Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: OCC1CN(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: OCC1CNCCNC1

Procedure:
2.26 g (7.3 mmol) of (1,4-dibenzyl-[1,4]-diazepan-6-yl)-methanol are dissolved in 150 ml of methanol and hydrogenated at room temperature and normal pressure in the presence of 0.5 g of 10% palladium on activated charcoal. [1,4]-Diazepan-6-yl-methanol is obtained in the form of a light yellow oil by filtration and concentration of the filtrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:19][C@@H:18]2[C@@H:20]([NH:23][C:24](=O)OC(C)(C)C)[CH2:21][CH2:22][C@@H:17]2[CH2:16]1)(=[O:14])=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:19][C@@H:18]2[C@@H:20]([NH:23][CH3:24])[CH2:21][CH2:22][C@@H:17]2[CH2:16]1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Cl)C[C@@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: CN[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Cl)C[C@@H]21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
tert-butyl(3aR,4S,6aS)-2-(2-chloro-4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate (62 mg, 0.132 mmol) from Example 284 Step A was dissolved in 1,2-dimethoxyethane (1.0 mL) and lithium aluminum hydride (10.04 mg, 0.264 mmol) was added portionwise. The reaction was stirred at 70° C. overnight, then it was quenched with wet sodium sulfate. The crude material was applied to a 4 g silica gel cartridge and purified with a gradient of 1-10% methanol (2 N ammonia)/dichloromethane over 20 minutes to give (3aR,4S,6aS)-2-(2-chloro-4-(trifluoromethyl)phenylsulfonyl)-N-methyloctahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.46 (s, 1H), 8.34 (d, J=8.2, 1H), 7.99 (s, 1H), 4.92 (s, 3H), 4.32 (dt, J=13.7, 7.0, 1H), 3.89 (dd, J=10.2, 3.0, 1H), 3.49 (dd, J=10.2, 7.5, 1H), 3.41-3.30 (m, 2H), 2.70-2.59 (m, 2H), 2.48 (dt, J=4.4, 2.2, 1H), 2.01 (td, J=11.8, 6.6, 1H), 1.95-1.83 (m, 1H), 1.59 (ddd, J=16.1, 10.8, 7.7, 1H), 1.37 (dt, J=22.2, 6.5, 1H); MS (APCI+) m/z 383 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][C:7](=[CH2:9])[CH2:6][N:5]1[C:10](=[O:29])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Br:25])=[CH:13][C:12]=1[N+:26]([O-:28])=[O:27].CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1.C(Cl)Cl.C1(C)C=CC=CC=1.CO>[Br:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([C:10]([N:5]2[CH2:6][C:7](=[CH2:9])[CH2:8][C@H:4]2[CH:3]=[O:2])=[O:29])=[C:12]([N+:26]([O-:28])=[O:27])[CH:13]=1
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)c2cc(OC)c(OCCCCCBr)cc2[N+](=O)[O-])C1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: C=C1C[C@@H](C=O)N(C(=O)c2cc(OC)c(OCCCCCBr)cc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
To a vigorously stirred solution of 1-[4-(5-bromopentyloxy)-5-methoxy-2-nitro-benzoyl]-4-methylene-L-proline methyl ester 18 (61 mg, 0.12 mmol) in anhydrous toluene —CH2Cl2 (3:1, 2.5 mL) was added dropwise solution of DIBAL-H (188 μL of a 1M solution in toluene) at −78° C. under argon atmosphere. After the mixture was stirred for an additional 45 min, excess reagent was decomposed by addition of three drops of methanol followed by 5% HCl (2 mL). The resulting mixture was allowed to warm to 0° C. Layers were separated and the aqueous layer was further extracted with CH2Cl2 (3×2 mL). Combined organic layers were washed with brine, and dried (MgSO4) and concentrated. Purification of the residue by flash chromatography (silica gel, 1:1 hexanes/EtOAc) yielded (S)-1-[4-(5-bromopentyloxy)-5-methoxy-2-nitro-benzoyl]-4-methylene-2-pyrrolidinecarboxaldehyde 19 as light yellow oil (44 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:23][CH:24]=1)(=[O:27])[CH3:26]
Reactant: Nc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reaction time: 0.75 h

Procedure:
1-[1-(4-Aminophenethyl)piperidin-4-yl]indoline (310 mg) was dissolved in methylene chloride (3 ml). Under ice cooling, acetyl chloride (0.103 ml) was added to the resultant solution followed by stirring the obtained mixture for 45 min. After adding a 10% aqueous solution of potassium carbonate, the reaction solution was extracted with ethyl acetate. Then the organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the resulting residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (200 mg) as an oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: Nc1cccc(S(=O)(=O)NCCO)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCCO)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-hydroxy-ethyl)-benzenesulfonamide [CAS 436095-41-9] according to general procedure II. Yellow solid. MS (ISP) 572.0 [(M−H)−]; mp 227° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)[OH:8])[OH:6])=[O:4].[NH2:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16]>[Ni]>[OH:12][CH2:11][CH:9]([NH:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16])[CH:7]([OH:8])[CH:5]([OH:6])[CH:3]([OH:4])[CH2:2][OH:1]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(CO)C(=O)O
Agent: [Ni]
Product: O=C(O)C(CO)NC(CO)C(O)C(O)C(O)CO

Procedure:
The product, obtained in the form of a resin, was made from D-fructose and DL-serine using Raney nickel as a catalyst and heating for 2 hours to 50° C. and for 3 hours to 70° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14](OCC)=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[NH3:21]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:21])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Reactant: N
Product: NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Temperature: 122.5 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A suspension of ethyl 9-bromo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (compound 61-4, page 196, WO 2011/036280) (0.3 g, 0.89 mmol) in 7 M ammonia solution (in methanol, 4 ml) was heated in a microwave apparatus to 120-125° C. for 2.5 hours. After cooling the mixture was left at room temperature for 18 hours before the solvent was removed in vacuo and the residue was then taken up in tetrahydrofuran and pre-absorbed onto a small amount of silica. Purification by FCC (silica, 20-100% ethyl acetate in heptane) gave 245 mg (89%) of the title compound. 1H NMR (250 MHz, DMSO-d6) 8 ppm 3.18 (2H, t, J=5.79 Hz), 4.46 (2H, t, J=5.79 Hz), 6.71 (1H, s), 7.18 (1H, dd, J=8.60, 0.69 Hz), 7.39 (1H, br, s.), 7.51 (1H, ddd, J=8.68, 2.44, 0.76 Hz), 7.84 (1H, br. s.), 8.19 (1H, dd, J=2.44, 0.76 Hz)); M+1=308/310.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:14](=[O:30])[N:15]([CH2:27][CH:28]=C)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26])[C:9]([CH3:13])([CH3:12])[CH:10]=C)([CH3:4])([CH3:3])[CH3:2]>ClCCl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[C:9]([CH3:12])([CH3:13])[CH:10]=[CH:28][CH2:27][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:14]1=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCN(Cc1ccc(OC)cc1OC)C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C=C
Solvent: ClCCl
Product: COc1ccc(CN2CC=CC(C)(C)C(NC(=O)OC(C)(C)C)C2=O)c(OC)c1
Yield: 62.9 %

Procedure:
{1-[Allyl-(2,4-dimethoxy-benzyl)-carbamoyl]-2,2-dimethyl-but-3-enyl}-carbamic acid tert-butyl ester (0.5 g, 1.16 mmol) was dissolved in dichloromethane (400 ml), bis(tricyclohexylphosphine)benzylidine ruthenium dichloride (145 mg, 0.17 mmol) was added and the purple solution was refluxed for 48 hours. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with NaHCO3 solution, 1M KHSO4 solution and brine. After drying with magnesiumsulfate the organic layer was concentrated and purified by flash chromatography (heptane/ethyl acetate=4:1) to yield 295 mg (63%) of [1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]-carbamic acid tert-butyl ester; MS: m/e=405.5 (MH+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)[CH:2]=[CH2:3].N1CCC1>>[N:4]1([C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:3][CH2:2][CH2:1]1
Reactant: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Agent: C1CNC1
Product: COc1ccc2c(N3CCC3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using azetidine in place of allylamine, the title compound was synthesized.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH:32]1([C:2]2[C:3]([NH:12][C@H:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]3[N:30]=[CH:29][CH:28]=[N:27]3)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH2:34][CH2:33]1
Reactant: OB(O)C1CC1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl)c1ccccc1-n1nccn1
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: C1COCCO1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1)c1ccccc1-n1nccn1

Procedure:
A mixture of N-[(1S,2S)-2-{[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 29; 170 mg, 0.38 mmol), cyclopropylboronic acid (CAS number 411235-57-9; 97 mg, 1.13 mmol), potassium carbonate (aq. 2 M, 752 μl, 1.51 mmol) and tetrakis(triphenylphosphine)palladium (44 mg, 0.038 mmol) in 1,4-dioxane (1.3 ml) was sealed, purged and evacuated with nitrogen and then subjected to microwave irradiation 120° C. for 1 hour. The reaction was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. This was then purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:12]([CH3:13])=[CH:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5].CC1[C:20](=[O:21])[CH2:19][CH:18](C(C)=C)CC=1.ClCCC(OCC)=O.C(C(CC)=O)=C>>[C:4]([C:6]12[CH2:18][CH2:19][C:20]([OH:21])=[CH:13][C:12]1=[CH:11][C:9](=[O:10])[CH2:8][CH2:7]2)([O:3][CH2:2][CH3:1])=[O:5]
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Agent: C=CC(=O)CC
Agent: CCOC(=O)CCCl
Product: CCOC(=O)C12CCC(=O)C=C1C=C(O)CC2

Procedure:
This material is prepared according to the procedure for Preparation 6 wherein Hagemann's ester (ethyl 2-methyl-4-oxocyclohex-2-enyl-1-carboxylate) is substituted for carvone and ethyl 3-chloropropionate is substituted for ethyl vinyl ketone.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:3]1[N:4]=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccccc2)n[nH]c1=O
Product: Cc1cc(-c2ccccc2)nnc1Cl

Procedure:
A mixture of 13.2 g. of 4-methyl-6-phenyl-3(2H)-pyridazinone and 200 ml. of phosphorus oxychloride is heated on a steam bath for 18 hours. The reaction mixture is filtered. The filtrate is concentrated free of excess phosphorus oxychloride. The residue is stirred with ice water and filtered. The solid is washed with water and air dried giving 3-chloro-4-methyl-6-phenylpyridazine as a cream colored solid.
Reaction SMILES: [CH:1]1(COC2C(C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH:48]3[CH2:53]CCC[CH2:49]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.BrCC(C)(C)C>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][C:48]([CH3:49])([CH3:1])[CH3:53])[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH3:61])[CH:37]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Agent: CC(C)(C)CBr
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC(C)(C)C

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 1-bromo-2,2-dimethyl-propane (CAS Reg. No. 630-17-1). Light brown solid (20%). MS (Turbo Spray): m/z=365.1 (M+H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:34])[CH3:33]>>[CH3:33][C:32]1[N:34]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:31]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 19.9 mg (0.269 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 55.5 mg (47% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C)C=O>[Si:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 14 h

Procedure:
To a solution of ethyl 3-(4-hydroxyphenyl)propionate (940 mg, 4.84 mmol) in anhydrous dimethylformamide (9.4 mL) were added t-butyldimethylsilyl chloride (1.0 g, 6.6 mmol) and imidazole (490 mg, 1.5 mmol) at room temperature, and the mixture was left standing at the same temperature for 14 h. The reaction mixture was directly concentrated, and subjected to silica gel column chromatography (hexane-ethyl acetate 25:1→20:1) to give 1.49 g (quantitative) of the title compound as a solid.
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH:5]([CH:7]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[OH:6].OC(CCCC(O)CCCCC)CCCCCCC(O)=O>C(Cl)(Cl)Cl>[OH:6][CH:5]([CH:7]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:4][CH2:3][OH:2]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(O)CCOC
Agent: CCCCCC(O)CCCC(O)CCCCCCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(O)CCO

Procedure:
The crude reduction mixture (1.55 g.) is applied to a silica gel column (30 g., 0.05-0.2 mm.; E. Merck, Darmstadt) with chloroform. Impurities are eluted with chloroform (260 ml.) followed by chloroform-methanol (98:2, 145 ml.) and chloroform-methanol (95:5, 60 ml.). Continued elution with the latter eluant (225 ml.) provides oil A (0.5 g.) which is a mixture of 8-(3-methoxy-1-hydroxy-1-propyl)-12-hydroxyheptadecanoic acid and 8,12-dihydroxyheptadecanoic acid.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([CH:7]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]([CH3:22])=[N:11]2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(F)ccc1-n1cc(C(O)C2CCCCC2)c(C)n1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: Cc1cc(F)ccc1-n1cc(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)c(C)n1
Yield: 63.8 %

Procedure:
Using cyclohexyl[1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.52 g, 70%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([F:19])[C:13]=4[CH:12]=[C:9]3[C:10]=2[CH:11]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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]>[F:19][C:14]1[C:13]2[CH:12]=[C:9]3[C:10]4[CH:11]=[C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]6[O:28][C:27]([C:24]7[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=7)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=6[CH:36]=5)[N:3]=[CH:4][C:5]=4[CH2:6][CH2:7][N:8]3[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2cnc(Cl)cc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cc4c(cn3)CCn3c-4cc4c(F)cccc43)cc12
Temperature: 120 °C
Yield: 31.4 %

Procedure:
To a solution of compound 2-chloro-11-fluoro-5,6-dihydroindolo[2,1-a][2,6]naphthyridine (70 mg, 0.26 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (155 mg, 0.31 mmol) and K2CO3 (53 mg, 0.38 mmol) in 1,4-dioxane (2 mL) and water (0.05 mL) were added X-Phos (10 mg) and Pd2(dba)3 (10 mg) under nitrogen. The mixture was heated at 120° C. for 3 hours and filtered through the celite pad. The filtrate was extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by prep-HPLC to give the desired compound (50 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H), 7.91˜7.98 (m, 4H), 7.62 (s, 1H), 7.09˜7.16 (m, 5H), 6.74 (t, J=8.8 Hz, 1H), 5.95 (s, 1H), 4.29 (t, J=6.0 Hz, 2H), 3.23 (t, J=6.0 Hz, 2H), 3.17 (s, 3H), 2.95 (d, J=4.0 Hz, 3H), 2.83 (s, 3H). MS (M+H)+: 613.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:17][CH2:18][C:19]([OH:21])=[O:20]>CCO.O>[N+:8]([C:7]1[C:2]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)CNc1ncccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2-Chloro-3-nitropyridine (5 g, 31.5 mmol) was dissolved in EtOH (125 ml), added potassium carbonate (4.35 g, 31.5 mmol) and to this mixture glycine (4.73 g, 6.3 mmol) in 25 ml water was added and refluxed for overnight. The reaction mixture cooled to 0° C. to obtain the solid. Then EtOH was removed on rotavapour and acidified with 2N HCl and solid filtered and dried on vacuum to obtain the title compound quantitatively as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:16])([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:16][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[Cl:17])([C:10]([NH2:12])=[O:11])[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC(=O)C(O)(C(N)=O)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(=O)C(OC(=O)c1ccccc1Cl)(C(N)=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
26.3 g of 3,4-dichlorophenylhydroxymalonic acid diamide were dissolved in 50 ml of pyridine, and 17.1 g of o-chlorobenzoyl chloride were added at below 30° C. After one hour, the mixture was stirred into cold 1NCl, the precipitate was taken up in ethyl acetate, the mixture was extracted by shaking and the extract was worked up. 26.5 g of crude product remained, and were recrystallised from 400 ml of ethanol. 13 g of pure 3,4-dichlorophenyl-(2-chlorobenzoyloxy)-malonic acid diamide of melting point 220° C. were obtained.