Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.[I-:11].[Na+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:11])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Fc1ccc(CCBr)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: Fc1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture containing 2-(4-fluorophenyl)ethyl bromide (see Preparation 76) (10 g), sodium iodide (10 g) and acetone (200 ml) was stirred at room temperature for 20 hours then filtered. The filtrate was concentrated in vacuo to give the title compound as a colourless oil, 12 g.
Reaction SMILES: C([O-])(C)(C)C.[K+].[CH3:7][O:8][C:9](=[O:20])[C:10](=[N:18][OH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].Cl[CH:22]([F:24])[F:23]>COCCOC>[F:23][CH:22]([F:24])[O:19][N:18]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:9]([O:8][CH3:7])=[O:20]
Reactant: FC(F)Cl
Reactant: COC(=O)C(=NO)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)C(=NOC(F)F)c1ccccc1C
Reaction time: 5 h

Procedure:
At 10-20° C., 28.4 g of potassium tert-butanolate are introduced into a solution of 19.35 g of 2-tolylglyoxylic acid methyl ester oxime in 250 ml of 1,2-dimethoxyethane. As soon as a fine suspension has formed, chlorodifluoromethane is introduced at 25-30° C. After 5 hours, the reaction mixture is concentrated by evaporation in vacuo, water is added to the residue and the product is weakly acidified with 2N hydrochloric acid and extracted several times with ethyl acetate. After washing and concentrating the combined organic phases by evaporation, purification is carried out by flash chromatography (silica gel, ethyl acetate/hexane 1:5), yielding 2-tolylglyoxylic acid methyl ester O-difluoromethyloxime in the form of a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:29]([C:36]1[O:37][C:38]([CH3:42])=[C:39]([CH3:41])[CH:40]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C=O>[CH2:29]([C:36]1[O:37][C:38]([CH3:42])=[C:39]([CH3:41])[C:40]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
At ambient temperature, to a stirred suspension containing 3,5-diisopropyl-p-anisic acid (1.95 g, 8.23 mmol, RN-117439-59-5) and oxalyl chloride (0.8 mL, 9.20 mmol) in CH2Cl2 (22.5 mL) was added N,N-dimethylformamide (2 drops). After 2 h, the reaction was cooled to −78° C. To the reaction was added tin (IV) chloride (1.05 mL) followed by a solution of 2-benzyl-4,5-dimethylfuran (1.8 g, 9.68 mmol) in CH2Cl2 (10.0 mL). After the additions were complete, the reaction was allowed to warm to ambient temperature and stirred for 24 h. The reaction was quenched into crushed ice (100 g), diluted with sat. aq. KH2PO4 (100 mL) and extracted with ether. The combined ethereal extracts were washed with sat aq. NaHCO3 (2×60 mL), with brine (1×60 mL), dried (Na2SO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 1% EtOAc/pet. ether to give 2.07 g, (62%) of the title compound as an oil; 1H NMR (DMSO-d6) δ 1.17 (d, 12H), 1.81 (s, 3H), 2.19 (s, 3H), 3.29 (septet, 2H), 3.74 (s, 3H), 3.84 (s, 2H), 7.01-7.03 (m, 2H), 7.16-7.25 (m, 3H), 7.47 (s, 2H). mass spectrum (EI), m/z 404 (M+). Anal. Calcd. for C27H32O3.0.6H2O: C, 78.07; H, 8.06; N, 0.00. Found: C, 78.04; H, 7.93; N, −0.02.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)#[N:4].Cl[C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[C:3]([C:5]1[CH:20]=[C:19]([CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1)#[N:4]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2C#N)cc1F
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from sodium hydride, 4-(2-cyano-4-(hydroxymethyl)phenoxy)-2-fluorobenzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)([Cl:30])=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:30])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 91.4 %

Procedure:
Part B: To a mixture of 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one 4.83 g, 20.0 mmol) in toluene (80 mL) at 25° C. was added N,N-diisopropylethylamine (3.48 mL, 20.0 mmol), followed by phosphorous oxychloride (2.24 mL, 24.0 mmol). The reaction mixture was heated at reflux for 2.00 h. After cooling to room temperature, the mixture was diluted with water and ethyl acetate. The aqueous phase was adjusted to ˜pH 7 employing saturated aqueous sodium bicarbonate solution. The phases were separated. The organic phase was washed with water and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. The residue was dissolved in 1-chlorobutane, and the resulting mixture was filtered. The filtrate was concentrated under vacuum to provide 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (4.75 g, 91%) as an orange-red oil; Mass Spec.: m/e: 260.10/262.05 (M+H)+ [calc'd: 260.09/262.08].
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].C([O-])(=O)C=CC1C=CC=CC=1.[Na+]>S(=O)(=O)(O)O>[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C=Cc1ccccc1
Agent: O=C([O-])C=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A 3 l flask equipped with a stirrer was charged with 100.0 grams (0.617 mol) of methyl cinnamate and 1260 grams of aqueous solution containing 25.9 grams (0.647 mol) of sodium hydroxide and vigorously stirred for 15 minutes at 80° C. The obtained aqueous alkaline solution of sodium cinnamate having concentration of 7.7% by weight was added in a lump with 1240 ml of aqueous sulfuric acid solution containing 0.35 ml of sulfuric acid. The resultant slurry having concentration of 3.4% by weight was cooled to room temperature and measured pH to give a value of about 2. The total reaction mixture was discharged and filtered with suction. The separated precipitates were 87.8 grams (96.0% yield) and had purity of above 99.9%. The quantity of cinnamic acid produced per l of water used and per unit volume of the reaction vessel were 36 g/l and 35 g/l respectively.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH:9]2[CH:11]([C:15]([CH2:21][S:22]C(OCC)=S)(O)[C:16]([F:19])([F:18])[F:17])[C:12](=O)[CH2:13][CH:8]2[CH2:7]1)=[O:5])[CH3:2].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH:9]2[C:11]3[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:21][S:22][C:12]=3[CH2:13][CH:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2CC(=O)C(C(O)(CSC(=S)OCC)C(F)(F)F)C2C1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1CC2Cc3scc(C(F)(F)F)c3C2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
Deoxygenated (N2 sparge for 15 min) N-methylpiperazine (1.3 ml) was placed in a 5 dram vial and cooled to 0° C. Next, a solution of 4-(1-Ethoxythiocarbonylsulfanylmethyl-2,2,2-trifluoro-1-hydroxy-ethyl)-5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester (44 mg, 0.10 mmol) in CH2Cl2 (400 μl) was added dropwise over 15 minutes. After 3 hours, at 0° C., 12M HCl (10 ml) was added dropwise until pH 1-2 had been reached. The reaction was warmed to 22° C. and stirred for 1 hour. The reaction mixture was extracted with CH2Cl2 (3×20 ml) and H2O (30 ml). The organic layer was dried (MgSO4) and the crude oil was purified by flash chromatography (hexanes:EtOAc-7:3) providing the subtitle product as a clear oil (13.5 mg, 43%). 1H NMR (300 MHz, CDCl3, ppm) 1.24 (t, J=7 Hz, 3H); 2.78 (br d, J=16 Hz, 1H); 3.14 (dd, J1=16 Hz, J2=8 Hz, 1H); 3.20-3.38 (br m, 1H); 3.48-3.62 (br m, 2H); 3.63-3.88 (m, 3H); 4.11 (q, J=7 Hz, 2H); 7.59 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[O:14][CH2:13][CH:12]([OH:15])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].CO.O>C(Cl)Cl>[C:16]([O:15][CH:12]1[CH:11]=[CH:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:14][CH2:13]1)(=[O:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(O)CO1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OC1C=CC(O[Si](C)(C)C(C)(C)C)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-ol (13.3 g, 57.7 mmol) and TEA (16.09 mL, 115 mmol) in DCM (200 mL) was added acetic anhydride (27.2 mL, 289 mmol), and the mixture was stirred at room temperature overnight. Methanol (˜3 mL) was added and the mixture was stirred for 30 min at room temperature before adding water and transferring to a separatory funnel. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and condensed. The crude material was purified on a 340G SNAP Biotage column (0-50% ethyl acetate in hexane) to give 6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-yl acetate (13.6 g, 49.9 mmol, 86% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ ppm 5.84-5.88 (m, 2H), 5.26-5.28 (m, 1H), 5.20-5.25 (m, 1H), 3.84 (dd, J=6.25, 1.95 Hz, 2H), 2.08 (s, 3H), 0.91 (s, 9H), 0.13 (d, J=1.17 Hz, 6H).
Reaction SMILES: C([O:8][C@H:9]([C@@H:11]1[N:16]2[C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([NH2:27])[C:18]=3[N:28]=[C:15]2[CH2:14][O:13][CH2:12]1)[CH3:10])C1C=CC=CC=1.Cl>CO.[Pd].C(O)C>[NH2:27][C:19]1[C:18]2[N:28]=[C:15]3[CH2:14][O:13][CH2:12][C@H:11]([C@@H:9]([OH:8])[CH3:10])[N:16]3[C:17]=2[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: C[C@H](OCc1ccccc1)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: C[C@H](O)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 24 h
Yield: 32.1 %

Procedure:
(11R)-11-[(1S)-1-(Benzyloxy)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (512 mg, 1.37 mmol) was dissolved in 30 mL of methanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 200 mg) and 2.5 mL of 3 M HCl in ethanol were then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 24 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in H2O and the solution was made basic by the addition of concentrated aqueous NH4OH solution. The aqueous solution was extracted with 10% MeOH/CHCl3 several times and the combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 25-75% CMA/CHCl3) gave an off-white powder. Crystallization from ethyl acetate and methanol gave 125 mg of the desired compound as a white, fluffy solid, mp 207.6-208.7° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:13]1[C:21](=[O:22])[NH:20][C:19]2[C:14]1=[N:15][C:16]([CH:23]1[CH2:25][CH2:24]1)=[N:17][CH:18]=2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:34][N:35]1[C:43]2[C:38](=[C:39]([CH3:44])[CH:40]=[CH:41][CH:42]=2)[C:37]([CH2:45][N+](C)(C)C)=[CH:36]1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:13]1[C:21](=[O:22])[N:20]([CH2:45][C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])[N:35]([CH3:34])[CH:36]=2)[C:19]2[C:14]1=[N:15][C:16]([CH:23]1[CH2:24][CH2:25]1)=[N:17][CH:18]=2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(C3CC3)nc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cnc(C3CC3)nc21
Temperature: 100 °C
Yield: 50.9 %

Procedure:
To a solution of (R)-3-(2-cyclopropyl-8-oxo-7,8-dihydro-purin-9-yl)-3-phenyl-propionic acid ethyl ester (313 mg, 0.89 mmol) in DMF (5 ml) were added K2CO3 (234 mg, 1.7 mmol) and (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (275 mg, 1.27 mmol). The reaction mixture was heated to 100° C. for 4 hours. The reaction mixture was therefore diluted with ethyl acetate and washed with water (×4). The organic phase was dried over MgSO4 and concentrated. The resulting residue was purified by chromatography, eluded with 3% methanol to 10% in CH2Cl2 to afford the titled compound (231 mg, 50%). LCMS, M++1, m/z: 509.59.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12](O)=[O:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1.S(Cl)(Cl)=O.[NH3:29]>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH2:29])=[O:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1
Reactant: N
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1

Procedure:
To a suspension, stirred at 20° C., of 1.5 g (4.43 mmol) of 5-trifluoromethyl-1-[(3-fluoro-phenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (WO 2008/093024) in 40 mL of dry toluene are added 3.2 mL (44.34 mmol) of thionyl chloride. The reaction mixture is stirred at reflux for 2 hours and then concentrated under reduced pressure. The resulting product is taken up in 20 mL of dichloromethane and this solution is poured dropwise into a solution of 5.81 mL (44.34 mmol) of 30% aqueous ammonia. The reaction mixture is stirred for 14 hours at 20° C. After this time, a solid is collected by filtration, and is triturated in 50 mL of diisopropyl ether. After filtering off and drying under reduced pressure, 1.5 g of the expected product are collected.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>[OH-].[Na+]>[CH2:7]([O:14][C:15]([N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1ccccc1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
3-Hydroxy-pyrrolidine (10 g, 115 mmol, 1.0 equiv) was dissolved in 2 N NaOH (100 mL) and the mixture was cooled to 0° C. Benzylchloroformate (21 g, 126 mmol, 1.1 equiv) was added dropwise over a 45 min period. After addition, the reaction was stirred at room temperature for 4 h at which time the pH was adjusted to 7-8 using concentrated HCl. The product was extracted with 3×100 mL of CH2Cl2. The organic extracts were combined and dried over Na2SO4, decanted and concentrated in vacuo to yield the desired product as a light yellow oil (24.1 g, 95%) that was used without further purification.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]([CH3:24])[NH:19][C:20](=[O:23])[NH:21][N:22]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>CN(C)C=O>[CH:1]1([C:4]([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:18]([CH3:24])[NH:19][C:20](=[O:23])[NH:21][N:22]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2C(=O)C1CC1
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
Cyclopropanecarbonyl chloride (0.47 g) was added dropwise to a stirred solution of 6-(1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.73 g) and triethylamine (0.6 g) in N,N-dimethylformamide (7.3 ml) under ice cooling and the stirring was continued for 30 minutes. The solution was evaporated in vacuo and the residue was dissolved in chloroform. The solution was washed with diluted hydrochloric acid, dried, and evaporated. The residue was chromatographed on silica gel (5 g) using chloroform and then a mixture of chloroform and methanol (20:1) as an eluents. The eluates were evaporated in vacuo and the oily residue was crystallized from ethanol to give 6-(1-cyclopropanecarbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.26 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]([C:20]3[CH:21]=[CH:22]C4[C:24]([CH:28]=3)=[N:25]SN=4)[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][NH:12]2)=[CH:8][CH:7]=1.CS[C:31]1[NH:32][CH2:33][C:34](=[O:36])[N:35]=1>>[O:36]=[C:34]1[CH2:33][NH:32][C:31]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[C:13]3[C:9]([C:10]([CH:15]([C:20]4[CH:21]=[CH:22][N:25]=[CH:24][CH:28]=4)[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][NH:12]3)=[CH:8][CH:7]=2)=[N:35]1
Reactant: CSC1=NC(=O)CN1
Reactant: NCCCOc1ccc2c(C(CC(=O)O)c3ccc4nsnc4c3)c[nH]c2c1
Product: O=C(O)CC(c1ccncc1)c1c[nH]c2cc(OCCCNC3=NC(=O)CN3)ccc12

Procedure:
Analogously to Example 16, the reaction of 3-[6-(3-aminopropoxy)-1H-indol-3-yl]-3-benzo-1,2,5-thiadiazol-5-ylpropionic acid (prepared analogously to Example 1.1-1.2 and 15) with 2-methylsulfanyl-1,5-dihydroimidazol-4-one and subsequent synthesis sequence gives
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:3]=1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[NH2:29].O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[NH:29][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccc2C(F)(F)F)n1
Reactant: Nc1n[nH]c2ccc(F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2n[nH]c3ccc(F)cc23)nc(-c2ccccc2C(F)(F)F)n1
Temperature: 165 °C
Yield: 56.5 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (0.10 g, 0.37 mmol) and 5-fluoro-1H-indazole-3-ylamine (0.072 g, 0.48 mmol) was heated neat at 160-170° C. for 8 hours. The resulting residue was cooled to ambient temperature then dissolved in N-methyl-pyrrolidinone (2 mL). This mixture was poured into water (20 mL) and sodium bicarbonate (5 mL) was added and the resulting mixture filtered, washing with water. Purification by preparative HPLC provided the title compound (0.081 g, 43% yield) as a tan solid. 1H-NMR (500 MHz, DMSO-d6) δ 12.8 (br s, 1H), 10.6 (br s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.77 (m, 4H), 7.62 (br s, 1H), 7.50 (m, 1H), 7.29 (m, 1H), 2.44 (s, 3H) ppm; LC-MS 388.05 (M+H); Rt (Method A) 2.900 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:7][C:6](=[O:8])[CH:5]([C:9](=O)[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:4](=[O:31])[O:3]1.C(O)(=O)C.[BH4-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[O:3][C:4](=[O:31])[CH:5]([CH2:9][C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[C:6](=[O:8])[O:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)CC1C(=O)OC(C)(C)OC1=O
Reaction time: 0.08 h

Procedure:
(S)-tert-Butyl 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)propan-2-ylcarbamate in 100 mL DCM was cooled to −5° C. Acetic acid (4.45 g, 74.1 mmol) was added in one portion. The resulting mixture was stirred for 5 minutes and sodium borohydride (0.637 g, 16.8 mmol) was added portion-wise over 40 minutes. After stirring for another 40 minutes, the reaction mixture was washed with brine (3×150 mL) and water (2×100 mL). The organic layer was dried over MgSO4. After removing the solvent, the desired product compound (2.5 g, 83%) was obtained as a white solid. LCMS (API-ES) m/z (%): 447.0 (100%, M+H+).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH:25]2[CH2:28][CH2:27][CH2:26]2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=C1CCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C2CCC2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively aminated with cylobutanone in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-cyclobutyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 408.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]>>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([O:12][CH2:10][CH3:11])=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21])=[O:9]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: Cc1occc1C(=O)O
Product: CCOc1ccc(NC(=O)c2ccoc2C)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-methyl-3-furoic acid and 4-ethoxy-2-nitroaniline as an orange yellow solid as described in Example 15. 1H NMR (CDCl3): 10.66 (s, 1H), 8.82 (d, J=9.3, 1H), 7.70 (d, J=3.0, 1H), 7.34 (d, J=1.8, 1H), 7.28-7.24 (m, 1H), 6.68 (d, J=1.8, 1H), 4.09 (q, J=6.9, 2H), 2.67 (s, 3H), 1.45 (t, J=6.9, 3H).
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:3]2[CH:7]=[N:6][N:5]=[N:4]2)=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1nnn[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Brc1ccc(Cn2cnnn2)cc1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
Dimethyl sulphoxide (10 mL, dried over 4 A molecular sieve) was added to potassium hydroxide (1.12 g, 0.02 mol, crushed pellets) and the mixture was stirred for 5 minutes. 1H-Tetrazole (0.35 g, 0.005 mol) was then added and the mixture was stirred for 2 hours. 4-Bromobenzyl bromide (1.87 g, 0.0075 mol) was added and the mixture was cooled briefly and stirred for a further hour before adding water (50 mL). The mixture was extracted with ether (3×80 mL) and each extract was washed with water (3×50 mL). The combined ether layers were dried over MgSO4 and the solvent using removed in vacuo. The residue was chromatographed on silica gel with CHCl3:MeOH (40:1) as eluent yielding the sub-title compound (0.98 g, yield: 82%).