Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C(OC([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([C:20]([O:22]CC)=O)[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=O)C>C(O)C>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:14]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:20]1=[O:22]
Reactant: CCOC(=O)Nc1ccccc1N(CCN(C)C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CN(C)CCn1c(=O)[nH]c2ccccc21
Yield: 86.8 %

Procedure:
In ethanol (100 ml) was dissolved sodium metal (0.70 g) followed by addition of a solution of N-(2-ethoxycarbonylaminophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine (4.88 g) in ethanol (20 ml). The mixture was refluxed overnight and the solvent was then distilled off under reduced pressure. To the residue was added chloroform and the insoluble matter was filtered off. The solvent was distilled off and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=10:1) to give 2.69 g of 1,3-dihydro-1-(2-dimethylaminoethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:15]C1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)C1(c2ccc(O)c(O)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C1(c2ccc(O)c(O)c2)CC1
Temperature: 80 °C
Yield: 912.5 %

Procedure:
To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (190 mg, 1.0 mmol) in MeOH (3 mL) was added 4-methylbenzenesulfonic acid (19 mg, 0.10 mmol). The mixture was heated at 80° C. overnight. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with sat. NaHCO3 and brine and dried over MgSO4. After the removal of solvent, the residue was dried in vacuo to yield methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate (190 mg, 91%) that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.76-6.71 (m, 2H), 6.66 (d, J=7.9 Hz, 1H), 3.56 (s, 3H), 1.50 (q, J=3.6 Hz, 2H), 1.08 (q, J=3.6 Hz, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:12](=[O:13])[CH:11]2[C:14]([CH3:16])([CH3:15])[CH:7]([C:8](=[O:18])[NH:9][C:10]2=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:28]=1[CH2:29]Cl>CN(C)C=O>[CH2:1]([N:5]1[C:6](=[O:19])[CH:7]2[C:14]([CH3:15])([CH3:16])[CH:11]([C:10](=[O:17])[N:9]([CH2:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]=3[CH3:26])[C:8]2=[O:18])[C:12]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(C)c(CCl)c1
Reactant: CCCCN1C(=O)C2C(=O)NC(=O)C(C1=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C2C(=O)N(Cc3cc(C)ccc3C)C(=O)C(C1=O)C2(C)C
Temperature: 120 °C
Yield: 32 %

Procedure:
2.6 g of 3-butyl-9,9-dimethyl-2,4,6, 8-tetraoxo-3,7-diazabicyclo[3,3,1]nonane were heated to 120° C. in 50 ml of dimethyl formamide with 1.7 g potassium carbonate for one hour. After cooling, a solution of 1.8 g of 2,5-dimethylbenzyl chloride in 20 ml of dimethyl formamide was added dropwise to the reaction mixture, and the reaction mixture was heated to 120° C. for another 3 hours. The reaction mixture was worked up by distilling off the dimethyl formamide, taking up the residue in dichloromethane, and washing with water adjusted to an alkaline pH value. The dichloromethane phase was separated, dried over magnesium sulfate, and concentrated. After recrystallizing the remaining crude product residue from ether/acetone, 1.2 g of 3-butyl-7-(2,5-dimethylbenzyl)-9, 9-dimethyl-2,4,6,8-tetraoxo-3,7diazabicyclo[3,3, 1]nonane was obtained having a melting point of 159-161° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:12])[CH:8]=2)[N:3]=1.[CH2:13]([CH2:15][NH2:16])O.S(Cl)(Cl)=O>>[I:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]1[CH2:13][CH2:15][N:16]=[C:2]1[CH:11]=[CH:10]2
Reactant: NCCO
Reactant: Clc1ccc2cc(I)ccc2n1
Solvent: O=S(Cl)Cl
Product: Ic1ccc2c(c1)C=CC1=NCCN12
Temperature: 50 °C

Procedure:
2-Chloro-6-iodo-quinoline (200 mg, 0.69 mmol) and ethanolamine (1 mL) were heated at 130° C. for 1 hour. The reaction was cooled and purified by silica gel chromatography (4:1 EtOAc:Hex), and the isolated product was dissolved in CHCl3. Thionyl chloride (0.12 mL, 1.65 mmol) was added, and the reaction was heated at 50° C. for 1 hour. The reaction was quenched with methanol and basified with saturated aqueous Na2CO3. The mixture was extracted with CH2Cl2, and the combined organic layers were combined, dried, filtered, and concentrated to give the desired product, 2a.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:19][C:20]1[N:21]([CH2:25][CH2:26][CH3:27])[CH:22]=[CH:23][N:24]=1.O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:19][C:20]2[N:21]([CH2:25][CH2:26][CH3:27])[CH:22]=[CH:23][N:24]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: CCCn1ccnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccnc1CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
2-mercapto-5-nitropyridine (3.2 g) was dissolved in DMF (64 ml), potassium carbonate (8.5 g) and 2-chloromethyl-1-propylimidazole hydrochloride (4.8 g) were added to the mixture, and the mixture was stirred for 1 hour at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[[(1-propylimidazol-2-yl)methyl]sulfanyl]pyridine (4.8 g).
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]>>[O:1]=[C:2]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)([CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C(Cc2ccncn2)c2ccccc2N1c1ccccc1
Reactant: N#CCCCCBr
Product: N#CCCCCC1(Cc2ccncn2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 68 %

Procedure:
By substituting 2,3-Dihydro-2-oxo-1-phenyl-3-(4-pyrimidinylmethyl)1H-indole and 5-bromopentanenitrile in Example 1, the desired product was obtained in 68% yield as an oil; NMR(CDCl3TMS): δ1.21 (m, 1H); 1.35 (m, 1H); 1.60 (m, 1H); 1.65 (m, 1H); 2.00 (m, 1H); 2.20 (m, 1H); 2.26 (m, 2H); 3.25 (d, 1H, J=14 Hz); 3.55 (d, 1H, J=14 Hz); 6.65 (d, 1H, J=8 Hz); 6.98 (m, 1H); 7.09 (m, 2H); 7.21 (m, 1H); 7.27 (m, 2H); 7.42 (m, 1H); 7.51 (t, 2H, J=7 Hz); 8.44 (d, 1H, J=5 Hz); 8.90 (s, 1H); IR(KBr): 1718, 1612, 1583, 1549, 1500, 1481, 1465, 1454, 1376, 1326, 1221, 758, 733, 700 cm-1 ; mass spec m/e 383 (M+1). HRMS: m/e calcd 383.187187, m/e found 383.185396 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([Sn:14]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])N(C)C)[CH2:11][CH2:12][CH3:13]>>[CH2:22]([Sn:14]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Reactant: C#Cc1ccc(Cl)cc1
Product: CCCC[Sn](C#Cc1ccc(Cl)cc1)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A mixture of commercially available 1-chloro-4-ethynylbenzene (4 g, 29 mmol) and 1,1,1-tributyl-N,N-dimethylstannanamine (9.79 g, 29.3 mmol) was stirred at RT for 2 hours. The reaction was concentrated to afford the desired product tributyl((4-chlorophenyl)ethynyl)stannane 18A (13.1 g, 27.7 mmol, 95% yield) as a light yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C@@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:20]#[C:21]Br>CO>[C:9]1([C@@H:6]([CH2:7][CH3:8])[CH2:5][C@H:2]2[CH2:3][O:4][C:21]([NH2:20])=[N:1]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CBr
Reactant: CC[C@@H](C[C@H](N)CO)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@@H](C[C@H]1COC(N)=N1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred, cooled (0° C.) solution of (2S,4S)-2-amino-4-phenyl-hexan-1-ol (270 mg, 1.40 mmol) and sodium acetate (229 mg, 2.70 mmol) in methanol (20 ml) was added dropwise a solution of cyanogen bromide (180 mg, 1.68 mmol) in methanol (2 ml) over 10 min. The mixture was then allowed to warm to r.t. and stirring was continued for 16 h. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and with saturated brine. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/EtOAc/MeOH) to yield a light yellow solid. MS (ISP): 219.3 ([M+H]+).
Reaction SMILES: O1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:30]([C:31]5[N:32]=[CH:33][NH:34][CH:35]=5)[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.Cl.Cl.[NH2:38][OH:39]>O1CCOCC1.O>[NH:34]1[CH:35]=[C:31]([C:30]2[N:17]3[C:18]([C:19]4[CH:20]=[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:12]([C:9]5[CH:8]=[CH:7][C:6]([CH:2]=[N:38][OH:39])=[CH:11][CH:10]=5)=[N:13][C:14]=4[CH:15]=[CH:16]3)=[N:28][N:29]=2)[N:32]=[CH:33]1
Reactant: NO
Reactant: c1ccc(-c2cc3c(ccn4c(-c5c[nH]cn5)nnc34)nc2-c2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: ON=Cc1ccc(-c2nc3ccn4c(-c5c[nH]cn5)nnc4c3cc2-c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 22-1 (0.8 g, 1.7 mmol) in 1,4-dioxane (3 ml) was added 3N HCl (1.1 ml, 3.4 mmol) dropwise. After stirring for 10 min the solution was treated with hydroxylamine hydrochloride (0.5 g, 6.9 mmol) in water (0.5 ml). The mixture was stirred for 1 h and was then quenched with NaHCO3(s) until pH=8. Upon solvent removal the residue was taken up in water, filtered, and dried azeotropically with toluene to afford 22-2 as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1
Reactant: CCCOc1ccnc(C)c1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCOc1ccnc(CBr)c1OC
Yield: 27.9 %

Procedure:
To a solution of 3-methoxy-2-methyl-4-propoxypyridine (1.0 g) in carbon tetrachloride (70 ml), was added N-bromosuccinimide (1.0 g) and the mixture was irradiated with and infrared lamp (Toshiba, 100 V, 375 WR) for 2 hours at reflux. An insoluble substance was filtered off, and the filtrate was concentrated and purified by column chromatography on silica gel, to give 2-bromomethyl-3-methoxy-4-propoxypyridine (0.4 g) as a reddish brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([N:15]([CH2:22][CH3:23])[CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]([CH3:24])=[C:11]([C:25]([NH:27][CH2:28][C:29]3[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=3[CH3:35])=[O:26])[CH:10]=2)=[CH:5][CH:4]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][C:39]1=[O:44].[H-].[Na+]>CN(C=O)C>[CH3:35][C:34]1[CH:33]=[C:32]([CH3:36])[NH:31][C:30](=[O:37])[C:29]=1[CH2:28][NH:27][C:25]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:38]3[CH2:43][CH2:42][O:41][CH2:40][C:39]3=[O:44])=[CH:4][CH:5]=2)[CH:14]=[C:13]([N:15]([CH2:22][CH3:23])[CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:12]=1[CH3:24])=[O:26]
Reactant: O=C1COCCN1
Reactant: CCN(c1cc(-c2ccc(CBr)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3=O)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29.1 %

Procedure:
To an ice cooled stirred solution of 4′-(bromomethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-[1,1′-biphenyl]-3-carboxamide (250 mg, 0.44 mmol) and morpholin-3-one (67 mg, 0.66 mmol) in DMF (30 mL) was added sodium hydride (27 mg, 0.66 mmol). After 10 minutes, ice was removed and stirring continued for 16 h at room temperature. On completion, water was added and extracted with DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic and prep. HPLC purification afforded the title compound (75 mg, 29%). LCMS: 587.35 (M+1)+; HPLC: 98.69% (@254 nm) (Rt; 4.604; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.50 (bs, 1H), 8.25 (m, 1H), 7.65 (m, 2H), 7.37-7.35 (m, 3H), 5.87 (s, 1H), 4.59 (m, 2H), 4.29 (d, 2H), 4.12 (s, 2H), 3.82 (m, 4H), 3.28 (m, 4H), 3.17-3.09 (m, 2H), 2.32-2.28 (m, 4H), 2.22 (s, 3H), 2.11 (s, 3H), 1.57 (m, 4H), 0.86 (t, 3H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:13]1[C:18]([C:19]#[N:20])=[C:17]([C:21]2[S:25][CH:24]=[N:23][CH:22]=2)[C:16]([C:26]#[N:27])=[C:15]([S:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[S:33][CH:34]=2)[N:14]=1>CN(C=O)C>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:32]2[S:33][CH:34]=[C:30]([CH2:29][S:28][C:15]3[C:16]([C:26]#[N:27])=[C:17]([C:21]4[S:25][CH:24]=[N:23][CH:22]=4)[C:18]([C:19]#[N:20])=[C:13]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:14]=3)[N:31]=2)=[CH:36][CH:37]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Reactant: OCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCCCO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Reaction time: 0.25 h

Procedure:
30 μl (0.419 mmol) of 1,3-propanediol are initially charged in 2 ml of DMF, 18 mg (0.154 mmol) of potassium tert-butoxide are added and the mixture is stirred for 15 minutes, after which 75 mg (0.14 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, dissolved in 2 ml of DMF, are added. The reaction mixture is stirred at room temperature for 30 minutes and then purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 11 mg (15% of theory) of the target compound.
Reaction SMILES: CN(C(ON1N=NC2C=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]2[CH:38]=[C:39]([C:54]([OH:56])=O)[CH:40]=[C:41]3[C:46]=2[O:45][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:43][C:42]3=[O:53])[CH:29]=[CH:30][CH:31]=1.CCN(C(C)C)C(C)C.Cl.N1CCC1>C(Cl)Cl>[N:15]1([C:54]([C:39]2[CH:40]=[C:41]3[C:46](=[C:37]([C@H:33]4[CH2:34][CH2:35][CH2:36][N:32]4[C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[CH:38]=2)[O:45][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:43][C:42]3=[O:53])=[O:56])[CH2:14][CH2:13][CH2:10]1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
HATU (368 mg, 0.97 mmol) was added to a stirred solution of 8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (212 mg, 0.48 mmol >98% enantiomeric purity, see Example 1.06 for details of preparation) and DIPEA (0.674 mL, 3.87 mmol) dissolved in DCM (1 mL) under nitrogen. The resulting solution was stirred at room temperature for 1 h. Azetidine hydrochloride (271 mg, 2.90 mmol) was added and the mixture was stirred at room temperature for 15 h. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness to afford 6-(azetidine-1-carbonyl)-8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4H-chromen-4-one (28 mg, 12%) as a pale yellow foam.
Reaction SMILES: [C:1]([C:5]1[CH:6]2[CH2:13][CH2:12][CH:9]([CH2:10][CH:11]=1)[N:8]([CH3:14])[CH2:7]2)(=[O:4])[CH2:2][CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C1C2CCC(CC=1)N(C(OC1C=CC=CC=1)=O)C2)(=O)CC>C1COCC1>[OH:4][CH:1]([C:5]1[CH:6]2[CH2:13][CH2:12][CH:9]([CH2:10][CH:11]=1)[N:8]([CH3:14])[CH2:7]2)[CH2:2][CH3:3]
Reactant: CCC(=O)C1=CCC2CCC1CN2C
Agent: CCC(=O)C1=CCC2CCC1CN2C(=O)Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCC(O)C1=CCC2CCC1CN2C
Temperature: 25 °C

Procedure:
2-Propionyl-(6-methyl-6-azabicylo[3.2.2]non-2-ene) [22] A flask was charged with LiAlH4 (410 mg, 10.8 mmol) and dry THF (20 mL), giving a slurry. A solution of 21 (645 mg, 2.15 mmol) in dry THF (30 mL) was added dropwise with stirring, and the reaction was then heated to reflux for 1 h. The reaction was cooled to room temperature, and quenched with dropwise addition of 50 mL EtOAc. The reaction was diluted with H2O (40 mL) and NaCl (sat, aq, 40 mL), and the layers separated. The aqueous layer was extracted with 2×40 mL EtOAc. The organic layers were combined and extracted with 3×50 mL 10% HCl. The aqueous layers were then combined and neutralized with NaHCO3(s) and basified to pH=12 with NaOH (aq). The aqueous layer was extracted with 3×50 mL CH2Cl2, and the organic layers combined, dried (MgSO4), and evaporated to give 2-(1-hydroxy-1-propyl)-(6-methyl-6-azabicyclo[3.2.2]non-2-ene) as a yellow oil (1:1 ratio of diastereomers). Crude yield: 419 mg, 2.17 mmol, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[N:3]=1.O.[NH2:30][NH2:31]>O1CCOCC1.O>[Cl:16][C:13]1[N:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=3)[N:3]=[C:2]([NH:30][NH2:31])[N:7]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(NCc3ccc(Cl)nc3)n2)cc1C(F)(F)F
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1nc(NCc2ccc(Cl)nc2)nc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 6-Chloro-N-(6-chloropyridin-3-ylmethyl)-N′-(4-fluoro-3-trifluoromethylphenyl)-[1,3,5]triazine-2,4-diamine (XVIII) (3.0 g, 6.9 mmol) in dioxane (30 mL) was added hydrazine hydrate (2 mL), and the mixture stirred at ambient temperature for 30 min. The mixture was diluted with water, the resulting slurry stirred for 10 min and filtered under vacuum to give a white solid. This solid was washed with water and dried under vacuum to give N-(6-chloro-pyridin-3-ylmethyl)-N′-(4-fluoro-3-trifluoromethylphenyl)-6-hydrazino-1,3,5-triazine-2,4-diamine (XIX) (2.89 g, 97% yield): 1H NMR (CDCl3); δ 9.40 (m, 1H), 8.5-7.5 (m, 4H), 7.45 (m, 2H), 7.33 (m, 2H), 4.49, m, 2H), 4.17 (bs, 2H); ESI/MS 429 (M+H), 427 (M−H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[O:10])=[CH:6][CH:5]=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C@@H:9]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[OH:10])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)[C@H]2CCCO2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc([C@H](O)C2CCCO2)o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
2.27 g (59.9 mmol; 1.20 eq) of sodium borohydride were added in small portions to a solution of 9.00 g (49.9 mmol; 1.0 eq) of (5-methylfuran-2-yl)-(R)-tetrahydrofuran-2-ylmethanone in 100 ml of tetrahydrofuran cooled to 0° C. The reaction medium was stirred at ambient temperature for 3 hours. The reaction medium was poured into 200 ml of ethyl acetate and then 100 ml of water were added. The aqueous phase was extracted with ethyl acetate and then the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. 8.10 g de (5-methylfuran-2-yl)-(R)-tetrahydrofuran-2-ylmethanol were obtained. Yield=92%.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=1)=[NH:4].CN1CCC[C:22]1=[O:26].N1C=CC=CC=1.ClC(OCC)=O>O>[O:26]=[C:22]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([O:15][C:16]([F:18])([F:17])[F:19])[CH:6]=2)[NH:4]1
Reactant: CC(=O)Nc1ccc(C(=N)NO)cc1OC(F)(F)F
Reactant: CN1CCCC1=O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The mixture consisting of 130 mg of N-[4-(N-hydroxycarbamimidoyl)-2-trifluoromethoxyphenyl]acetamide, 2 ml of N-methylpyrrolidone, 0.55 ml of pyridine and 0.049 ml of ethyl chloroformate was stirred at 80° C. for 5 hours. After cooling, the mixture was diluted with water and the product was extracted with 20 ml of ethyl acetate. The organic phase was dried over sodium sulfate and evaporated at 40° C. under reduced pressure.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([CH:11]=O)=[N:2]1.OS([O-])=O.[Na+].[CH3:18][C:19]1[C:20]([NH2:36])=[C:21]([NH2:35])[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[CH:24]=1>CCO>[CH3:18][C:19]1[C:20]2[NH:36][C:11]([C:3]3[CH2:4][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[O:1][N:2]=3)=[N:35][C:21]=2[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:32])([F:33])[F:34])[CH:24]=1
Reactant: Cc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N
Reactant: O=CC1=NOC2(CCCCC2)C1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(-c2ccccc2C(F)(F)F)cc2nc(C3=NOC4(CCCCC4)C3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (135 mg, 0.807 mmol, as prepared in Example 19, step B) was placed in a 4 mL vial equipped with a magnetic stir bar. 40% Aqueous NaHSO3 (0.8 mL) was added via syringe, and the mixture stirred at rt for 2 h. 5-Methyl-2′-trifluoromethyl-biphenyl-3,4-diamine (246 mg, 0.923 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a magnetic stir bar. EtOH (2 mL) was added. The 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde solution was added to the 5-methyl-2′-trifluoromethyl-biphenyl-3,4-diamine solution. The flask which had contained the 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde solution was rinsed with EtOH (0.5 mL) and water (0.25 mL), and this was also added to the 5-methyl-2′-trifluoromethyl-biphenyl-3,4-diamine solution. The mixture was heated to 90° C. for 2 h. The mixture was poured into water, and the precipitate was isolated by filtration. The solid was washed with water, dissolved in EtOAc, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/heptane, 0:1 to 3:7, v/v over 30 min, yielding 136 mg (41%) of the title compound. 1H-NMR (400 MHz, d4-MeOH) δ: 7.76 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.26-7.49 (m, 2H), 7.03 (br. s., 1H), 2.63 (br. s., 3H), 1.69-1.88 (m, 6H), 1.45-1.63 (m, 4H).