Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>CC#N.CC(C)=O>[CH:40]([O:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:30])=[CH:34][CH:35]=1)([CH3:42])[CH3:41]
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Solvent: CC#N
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)c2cc1OC
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (1.86 g, 6.80 mmol), prepared essentially as described in the previous step, and (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (2.28 g, 7.22 mmol), prepared essentially as described in Example 1a, in CH3CN (13 mL) was added DIEA (1.24 mL, 7.50 mmol). The homogeneous solution was refluxed for 4 h, allowed to cool to rt, shaken with 1 M K2CO3, and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with 0.5 M NaH2PO4 (1×50 mL), 4 M NaCl (1×25 mL), dried three times (Na2SO4), and concentrated under reduced pressure to give crude title compound as a beige semisolid (3.5 g). Flash chromotography (3:4→1:2 hex/acetone) afforded the title compound as an off-white foam (2.21 g, 72%). 1H-NMR (300 MHz, CDCl3) 9.08 (s, 1H), 7.34 (s, 1H), 7.28-7.22 (m, 3H), 6.83 (m, 2H), 6.46 (br s, 1H), 4.47 (heptet, J=6.1 Hz, 1H), 4.27 (br m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.59 (tt, J=11.0 Hz, 3.7 Hz, 1H), 3.15 (td, J=12.8 Hz, 2.4 Hz, 2H), 2.22-2.06 (m, 2H), 2.04-1.92 (m, 2H), 1.31 (d, J=6.1 Hz, 6H). LC/MS (ESI): calcd mass 450.2, found 451.3 (MH)+. Anal. Calcd for C25H30N4O4: C, 66.65; H, 6.71; N, 12.44. Found: C, 66.41; H, 6.68; N, 12.22.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:6][CH2:7][C@H:8]1[O:27][C@H:11]([CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[OH:28])([CH3:4])[CH3:3].[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)CC)C>C(Cl)Cl>[CH3:41][S:42]([O:28][C@@H:9]1[C@@H:8]([CH2:7][O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:27][C@H:11]([CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1OS(C)(=O)=O)(c1ccccc1)c1ccccc1

Procedure:
The title compound is prepared by the procedure of Example 277 using 3.39 g of product from Example 284, 0.57 ml of methanesulfonyl chloride, 1.03 ml of triethylamine, and 30 ml of methylene chloride to give, after chromatography, 3.0 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[O:23])[CH:17]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(3-Formyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (16 mg, 0.034 mmol) was dissolved in ethanol (1 mL) and treated with sodium borohydride (15 mg) in one portion. After stirring at room temperature for 15 min the reaction mixture was quenched with an aqueous solution of ammonium chloride. The reaction mixture was then extracted with ethyl acetate and the organic layer dried over sodium sulfate, concentrated and the residue purified by to column chromatography eluted with 30% ethyl acetate to yield 4-(3-hydroxymethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24]/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:52][CH3:53])([CH2:54][CH3:55])[CH2:50][CH3:51])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(/C=C\CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 59.8 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthio-pregna-5,7,16-triene (33.0 mg, 0.0568 mmol), (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (91.0 mg, 0.284 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, hexane:ethyl acetate=2:1, developed once) to give the title compound as a pale yellow oil (23.8 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.[BH4-].[Na+]>CO>[N:15]1[CH:16]=[C:12]([CH2:10][NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:13][CH:14]=1
Reactant: O=Cc1c[nH]cn1
Reactant: COc1cccc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(NCc2cnc[nH]2)c1
Yield: 81.2 %

Procedure:
To a solution of m-anisidine (0.91 ml, 8.12 mmol) in methanol (25 ml) was added 4-formylimidazole (0.86 g, 8.93 mmol). After stirring the mixture overnight at room temperature sodium borohydride (0.46 g, 12.2 mmol) was added. The reaction mixture was then concentrated in vacuo. The residue was purified using flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: methanol/dichloromethane 9:1) to yield a white solid (1.34 g, 18%); MS (ISP): 204.1 ([M+H]+).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[C:13](Cl)(=[O:15])[CH3:14].CCN(CC)CC>>[C:13]([O:12][C:9]1[CH:10]=[CH:11][C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:7][C:6]=2[CH:8]=1)(=[O:15])[CH3:14]
Reactant: CCc1cc2ccc(O)cc2s1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CCc1cc2ccc(OC(C)=O)cc2s1
Yield: 147.8 %

Procedure:
This material was prepared by treatment of 2-ethyl-6-hydroxybenzo[b]thiophene 134b (1.60 g, 9 mmole) with acetyl chloride (1 ml, 1.10 g, 14 mmole) and Et3N (2 ml, 1.45 g, 14 mmole) in a manner as previously described for example 8b to give a white solid (2.93 g, 93%). 1H NMR (DMSO-d6) δ7.72 (1H, d, J=8.5 Hz), 7.68 (1H, d, J=2.2 Hz), 7.15 (1H, s), 7.08 (1H, dd, J=2.2, 8.5 Hz), 2.89 (2H, q, J=7.5 Hz), 2.28 (3H, s), 1.29 (3H, t, J=7.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]Br)[C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.[CH2:14]([NH2:16])[CH3:15].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][N:16]([CH2:14][CH3:15])[C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(Br)cc1CBr
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN1Cc2cc(Br)cnc2C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (0.39 g, 1.3 mmol), ethylamine in THF (0.88 mL, 2.0 M, 1.8 mmol) and potassium carbonate (0.26 g, 1.9 mmol) in ethanol (5 mL) in a sealed reaction vial was stirred at 40° C. for 2 h. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.24 g). LCMS (M+H)+=240.9/242.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.C(OC([N:50]1[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]1)=O)(C)(C)C>ClCCl>[NH:50]1[CH2:55][CH2:54][CH:53]([NH:56][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][CH:9]4[CH2:13][CH2:12][N:11]([CH:14]5[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]5)[C:10]4=[O:20])=[C:6]([Cl:21])[CH:5]=3)=[CH:27][CH:26]=2)=[O:29])[CH2:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NC1CCNCC1)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
Dissolve racemic 3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (0.200 g, 0.448 mmol) in dichloromethane (5 mL) and add 1,1′-carbonyl-diimidazole (0.125 g, 0.760 mmol). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.180 g, 0.90 mmol) and continue to stir until the starting material has been fully consumed. Dilute the reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) then brine (30 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with gradient (0-100%) dichloromethane to 15% ammonia methanol/85% dichloromethane. After concentrating, dissolve the 4-{[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir ½ hour to obtain an oily residue in reaction vessel. Concentrate the mixture under vacuum then dilute in dichloromethane (100 mL). Quench with saturated aqueous sodium bicarbonate solution (50 mL), dry the organic phase over magnesium sulfate and concentrate to obtain 0.195 g (82%) of a yellow foam: MS (m/z): 530 (M+2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([O:17][CH3:18])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].C(O)(=[O:21])C>>[CH3:18][O:17][C:15]([C:7]12[CH2:8][C:9]3([OH:21])[CH2:10][CH:11]([CH2:12][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:14]3)[CH2:6]1)[CH2:13]2)=[O:16]
Reactant: CC(=O)O
Reactant: COC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Product: COC(=O)C12CC3CC(O)(C1)CC(C(=O)OC)(C3)C2
Yield: 42 %

Procedure:
To 25 mL of acetic acid were added the 10 mmole of the 1,3-dimethoxycarbonyladamantane, 1 mmole of NHPI and 0.05 mmole of V(AA)3, and the resultant mixture was stirred for 8 hours at 85° C., under an oxygen atmosphere. As a result, 1,3-dimethoxycarbonyl-5-adamantanol (yield 42%) and 1,3-methoxycarbonyl-5,7-adamantanediol (yield 36%) were formed. The conversion of 1,3-dimethoxycarbonyladamantane was 92%.
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:18])[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:6]=1.[C:19]([NH:22][NH2:23])(=[O:21])[CH3:20]>CO>[C:19]([NH:22][NH:23][C:14](=[NH:17])[CH2:13][CH2:12][CH2:11][CH2:10][N:7]1[N:6]=[C:5]([NH:4][C:3]([NH2:18])=[N:2][CH3:1])[CH:9]=[N:8]1)(=[O:21])[CH3:20]
Reactant: CN=C(N)Nc1cnn(CCCCC(=N)OC)n1
Reactant: CC(=O)NN
Solvent: CO
Product: CN=C(N)Nc1cnn(CCCCC(=N)NNC(C)=O)n1

Procedure:
Methyl 5-[4-[2-methylguanidino)-1,2,3-triazol2-yl]valerimidate (1.0 g.) in MeOH (12 ml.) was treated with acethydrazide (0.22 g.) and the solution stirred for 18 nours. Evaporation of the solvent and trituration of the resioue with ether/EtOH gave N-acetylamino-5[4-(2-methylguanidino)-1,2,3-triazol-2-yl]valeramidine as a yellow sticky solid [0.54 g.) which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4](=[O:15])[NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C.CCOCC>[CH2:23]([N:3]1[C:4](=[O:15])[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N:6][C:2]1=[O:1])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOP(=O)(OCC)C1=NC(=O)NC1=O
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)N=C(P(=O)(OCC)OCC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (6.00 g, 0.025 moles) in DMF (15 mL), under N2, is added K2CO3 (17.5 g, 0.127 moles) and 1-iodohexane (3.75 mL, 0.025 moles). This mixture is stirred at room temperature for 16 hours. The mixture is diluted with ether (300 mL) and washed with water and brine and then dried over MgSO4. Evaporation of solvents under high vacuum affords the required product as a viscous yellow oil. (Mass spectrometry also revealed a small amount of diethyl 1,3-dihexyl-2,5-dioxo-4-imidazolylphosphonate).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13](Br)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([NH:19][NH2:20])[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: N#Cc1c(OCc2ccccc2)ccnc1Br
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(OCc2ccccc2)ccnc1NN
Temperature: 150 °C
Yield: 95.3 %

Procedure:
To a solution of compound D2 (1.2 g, 4.15 mmol) in THF (12 ml) was added hydrazine monohydrate (0.416 g, 8.301 mmol). The reaction mixture was heated at 150° C. under microwave irradiation for 1 min. After cooling, additional hydrazine monohydrate (1 eq) was added to the reaction mixture, which was then heated at 150° C. under microwave irradiation for 0.5 min. After cooling, the reaction mixture was concentrated in vacuo. The residue thus obtained was triturated with Et2O to yield intermediate compound D3 (0.95 g, 95%).
Reaction SMILES: N#N.Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[CH:19][C:18]=2[Cl:24])=[N:6][N:5]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C>[Cl:24][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:23])[C:17]=1[CH2:16][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:5][N:6]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: N#N
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCOCC3)c2c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 78.7 %

Procedure:
A solution under stirring and dry N2 of 4-chloro-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), prepared as described in example 45, in DMF (25 ml), at room temperature, was added with morpholine (0.73 g, 8.46 mmoles) and the temperature was raised to 100° C. After 14 hours the whole was brought to dryness and the solid partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and brought to dryness to give a solid which was flash chromatographed (eluent hexane/ethyl acetate 6:4, then in gradient up to 3:7) to give 0.9 g of the title compound (yield: 79%). m.p.: 179-180° C.
Reaction SMILES: Br[CH:2]1[CH2:28][C@@:27]2([CH3:29])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:26]2[CH2:25][C:24](=[O:30])[C@@:23]2([CH3:31])[C:9]3=[CH:10][C@@H:11]3[O:16][C@@:15]4([O:22][CH2:21][C@H:19]([CH3:20])[CH2:18][CH2:17]4)[C@@H:13]([CH3:14])[C@@H:12]32)[CH2:4][C:3]1=[O:32].[N-:33]=[N+]=[N-].[Na+].[I-].[Na+].O>CN(C)C=O>[NH:33]=[C:2]1[CH2:28][C@@:27]2([CH3:29])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:26]2[CH2:25][C:24](=[O:30])[C@@:23]2([CH3:31])[C:9]3=[CH:10][C@@H:11]3[O:16][C@@:15]4([O:22][CH2:21][C@H:19]([CH3:20])[CH2:18][CH2:17]4)[C@@H:13]([CH3:14])[C@@H:12]32)[CH2:4][C:3]1=[O:32]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C=C3[C@@H]4CC[C@H]5CC(=O)C(Br)C[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C=C3[C@@H]4CC[C@H]5CC(=O)C(=N)C[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
500 mg (0.99 mmol) of 2-bromo-(25R)-5α-spirost-14-ene-3,12-dione (II) is dissolved in 50 ml of dimethylformamide. After adding 700 mg of sodium azide and a few milligrams of sodium iodide, the solution is stirred for 2 hours at 50° C. The reaction mixture is brought to room temperature, poured into 20 ml of water and extracted with methyl-tert-butyl ether. This extract is washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. After crystallization, 407 mg (80%) of iminoketone III is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[C:10]#N)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:32]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:10]=[O:32])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=CC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
2-(3,4-Dichlorophenyl)-3-(1,3-dioxolan-2-yl)propanenitrile (64 g) (see Preparation 13) was suspended in anhydrous toluene (500 ml) and cooled to −70° C. under a nitrogen atmosphere. Diisobutylaluminium hydride (200 ml of a 1.5M solution in toluene) was then added over 50 minutes, by which time a clear solution was achieved. The mixture was stirred at −70° C. for a further 30 minutes and then allowed to warm slowly to −20° C. Water (24 ml) was carefully added (exothermic reaction) before pouring the mixture into a 15% (by weight) aqueous solution of citric acid (1800 ml). Toluene (100 ml) was added and the mixture was vigorously stirred for 1 hour. The resulting emulsion was filtered through a short column of Arbacel (trade mark) filter aid to give two clear phases which were separated. The organic phase was washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give 2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propan-1-al as a yellow oil (53.5 g)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.CCN(C(C)C)C(C)C.[CH3:51][O:52][C:53]1[CH:57]=[C:56]([C:58](O)=[O:59])[O:55][N:54]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:58]([C:56]4[O:55][N:54]=[C:53]([O:52][CH3:51])[CH:57]=4)=[O:59])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3)ccc21
Reactant: COc1cc(C(=O)O)on1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCc2cncc(-c3ccc4c(c3)CCC(=O)N4C)c2)on1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
To a solution of 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36, 0.05 g, 0.187 mmol) in dry DCM (1 mL) were added EDCI (0.039 g, 0.206 mmol), hydroxybenzotriazole (0.032 g, 0.206 mmol), Hünig's base (0.060 g, 0.468 mmol) and 3-methoxy-isoxazole-5-carboxylic acid (0.040 g, 0.281 mmol) and the resulting solution was stirred at room temperature over night. The reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (5 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.03 g, 41%) as a white solid. MS: 393.1 (M+H+).
Reaction SMILES: [CH:1]1([C:7]([O:9]C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][NH2:12]>CO>[CH:1]1([C:7]([NH:11][NH2:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)C1CCCCC1
Solvent: CO
Product: NNC(=O)C1CCCCC1
Temperature: 65 °C
Yield: 33.5 %

Procedure:
To a solution of methyl cyclohexane carboxylate (12 g, 83.9 mmol) in MeOH (50 mL) was added hydrazine (5.3 mL, 1.67 mol). The reaction mixture was heated at 65° C. overnight. The reaction mixture was cooled to room temperature and the resultant solid was collected by filtration and was dried in vacuo to give 4.0 g of cyclohexanecarboxylic acid hydrazide.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]2)(=[O:4])=[O:3].[Cl:19][C:20]1[CH:21]=[N+:22]([O-:45])[CH:23]=[C:24]([Cl:44])[C:25]=1[CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[N+:22]([O-:45])[CH:23]=[C:24]([Cl:44])[C:25]=1[CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:17][C:16](=[O:18])[CH2:15][N:11]1[C:12]2[C:8](=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCN2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 25.4 %

Procedure:
A mixture of 2-(5-(methylsulfonamido)indolin-1-yl)acetic acid (0.154 g, 0.571 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), EDC (0.128 g, 0.666 mmol) and DMAP (0.116 g, 0.952 mmol) in dry DCM (10 ml) was stirred at room temperature for 2.5 hours. Additional 2-(5-(methylsulfonamido)indolin-1-yl)acetic acid (0.072 g, 0.267 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was removed and the crude was purified by flash chromatography on silica gel column (DCM:MeOH=98:2). A further purification by preparative HPLC (Method 1) under neutral conditions was required to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(methylsulfonamido)indolin-1-yl)acetoxy)ethyl)-pyridine 1-oxide (0.0817 g, 0.121 mmol, 26% yield). MS/ESI+ 672.05 [MH]+; [αD]=+10.81, c=0.518; DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.84 (br. s., 1H), 8.55 (s, 2H), 7.17 (d, 1H), 7.08 (d, 1H), 6.94 (dd, 1H), 6.92 (d, 1H), 7.06 (t, 1H), 6.81 (dd, 1H), 6.22 (d, 1H), 6.03 (dd, 1H), 4.10 (d, 1H), 3.90 (d, 2H), 3.92 (d, 1H), 3.43 (dd, 1H), 3.32-3.39 (m, 2H), 3.22 (dd, 1H), 2.89 (t, 2H), 2.83 (s, 3H), 1.08-1.31 (m, 1H), 0.49-0.68 (m, 2H), 0.18-0.46 (m, 2H).