intermediate) with Tf2O by following the similar procedure as described in Step-8 of Intermediate-22
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[C:10]([CH:12]2[C:25]3[CH:24]=[CH:23][C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[NH:15][S:14](=[O:27])(=[O:26])[N:13]2[CH3:28])[CH:9]=[CH:8][C:7]=1[F:29]>O.C1COCC1.CO>[F:29][C:7]1[CH:8]=[CH:9][C:10]([CH:12]2[C:25]3[CH:24]=[CH:23][C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[NH:15][S:14](=[O:27])(=[O:26])[N:13]2[CH3:28])=[CH:11][C:6]=1[C:5]([OH:30])=[O:4]
Reactant: COC(=O)c1cc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(c2ccc(F)c(C(=O)O)c2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
LiOH (10 mg, 0.25 mmol) in water (0.5 ml) was added to a solution of 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzoic acid methyl ester 423 (50 mg, 0.12 mmol) in THF:MeOH (1:1; 2 ml) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, the residue was diluted in the minimum amount of water and acidified to pH=3-4 with 2 M HCl. The resulting precipitate was collected by filtration and dried. The crude solid was purified by preparative HPLC (acidic conditions 1) to give the title compound (8 mg, 17%).