Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-:44])[O:2][C@@:3]1(N2C(=O)CCC2=O)[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([F:26])[CH:24]=4)[N:19]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:18]=3)[N:11]=2)[CH2:4]1.[F:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1>C(#N)C>[F:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:1]([O:2][C@H:3]2[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]3[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]4[C:25]5[C:20](=[N:21][CH:22]=[C:23]([F:26])[CH:24]=5)[N:19]([S:27]([C:30]5[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=5)(=[O:29])=[O:28])[CH:18]=4)[N:11]=3)[CH2:4]2)=[O:44])[CH2:48]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@@](OC(=O)[O-])(N5C(=O)CCC5=O)C4)n3)c3cc(F)cnc32)cc1
Reactant: F[C@@H]1CCNC1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@H](OC(=O)N5CC[C@@H](F)C5)C4)n3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To (2,5-dioxopyrrolidin-1-yl) [(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbonate, 75c, (0.125 g, 0.195 mmol) already in acetonitrile was added (3R)-3-fluoropyrrolidine (0.445 g, 4.991 mmol) and the reaction mixture was stirred at room temperature for 20 hours; The reaction was monitored by HPLC until no more starting material was remaining. The reaction mixture was concentrated in vacuo and was carried on into the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1>CS(C)=O>[CH3:1][C:2]1[N:6]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:3]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (31 mg, 0.1 mmol) in DMSO (0.5 mL), Cs2CO3 (65 mg, 0.2 mmol) and α-bromo-p-xylene (20 mg, 0.11 mmol) were added at RT. The mixture was stirred at RT overnight. The resulting crude product was purified by pre-HPLC (Mobile phase: A=0.01% TFA/H2O, B=0.01% TFA/MeCN; Gradient: B=50%-90% in 12 min; Column: C18) and lyophilized to give 5-(5-methyl-1-(4-methylbenzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (20 mg, 48%). MS (ES+) C20H16F3N5O2 requires: 415. found: 416 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 8.22 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 5.52 (s, 2H), 2.57 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:24][C:20]=2[CH3:19])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-2-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([NH2:15])([CH3:14])[CH3:13]>C(O)CCC>[CH:12]([NH:15][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Reactant: CC(C)N
Solvent: CCCCO
Product: CC(C)Nc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Heat a mixture of 2,4-dibromonitrobenzene (3.50 g, 12.5 mmol), isopropylamine (4.42 g, 6.40 ml, 74.8 mmol) and n-butanol (20 ml) in a sealed reaction vessel to 117° C. overnight. Cool to room temperature and concentrate under reduced pressure. Partition the residue between ethyl acetate and saturated aqueous sodium chloride, dry the organic layer over sodium sulfate, and concentrate under reduced pressure to provide the desired compound as a yellow solid (3.0 g, 94%).
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.CC(C)([O-])C.[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a stirred solution of 2-bromo-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridin-4-amine (Description 49) (1 g, 2.51 mmol) in THF (10 mL) and DMF (5 mL) was added sodium tert-butoxide (0.603 g, 6.28 mmol) and benzenesulfonyl chloride (0.648 mL, 5.02 mmol). The reaction mixture stirred at RT under nitrogen for ca. 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (ca. 30 mL) and extracted with DCM (25 mL×4). The combined organics were dried and concentrated. The residue was purified via normal phase chromatography eluted with a gradient of 0-50% ethyl acetate in DCM, to afford the title compound (1.12 g). LCMS (A) m/z: 539 [M+1]+, Rt 1.45 min (acidic).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH3:21])[C:15]=2[O:22][CH3:23])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:19]([N:18]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([O:22][CH3:23])[C:16]([CH3:21])=[N:17]1)[CH3:20]
Reactant: CCn1nc(C)c(OC)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(C)c(OC)c1C1CCNCC1

Procedure:
A solution of 16 mg (0.0.49 mmol) of 1-tert-butoxycarbonyl-4-(1-ethyl-4-methoxy-3-methyl-(1H)-pyrazol-5-yl)piperidine (from Step E) in 0.1 mL of trifluoroacetic acid and 0.15 mL of CH2Cl2 at 0° C. was stirred for 30 min. Volatiles were removed under reduced pressure. The crude product was partitioned between 25 mL of 1 N NaOH and 25 mL of CH2Cl2. After separating phases, the aqueous layer was extracted with 3×25 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated to afford the title compound as a yellow film: 1H-NMR (500 MHz) δ 1.36 (t, J=7.2, 3H), 1.72–1.74 (m, 2H), 1.91–2.03 (m, 2H), 2.07 (s, 1H), 2.21 (s, 3H), 2.65–2.73 (m, 3H), 3.19–3.21 (m, 2H), 3.71 (s, 3H), 3.99 (q, J=7.2, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][N:3]=1.[F:11][C:12]1([F:19])[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.CC([O-])(C)C.[K+]>O1CCOCC1>[F:11][C:12]1([F:19])[CH2:17][CH2:16][C:15](=[C:8]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=2)[C:9]#[N:10])[CH2:14][CH2:13]1
Reactant: O=C1CCC(F)(F)CC1
Reactant: Cc1ncc(CC#N)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(C(C#N)=C2CCC(F)(F)CC2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (1 g, 7.52 mmol) and 4,4-difluorocyclohexanone (1.1 g, 8.27 mmol) in 1,4-dioxane (40 mL) was added t-BuOK (0.8 g, 8.27 mmol) in two portions. After the addition was completed, the reaction was heated to 60° C. and stirred overnight. The reaction solution was cooled to 0° C., quenched by saturated NH4Cl aq. solution and extracted with EtOAC (50 m×3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (Petroleum ether: EtOAc=4:1˜2:1) to afford 2-(4,4-difluorocyclohexylidene)-2-(2-methylpyrimidin-5-yl)acetonitrile (440 mg, yield: 23.5%). 1H NMR (CDCl3 varian 400 MHz): δ8.61 (s, 2H), 2.97 (t, J=8.0 Hz, 2H), 2.80 (s, 3H), 2.55 (t, J=8.0 Hz, 2H), 2.27-2.17 (m, 2H), 2.09-1.98 (m, 2H).
Reaction SMILES: Cl.CN.CN.[BH3-][C:7]#[N:8].[Na+].[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([CH:36]=O)=[C:28]([CH:31]([O:34][CH3:35])[O:32][CH3:33])[N:29]=3)[CH2:24][CH2:23][CH2:22]2)=[O:20])=[N:16][CH:17]=1)#[N:11]>CO>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([CH2:36][NH:8][CH3:7])=[C:28]([CH:31]([O:34][CH3:35])[O:32][CH3:33])[N:29]=3)[CH2:24][CH2:23][CH2:22]2)=[O:20])=[N:16][CH:17]=1)#[N:11]
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2C(=O)Nc1ccc(C#N)cn1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1ccc(C#N)cn1)CCC2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A tube was charged with methylamine hydrochloride (7.79 mg, 0.115 mmol) followed by methylamine (2 M in MeOH, 0.058 ml, 0.115 mmol) and NaCNBH3 (14.5 mg, 0.231 mmol). Then, a suspension of N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 36, 22 mg, 0.058 mmol) in MeOH (1 ml) was added, the tube was sealed and the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was quenched with water and concentrated until the organic solvents had mostly been removed. Water was added and the mixture was extracted with DCM (3×). The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(7 M NH3 in MeOH) 9/1) 100:0 to 50:50) to give the title compound as a yellow resin. (UPLC-MS 3) tR 0.72 min; ESI-MS 397.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:11]Br>C(Cl)(Cl)(Cl)Cl>[Br:11][C:8]1[C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[O:10][CH:9]=1
Reactant: Clc1nccc2occc12
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nccc2occ(Br)c12
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A solution of 4-chlorofuro[3,2-c]pyridine (10.60 g, 69 mmol, 1.0 eq) in carbon tetrachloride (135 mL) was cooled to −15° C. and bromine (12.13 g, 80 mmol, 1.2 eq) was added drop-wise over a fifteen minute time period. The mixture was stirred at ambient temperature for eighteen hours. The solvent was removed in vacuo, and the residue was dissolved in methanol (250 mL). A solution of 20% aqueous sodium hydroxide (35 mL) was added and the mixture was stirred 1 hour at ambient temperature. The methanol was removed in vacuo, and the residue was partitioned between water (100 mL) and dichloromethane (50 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the title compound (15.45 g, 96%) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (s, 1H), 8.37 (d, 1H), 7.87 (d, 1H); RP-HPLC (Conditions f) Rt 11.46 min.; MS: MH+232, 234.
Reaction SMILES: [C@H:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN(CC[N:55]2[CH2:60][CH2:59][CH:58]([OH:61])[CH2:57][CH2:56]2)CC1>>[OH:61][CH:58]1[CH2:59][CH2:60][N:55]([CH2:1][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:56][CH2:57]1
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c12
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 122 (see example 94) and amine 21.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.Cl.[CH3:26][O:27][NH:28][CH3:29].Cl>ClCCl.O1CCOCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:28]([O:27][CH3:26])[CH3:29])=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(C)=O)CC1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 1-acetylpiperidine-4-carboxylic acid (58.50 g, 342 mmol) in dichloromethane (700 mL) was added di(1H-imidazol-1-yl)methanone (58.18 g, 359 mmol). After the addition the mixture was agitated for two hours and N-methoxymethanamine hydrochloride (35.00 g, 359 mmol) was added at once. The mixture was allowed to agitate overnight at ambient temperature and 4M HCl in dioxane (75 mL) was added slowly. The slurry was agitated for 30 minutes and then filtered. Filtrate was washed twice with sodium bicarbonate solution, dried and concentrated to give the title compound (59.10 g, 80.72% yield).
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]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:8]([CH3:25])[CH2:7][C:6]2=[O:26].[CH:27](OCC)=[O:28].[O-]CC.[Na+].[H-].[Na+]>C1C=CC=CC=1.C(O)C>[OH:28][CH:27]=[C:7]1[C:6](=[O:26])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:8]1[CH3:25]
Reactant: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)CC2=O
Reactant: CCOC=O
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)C(=CO)C2=O

Procedure:
Following the procedure of Examples 1-E, 16-B and 17-B, 9.5 g. of benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate, 10.95 ml. of ethyl formate and sodium ethoxide prepared from 2.57 g. of sodium hydride and 3.23 ml. of ethanol in 120 ml. of benzene gave on work-up a yellow oil which on crystallization afforded 6.0 g. of crude product, m.p. 106°-110°C. The analytical same is recrystallized several times from methanol, m.p. 116°-118°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[OH-].[Na+]>CC(C)=O>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:14]
Reactant: C1CNCCN1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccco1)N1CCNCC1

Procedure:
To a solution of 21.5 g. (0.25 mol) of piperazine in a mixture of 960 ml. of acidified water (pH = 4.5) and 1200 ml. of acetone, 32.5 g. (0.25 mol) of furoyl chloride are added dropwise while the pH is maintained at 4.5 by dropwise addition of a sodium hydroxide solution. The mixture is made alkaline, and extracted several times with chloroform. The chloroform is distilled off and the concentrated extract is distilled in vacuo. 18.3 g. of the N-(2-furoyl)piperazine thus obtained in 50 ml. of diethyl ether are added to an equivalent amount of cyanogen bromide in a mixture of 60 ml. of water and 60 ml. of diethyl ether. The mixture is stirred overnight at room temperature and then subjected to continuous extraction with benzene. The extract is dried over sodium sulphate and the solvent is distilled off. According to the NMR and IR spectra the residue consists of 1-cyano-4-(2-furoyl)piperazine, m.p. 63°-65°C.
Reaction SMILES: C([N:4]1[C:17]2[C:12]3=[C:13]([C:18](=[O:28])[C:19]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:20][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=3)[CH:14]=[CH:15][CH:16]=2)(=O)C.N1CCCCC1>C(O)C>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][C:19]2[C:18](=[O:28])[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[N:11]([CH:20]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]4)[CH:23]=1
Reactant: CC(=O)N1c2ccccc2-n2cc(Cc3cccnc3)c(=O)c3cccc1c32
Solvent: C1CCNCC1
Solvent: CCO
Product: O=c1c(Cc2cccnc2)cn2c3c(cccc13)Nc1ccccc1-2
Yield: 26 %

Procedure:
The compound (500 mg) obtained in Example 9 was suspended in ethanol (20 mL) and to the suspension was added piperidine (2 mL). The mixture was heated under reflux for 30 hours under an argon atmosphere and allowed to cool. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =1:1) to obtain the title compound (115 mg; 26%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:33])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]3[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=3[CH3:22])[C:10]=2[O:29]C(=O)C)[CH:2]=1.C(=O)([O-])O.[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:33])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]3[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=3[CH3:22])[C:10]=2[OH:29])[CH:2]=1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3cccnc3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3cccnc3)c2O)=C(C)C1=O
Yield: 64.4 %

Procedure:
N-(Pyridin-3-yl)-3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.060 g, 0.133 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 2 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=4:1) and then recrystallized from methanol to obtain the titled compound (0.035 g, 0.0857 mmol, 64%).
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24](OCCCC)=O)[CH2:20][CH2:19]4)=[CH:14][N:13]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:33]([C:35]1[CH:36]=[N:37]C(Br)=[N:39][CH:40]=1)[CH3:34]>>[CH2:33]([C:35]1[CH:36]=[N:37][C:24]([N:21]2[CH2:20][CH2:19][CH:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:9]4[CH:31]=[CH:32][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:7][CH:8]=4)=[N:13][CH:14]=3)[CH2:23][CH2:22]2)=[N:39][CH:40]=1)[CH3:34]
Reactant: CCc1cnc(Br)nc1
Reactant: CCCCOC(=O)N1CCC(c2ccc(COc3ccc(-n4cnnn4)cc3)nc2)CC1
Product: CCc1cnc(N2CCC(c3ccc(COc4ccc(-n5cnnn5)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tort-butyl 4-[2-[4-(tetrazol-1-yl)phenoxymethyl]pyridin-5-yl]piperidine-1-carboxylate (Example 17) (26 mg, 0.06 mmol) and 5-ethyl-2-bromopyrimidine (14 μL, 0.12 mmol) following a procedure analogous to that in Example 48 as a white crystal (10 mg, yield 38%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.O[NH:64][C:65]([C:67]1[CH:76]=[CH:75][C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH:68]=1)=[NH:66]>CN(C=O)C>[CH:68]1[C:69]2[C:74](=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:75]=[CH:76][C:67]=1[C:65]1[N:64]=[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[O:12][N:66]=1
Reactant: N=C(NO)c1ccc2ccccc2c1
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc3ccccc3c2)no1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid (1 eq), TBTU (1.2 eq), HOBt (0.2 eq) and DIPEA (5 eq) in DMF was stirred at RT for 5 min; then added N-hydroxynaphthalene-2-carboximidamide was added and the mixture was stirred at RT for 20 min, after which time the mixture was warmed to 110° C. for 2 h. The solvent was removed under reduced pressure and the resulting crude used as such in the next step. MS (ES) C26H33N3O4 requires: 451, found: 452 (M+H+).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:11])[N:28]=2)=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCOc1cc(C#N)ccc1Cl
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1cc(-c2nc(-c3ccccc3Cl)nn2C)ccc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (1.50 g), 4-chloro-3-octyloxybenzonitrile (1.30 g), anhydrous iron (III) chloride (0.80 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.80 g of desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>COCCOC>[CH2:22]([NH:29][C:6]1[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Reactant: NCc1ccccc1
Solvent: COCCOC
Solvent: O
Product: Cc1c(NCc2ccccc2)nc(N)nc1-c1ccco1
Temperature: 80 °C
Yield: 64.9 %

Procedure:
To a stirred solution of 250 mg (0.77 mmol) trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-methyl-pyrimidin-4-yl ester in 10 ml DME in a pressure tube was added 0.63 ml (5.77 mmol) benzylamine and the mixture heated at 80° C. for 16 hours. The reaction mixture was then poured onto 80 ml water and cooled to 0° C. The resulting crystals were collected by filtration and washed sequentially with water, ether/hexane and a minimum quantity of ice-cold ether to afford 140 mg (65%) N4-benzyl-6-furan-2-yl-5-methyl-pyrimidine-2,4-diamine as a white crystalline solid. ES-MS m/e (%): 281 (M+H+, 100).