Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[N:13][C:14]([CH2:17][CH2:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24](C3CCCCO3)[N:23]=[CH:22]4)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([CH2:18][CH2:17][C:14]3[N:13]=[N:12][C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:34])[F:1])=[CH:5][CH:6]=4)=[CH:16][CH:15]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: FC(F)Oc1ccc(Nc2ccc(CCc3ccc4c(cnn4C4CCCCO4)c3)nn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)Oc1ccc(Nc2ccc(CCc3ccc4[nH]ncc4c3)nn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(4-(difluoromethoxy)phenyl)-6-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)pyridazin-3-amine (0.12 g, 0.258 mmol) in DCM (10 mL) was added TFA (1 mL, 12.98 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and washed with diethyl ether. The crude product was purified by preparative LCMS on a Waters Xbridge C18 column (19×150 mm, 5 μm) using 0-100% mobile phase B (95:5 Methanol:water with 10 mM NH4OAc) in mobile phase A (5:95 Methanol:water with 10 mM NH4OAc) to give 6-(2-(1H-indazol-5-yl)ethyl)-N-(4-(difluoromethoxy)phenyl)pyridazin-3-amine. 1H-NMR (300 MHz, DMSO-d6) δ ppm 3.07-3.14 (m, 4H) 6.28 (s, 1H) 7.00-7.37 (m, 6H) 7.46 (s, 1H) 7.56 (s, 1H) 7.78 (s, 3H) 7.97 (s, 1H) 9.19 (s, 1H) 12.93 (br. s., 1H).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1([CH2:20][OH:21])[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH2:13][NH:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[C:26](O)(=O)[CH3:27]>CO.O>[CH2:1]([N:12]1[CH2:13][CH:14]([OH:19])[CH:15]([OH:18])[CH:16]([OH:17])[C:11]1([CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:26][CH3:27]
Reactant: O=C(NCC1(CO)NCC(O)C(O)C1O)c1ccccc1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCN1CC(O)C(O)C(O)C1(CO)CNC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2.96 g of 2-benzoylaminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine (Example 3) are dissolved in a mixture of 40 ml of methanol, 2 ml of water and 2.7 ml of acetic acid, and 5.7 ml of nonylaldehyde are added. The solution is cooled to 5° C. in an ice-bath; 1.35 g of sodium cyanoborohydride are then added. The mixture is stirred for 30 minutes, whilst cooling, and then at room temperature for 24 hours. It is concentrated, the residue is dissolved in 30 ml of methanol/water 6:1 and the solution is discharged onto a column 30 cm long and 3 cm wide which is filled with Amberlite IR 120, H+ form. The column is washed thoroughly with methanol/water in the ratio 8:1 and then eluted with 0.2% strength ammonia in methanol/water 6:1. The pure fractions, determined by thin layer chromatography, are combined and concentrated. 2.6 g of an almost colourless oil are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:14]2[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:13]=2)[CH:28]=1)[CH3:19]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: CCOC(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-ethoxycarbonyl-phenylboronic acid gives “A67”; method 1: HPLC/MS: 1.48 min, [M+H]=363;
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.I[CH:43]([CH3:49])[CH2:44][C:45]([F:48])([F:47])[F:46]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:49][CH2:43][CH2:44][C:45]([F:48])([F:47])[F:46])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: CC(I)CC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CCCC(F)(F)F)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 72.3 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), 3-iodo-1,1,1-trifluorobutane (0.127 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.172 g (72%) of the title compound as a yellow oil.
Reaction SMILES: C1COCC1.[OH-].[Na+].[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[O:17][C:18]2[CH:24]=[C:23]([CH2:25][C:26]([O:28]C)=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1>Cl>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[O:17][C:18]2[CH:24]=[C:23]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3ccccc3C)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
THF (30 ml) and 0.25N NaOH (32 ml, 8.00 mmol) were added to methyl 2-(2-methylphenylamino)-6-benzoxazolylacetate (1.18 g, 3.98 mmol), followed by stirring at room temperature for 5 hours. The reaction mixture was poured in 1N HCl (50 ml), followed by extraction with a chloroform-methanol (5:1, 2×200 ml) mixture. The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (867 mg, 77%) was obtained as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: Cc1cccnc1C(=O)CBr
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2ncccc2C)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-3-methylpyridine hydrobromide*.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH:22]=C)[C:3]=1[F:24].[O:25]=[O+][O-]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH:22]=[O:25])[C:3]=1[F:24]
Reactant: O=[O+][O-]
Reactant: C=Cc1c(F)c(Cl)cc(C2(C)OCCO2)c1OC(C)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1c(C2(C)OCCO2)cc(Cl)c(F)c1C=O
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of ethyl 2-[4-chloro-3-fluoro-6-(2-methyl-1,3-dioxolan-2-yl)-2-vinylphenoxy]propanoate (400 mg, 1.11 mmol) in methylene chloride (40 mL) at −78° C. was treated with ozone until a purple color persisted. The reaction mixture was purged with oxygen, treated with dimethyl sulfide (1 mL) and warmed to room temperature. The reaction mixture was concentrated to give the crude product (392 mg, 98%) as a mixture of enantiomers that was used without further purification. LCMS calculated for C16H19ClFO6 (M+H)+: m/z=361.1; found: 361.1.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=3)[CH:13]=2)=[CH:41][CH:40]=1)(=[O:38])=[O:37]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-methylsulfonyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.98 (dd, J=6.60, 3.18 Hz, 6H), 1.57 (dt, J=13.45, 6.72 Hz, 1H), 1.77 (ddd, J=13.69, 7.21, 6.97 Hz, 1H), 2.06 (ddd, J=13.57, 7.70, 7.58 Hz, 1H), 3.17 (s, 3H), 3.87 (t, J=7.83 Hz, 1H), 7.72 (d, J=1.71 Hz, 2H), 7.78 (d, J=8.56 Hz, 2H), 7.87-7.91 (m, 3H), 7.95-7.98 (m, 2H), 8.05-8.08 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=CC=C(F)[C:3]=1[C:9]1[C:13](C(OC)=O)=[C:12](C(C(=O)C(F)(F)F)=CN(C)C)[O:11][N:10]=1.ClC1C=C([NH:36][NH2:37])C=CC=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH:36]1[CH:7]=[CH:2][C:3]([C:9]2[CH:13]=[CH:12][O:11][N:10]=2)=[N:37]1
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C(=CN(C)C)C(=O)C(F)(F)F
Reactant: NNc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1cc(-c2ccon2)n[nH]1
Yield: 225.8 %

Procedure:
To a solution of 0.5047 g (1.1994 mmol) methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole-4-carboxylate in dry ethanol, 0.1790 g (0.9995 mmol) 3-Chlorophenylhydrazine and 0.17 mL (0.9995 mmol) N,N-Diisopropylethylamine (DIPEA) were added. The reaction mixture was heated under reflux for 2 h. The product was isolated by using column chromatography (Petroleum ether:Diethyl ether 80:20), and 0.305 g (yield of theory: 61%) of the pyrazolyl-isoxazole derivative were obtained. Result of LC/MS [M+H]+: 499.9; 1H NMR (DMSO-d6; CCl4): 3.66 (3H, s, CH3), 7.45-7.50 (1H, dd, CH-arom.), 7.55-7.58 (1H, d, CH-arom.), 7.65-7.77 (1H, d, CH-arom.), 7.65-7.77 (1H, dd, CH-arom phenylhydrazine), 7.65-7.77 (1H, d, CH-arom. phenylhydrazine), 7.85 (1H, s, CH-arom phenylhydrazine), 8.56 (1H, s, 1-pyrazole)
Reaction SMILES: [CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][CH:20]=[C:16]3[N:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)[N:13]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.FC(F)(F)[C:34](O)=[O:35]>ClCCl>[CH:1]1([NH:4][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:34]=[O:35])=[C:16]3[N:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:22]=3)[N:13]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N(c1nc(-c2cccc(OC(F)(F)F)c2)nc2ccnn12)C1CC1
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)nc(-c3cccc(OC(F)(F)F)c3)nc12
Reaction time: 1 h

Procedure:
Tert-butyl cyclopropyl(2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)carbamate was dissolved in dichloromethane (0.7 mL) and trifluoroacetic acid (0.7 mL). After 1 h, the solution was concentrated under a stream of air to give crude 4-(cyclopropylamino)-2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a][1,3,5] triazine-8-carbaldehyde which was used without further purification. LCMS (ES): >90% pure, m/z 336 [M+1]+. 4-(cyclopropylamino)-2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde (87 mg, 0.26 mmol) was dissolved in DMF (0.8 mL). Phosphorus(V) oxychloride (318 μL, 3.47 mmol) was added was added dropwise and the reaction was heated to 70° C. After 6 h, the solution was added dropwise to 6M NaOH (˜10 mL) cooled to 0° C. The pH was adjusted to 7 by the addition of 12N HCl. The precipitate was filtered off and dried in vacuo to furnish 4-(cyclopropylamino)-2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde (71 mg, 75%) as a tan solid. LCMS (ES): >95% pure, m/z 364 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([S:14][C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][C:16]=2[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([S:14][C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][C:16]=2[C:30]([OH:32])=[O:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2SC2CCCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2ncc(C(=O)O)c2SC2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 101.5 %

Procedure:
Trifluoroacetic acid (4.72 mL, 61.46 mmol) was added to tert-butyl 5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate#89) (2.56 g, 6.15 mmol) in CH2Cl2 (40 mL) The resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness, re-dissolved in dioxan (20 mL) and re-evaporated to dryness to afford 5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylic acid (2.25 g, 100%) as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:34])[N:21]([N:30]=[CH:31][CH2:32][CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Li+]>O1CCCC1.Cl>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:34])[N:21]([NH:30][CH2:31][CH2:32][CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC=Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
The product of Example 358A (0.045 g, 0.09 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated with methanol (0.005 mL, 0.35 mmol), followed by dropwise addition of a 2.0 M solution of lithium borohydride in tetrahydrofuran (0.07 mL, 0.13 mmol), stirred at 25° C. for one hour, and diluted with 1 N hydrochloric acid. The resulting precipitate was filtered and dried. The solid was dissolved in tetrahydrofuran and absorbed onto silica gel by evaporating to dryness. The resulting silica was loaded onto a 2 g Alltech sep pack and eluted with dichloromethane to give the title compound (0.020 g, 44%). MS (ESI−) m/z 503 (M−H)−.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:6][C:7]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][CH2:10]1)=[O:8]>>[CH3:15][C:13]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]([C:7]([OH:8])([CH2:2][CH:3]([CH3:5])[CH3:4])[CH3:6])[CH2:14]1
Reactant: CC(C)CBr
Reactant: CC(=O)C1CCCC(C)(C)C1
Product: CC(C)CC(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with 1-bromo-2-methylpropane replacing bromoethane, and herbac replacing dehydroherbac.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:46]=[C:22]([C:23]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH2:43][CH2:44]O)[CH:36]=5)=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>C(Cl)Cl>[CH3:54][S:55]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:46]=[C:22]([C:23]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH2:43][CH2:44][S:55]([CH3:54])(=[O:57])=[O:56])[CH:36]=5)=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=1)(=[O:57])=[O:56]
Reactant: OCCCOc1cccc(-c2c3nc(cc4ccc([nH]4)c(-c4cccc(OCCCO)c4)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCCOc1cccc(-c2c3nc(cc4ccc([nH]4)c(-c4cccc(OCCCS(C)(=O)=O)c4)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a solution of 5,15-bis-[3-(3-hydroxypropoxy)phenyl]porphyrin (30 mg, 0.049 mmol) in anhydrous CH2Cl2, under nitrogen atmosphere, at 0° C., triethylamine (29 mg mg, 0.29 mmol) and methansulphonylchloride (17 mg, 0.15 mmol) were added. The mixture was kept under magnetic stirring at 0° C. for 3 hours, then washed with NaHCO3 saturated solution and with water. The organic phase was dried under Na2SO4 and the solvent removed by evaporation. The crude product was purified by chromatography on silica gel (CHCl3), to obtain 17 mg of the pure title product (yield 45%).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:15](O)[C:16]3[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][C:17]=3[CH3:31])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>CO.[Pd].[C]>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:18][C:17]=2[CH3:31])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(O)c2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Yield: 78.8 %

Procedure:
590 mg of tert-butyl 4-[[3-(4-fluorobenzyl)-4-methoxyphenyl](hydroxy)methyl]-3,5-dimethylphenylcarbamate (Example VIII), 24 mg of Pd/carbon (10%) and a drop of acetic acid are hydrogenated in 10 ml of methanol with hydrogen at atmospheric pressure for 4 h. The suspension is filtered through kieselguhr. The filtrate is concentrated in a rotary evaporator. Chromatography (cyclohexane/ethyl acetate=6:1) affords 449 mg (77%) of tert-butyl 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenylcarbamate.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1.[C:21](Cl)(=[O:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:13]=[C:12]([NH:14][C:21](=[O:23])[CH3:22])[CH:11]=[N:10][C:9]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1
Reactant: Nc1cnc(-c2ccncn2)c(-c2ccco2)n1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cnc(-c2ccncn2)c(-c2ccco2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
Sodium hydride (42 mg, 1.05 mmol) was added to a stirred solution of 6-(2-furyl)-5-pyrimidin-4-ylpyrazin-2-amine (Example 8, 100 mg, 0.42 mmol) in DMF (4 mL) at 0° C. under nitrogen. The solution was allowed to stir for 30 min. at 0° C. Acetyl chloride (60.0 μL, 0.84 mmol) was then added and the reaction mixture was warmed up to room temperature and stirred for 3 days. The reaction was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by silica gel flash chromatography (50% ethyl acetate in hexanes to 75% ethyl acetate in hexanes). Concentration in vacuo of the product-rich fractions provided the titled compound as a pale-yellow solid (8 mg, 7%).
Reaction SMILES: [ClH:1].[Cl:2][CH:3]([CH2:6][C:7]([Cl:11])(Cl)[CH:8]=O)[C:4]#[N:5]>CN(C)C=O>[Cl:1][C:8]1[C:7]([Cl:11])=[CH:6][C:3]([Cl:2])=[CH:4][N:5]=1
Reactant: Cl
Reactant: N#CC(Cl)CC(Cl)(Cl)C=O
Solvent: CN(C)C=O
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 66 %

Procedure:
Hydrogen chloride is passed into a solution of 25.0 g (0.125 mol) of 2,4,4-trichloro-4-formylbutyronitrile in 50 mml of N,N-dimethylformamide at a rate such that the temperature of the reaction mixture does not exceed 120° C. After completion of the reaction, the reaction mixture is poured into ice water. The beige-coloured precipitate is filtered off and dried. There is obtained 15.1 g (66% of theory) of 2,3,5-trichloropyridine, m.p. 48°-50° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:40])[CH2:36][CH2:37][CH2:38]Cl)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([C:35](=[O:40])[CH2:36][CH2:37][CH2:38][N:21]2[CH2:22][CH2:23][CH:18]([C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])[CH:17]=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[CH:33][CH:34]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C(C)(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 1-(4-tert-butylphenyl)-4-chloro-1-butanone: ESMS m/e: 449.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].Cl.[NH2:23][CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl.Cl.NCC1(O)CCCCC1>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:23][CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[N:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: NCC1(O)CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Triethylamine (8.38 mL, 60.1 mmol) was added over 10 min to a stirred mixture of 4-chloro-3-nitro-1,5-naphthyridine (6.00 g, 28.6 mmol) and 1-aminomethyl-1-cyclohexanol hydrochloride (5.00 g, 30.1 mmol) in dichloromethane (115 mL) at 0° C. The solution was allowed to warm to rt and more 1-aminomethyl-1-cyclohexanol hydrochloride (0.2 g) was added. The solution was stirred overnight and more triethylamine (0.5 mL) was added. After 30 min, the solution was partitioned between saturated aqueous sodium bicarbonate (100 mL) and chloroform (200 mL). The aqueous layer was extracted with chloroform (3×200 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (80 mL), dried over MgSO4, filtered, concentrated under reduced pressure, and dried under vacuum to afford 1-{[(3-nitro[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol as a yellow solid (8.65 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:29]
Reactant: CCOC(=O)CI
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 355 mg, 1.16 mmol) and ethyl iodoacetate (700 μL, 5.91 mmol) in dimethylformamide (5 mL) was heated at 100° C. for 2 h. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with 1:1 water/aqueous sodium thiosulfate (25 mL). The aqueous layer was back-extracted with dichloromethane (2×25 mL) and the combined organic layers were washed with brine (25 mL). The solution was dried (magnesium sulfate), filtered, evaporated, purified using an ISCO 12 g column, eluting with 40-100% ethyl acetate/petroleum ether, and dried under high vacuum at 75° C. to give [(4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-3-oxo-2,3,4,5,6,7-hexahydro-4,7-methano-indazol-1-yl]-acetic acid ethyl ester (269 mg, 59%) as an off-white solid. ES(+)-MS (M+H) 391.