Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[CH:4][N:3]=1.Cl.C([O:26][C:27]([C@H:29]1[CH2:32][C@@H:31]([NH2:33])[CH2:30]1)=[O:28])C.OP([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>O.CS(C)=O>[ClH:1].[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:33][CH:31]4[CH2:32][CH:29]([C:27]([OH:28])=[O:26])[CH2:30]4)=[N:3][CH:4]=3)[N:12]=2)=[CH:14][CH:15]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(Cl)nc3)no2)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(NC4CC(C(=O)O)C4)nc3)no2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A solution of 2-chloro-5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridine (50 mg, 0.16 mmol), cis-3-amino-cylcobutanecarboxylic acid ethyl ester, hydrochloride (57.1 mg, 0.319 mmol), potassium phosphate dibasic (58.3 mg, 0.335 mmol) and DMSO (5 mL) was stirred in a sealed tube in the microwave at 200° C. for 10 minutes. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in EtOH (3 mL). NaOH (19 mg, 0.478 mmol) and water (2 mL) were added to the reaction mixture and stirred in a sealed tube in the microwave at 180° C. for 10 minutes. The reaction mixture was cooled to room temperature, acidified with 1N HCl (5 mL), filtered and dried to provide the title compound (59 mg, 86% yield) as a solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:45])[C@@H:33]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH:34][C:35](=[O:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:45])[C@@H:33]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[NH:34][C:35](=[O:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
185 mg (0.411 mmol) of the mixture of (2R*,4S*)-2-benzyl-1-((R)-N-acetyl-phenylalanyl)N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine diastereomers are reacted with 62 mg (1.64 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR58## is obtained as mixture of diastereomers (white foam). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.42, FD-MS: M+ =520.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])/[CH:14]=[CH:4]/[C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1c(F)cccc1Cl)/C=C/c1c(F)cccc1Cl
Temperature: 25 °C
Yield: 51.8 %

Procedure:
(72) To a solution of the 2-chloro-6-fluoro-benzaldehyde (1.59 g, 10.0 mmol) and acetone (290 mg, 5.00 mmol) in 15 ml of ethanol was added 5 ml of 40% potassium hydroxide at 10° C. After stirring for several hours at room temperature, the solution was filtered. The precipitate was recrystallized from ethanol to afford 879 mg (51.7%) of a light-yellow powder: mp 143.5-144.3° C. 1H NMR (250 MHz) δ 7.98-7.91 (d, 2 H), 7.36-7.22 (m, 6 H), 7.13-7.03 (m, 2 H); 13C NMR (62.7 MHz) 189.6, 134.0, 132.1, 131.8, 131.2, 131.0, 126.3, 115.4, 115.0 ppm. Elemental Analysis. Calculated for C17H10Cl2F2O5: C, 60.20; H, 2.98. Found: C, 60.07; H, 2.99
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[Cl:9][C:10]1[CH:15]=[C:14]([N+]([O-])=O)[CH:13]=[CH:12][N+:11]=1[O-].C(=O)(O)[O-].[K+]>CC(O)C>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:9])[CH:15]=2)[N:8]=[CH:7]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: NCCc1c[nH]cn1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)O
Product: Clc1cc(NCCc2c[nH]cn2)ccn1

Procedure:
38 mg (0.34 mmol) of histamine and 55 mg (0.31 mmol) of 2-chloro-4-nitropyridine N-oxide in 15 ml of 2-propanol are stirred with potassium bicarbonate at 21° C. for 3 days. The mixture is then filtered and evaporated. The resulting solid residue is chromatographed on a column of silica gel, using a chloroform/methanol (10/1) mixture. The pure fractions are evaporated under reduced pressure to give the title compound which, after crystallization from a 2-propanol/ether (1/1) mixture, melts at 164°-165° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C@:17]4([CH3:22])[C@H:20]([CH3:21])[C@H:13]3[CH2:14][C:15]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:16]=34)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1>N.CO.[Ni]>[NH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:15]2[CH2:14][C@@H:13]3[C@@H:20]([CH3:21])[C@:17]([CH3:22])([C:16]=2[CH:23]=1)[CH2:18][CH2:19][N:12]3[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH:9]=1)=[O:11]
Reactant: C[C@@H]1[C@H]2Cc3ccc(C#N)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: C[C@@H]1[C@H]2Cc3ccc(CN)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1

Procedure:
A solution of (2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carbonitrile (50 mg) in 1 M ammonia in methanol (5 mL) is treated with Raney Ni (50 mg) under hydrogen atmosphere at 50° C. for 3 h. Then, the catalyst is separated by filtration and the filtrate is concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:16]([O:26][CH3:27])=[C:15]([NH2:28])[N:14]=2)=[N:6]1.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>CN(C=O)C>[NH2:28][C:15]1[N:14]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=3[F:1])[N:6]=2)[N:18]=[C:17]([N:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:43](=[O:44])[CH2:42][O:41][CH3:40])[C:16]=1[O:26][CH3:27]
Reactant: COCC(=O)Cl
Reactant: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC(=O)N(c1ccncc1)c1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc(N)c1OC
Temperature: 0 °C

Procedure:
50 mg of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4,6-diamine 2-1-4 (0.116 mmol, 1.0 eq.) and 12 mg of triethyl amine (0.116 mmol, 1.0 eq.) were dissolved in 600 μL DMF and were cooled to 0° C. After addition of 13 mg of methoxyacetyl chloride (0.116 mmol, 1.0 eq.), the reaction mixture was stirred for five h at rt. After dilution with water, the crude product was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography yielding 37 mg (0.07 mmol, 60%) of analytically pure target compound.
Reaction SMILES: [CH3:1][CH:2](C)[O-].[Li+].[I-].[Li+].[C:8]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=1)#[N:9].C([Zn]CC)C>C1COCC1.CCCCCC.CC(C)[O-].C[Ti+3].CC(C)[O-].CC(C)[O-].O>[NH2:9][C:8]1([C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[CH:12][CH:11]=2)[CH2:2][CH2:1]1
Reactant: CC(C)[O-]
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Agent: C[Ti+3]
Agent: CC[Zn]CC
Agent: [I-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C2(N)CC2)cc1
Reaction time: 0.25 h

Procedure:
50 mL of a 2M lithium isopropoxide solution in THF was placed under an argon atmosphere and 13.4 g of anhydrous lithium iodide was added thereto. After 15 minutes, 45 mL of a 1M methyltitanium isopropoxide solution in THF was added. Then the mixture was combined with 8.1 g of tert-butyl 4-cyanobenzoate and stirred for 10 minutes. Then within 60 minutes, 47.3 mL of a 15% diethylzinc solution in hexane was added thereto and the mixture was stirred for 12 hours at RT. After hydrolysis with 20 mL of water, it was stirred for a further 30 minutes, filtered off, and washed 3× with 100 mL of ether. After extraction of the organic phase with water, the mixture was evaporated down with silica gel and the substance was chromatographed with dichloromethane/methanol (98:2) at 20 mL/min on silica gel 70. Residue: 3 g oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[C:21]([CH:30]2[CH2:32][O:31]2)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26]>>[F:19][C:20]1[C:21]([CH:30]([OH:31])[CH2:32][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:18]=[CH:17][C:12]4[C:13](=[O:16])[O:14][CH2:15][C:11]=4[CH:10]=3)[CH2:2][CH2:3]2)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26]
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: COc1cc(C2CO2)c(F)cc1C#N
Product: COc1cc(C(O)CN2CCN(CCc3ccc4c(c3)COC4=O)CC2)c(F)cc1C#N

Procedure:
5-fluoro-4-(1-hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one and 5-fluoro-2-(methyloxy)-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].Cl[CH2:27][N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[N:29]1.O>CN(C)C=O>[N:28]1([CH2:27][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:8]3[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([O:5][CH2:3][CH3:4])=[N:7]3)=[CH:24][CH:23]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[N:29]1
Reactant: ClCn1nnc2ccccc21
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCn3nnc4ccccc43)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 1-chloromethyl-1H-benzotriazole (251 mg) in N,N-dimethylformamide (10 ml) at, 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[4-(1H-benzotriazol-1-ylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (652 mg, yield: 97%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH:37]1[CH2:41][CH2:40][CH2:39][NH:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:38]5[CH2:39][CH2:40][CH2:41][CH:37]5[C:33]5[S:32][CH:36]=[CH:35][CH:34]=5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: c1csc(C2CCCN2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCCC5c5cccs5)c4)cc23)CC1
Yield: 31 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(2-thienyl)pyrrolidine (132.4 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (20.0 mg, 30.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([OH:12])[CH2:9][CH2:8][CH2:7]2
Reactant: O=C1CCCc2cccc(Cl)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCCc2cccc(Cl)c21
Reaction time: 1.5 h

Procedure:
A solution of 8-chloro-3,4-dihydronaphthalen-1(2H)-one (1.26 mmol) in MeOH (4 mL) at 0° C. was quickly charged with a solution of sodium borohydride (3.23 mmol, 2.5 eq) in MeOH (2 mL). The reaction was stirred for 1.5 h from 0° C. to ambient temperature. The reaction was quenched with water and extracted with ether. All organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was dissolved in minimal CH2Cl2 and was purified by two rounds of pTLC [Silicycle, 20×20 plate, 1000 μm, one development in neat CH2Cl2], giving the title material as an off-white solid. 1H NMR (400 MHz, CDCl3) δ=1.72-1.85 (m, 2H), 1.92-2.05 (m, 1H), 2.16-2.24 (m, 1H), 2.38 (dd, J=3.8, 1.3 Hz, 1H), 2.71 (ddd, J=17.7, 12.1, 5.8 Hz, 1H), 2.82-2.92 (m, 1H), 5.09 (q, J=3.5 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.15 (dd, J=7.7, 7.7 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H). MS (ES+): m/z 164.98/166.98 (100/53) [MH+−H2O]. HPLC: tR=3.14 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][CH:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].Br[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:1][CH:2]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:3])[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: CC(N)Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(Cc1ccccc1)NCCCCN1C(=O)c2ccccc2C1=O
Yield: 32 %

Procedure:
A mixture of 2.00 g of amphetamine (AP), 4.17 g of N-bromobutylphthalimide (manufactured by Aldrich Chemical Company Inc.) and 3.14 g of sodium hydrogen-carbonate was refluxed in 10 ml of benzene for 16 hours. After the solvent was removed from the reaction solution, the residue was purified by preparative thin layer chromatography (TLC, manufactured by Merck and Co. Inc.) using silica gel as carrier. As an elution solvent, a mixture of methanol and chloroform in a volume ratio of 5:95 which had been previously saturated with ammonia was used. Rf value of the product was 0.7. Extraction of the product on silica gel with methanol gave 1.59 g of N-(4-phthalimidylbutyl)amphetamine (PIBAP).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:28])([F:27])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1.FC1C=C(C2C=C(F)C3N(C(C(F)(F)C4C=C5C(=CC=4)N=CC(OC)=C5)=NN=3)C=2)C=C(F)C=1>>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:28])([F:27])[C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]5)=[N:9][N:10]=3)[N:7]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COCCOc1cnc2ccc(C(F)(F)c3nnc4ccc(Cl)nn34)cc2c1
Agent: COc1cnc2ccc(C(F)(F)c3nnc4c(F)cc(-c5cc(F)cc(F)c5)cn34)cc2c1
Product: COCCOc1cnc2ccc(C(F)(F)c3nnc4ccc(-c5cc(F)cc(F)c5)nn34)cc2c1

Procedure:
The title compound was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline and 3,5-difluorophenylboronic acid in a similar manner as that described for 6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline. LRMS (ESI) m/z calcd for C24H18F4N5O2 (M+H) 484. 1, found 484.2.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[OH:27].[CH3:28][C:29]1([N:33]2[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]2)[CH2:32][O:31][CH2:30]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[O:27][CH:36]1[CH2:35][CH2:34][N:33]([C:29]2([CH3:28])[CH2:30][O:31][CH2:32]2)[CH2:38][CH2:37]1
Reactant: N#Cc1cc(O)c(Cl)c([N+](=O)[O-])c1
Reactant: CC1(N2CCC(O)CC2)COC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(N2CCC(Oc3cc(C#N)cc([N+](=O)[O-])c3Cl)CC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
DIAD (0.132 mL, 0.638 mmol) was added to a solution of 4-chloro-3-hydroxy-5-nitrobenzonitrile (95 mg, 0.478 mmol), 1-(3-methyloxetan-3-yl)piperidin-4-ol (78 mg, 0.456 mmol) and triphenylphosphine resin (3 mmol/g loading, 560 mg, 2.136 mrnmol) in THF (2 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 1-6% 2 N ammonia in methanol/dichloromethane). 4-chloro-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)-5-nitrobenzonitrile (106 mg) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[C:25]([CH3:42])=[CH:24][N:23]=1>CN(C=O)C>[CH3:38][N:34]1[C:33]2[C:39]([CH3:41])=[CH:40][C:30]([C:28]([C:26]3[C:25]([CH3:42])=[CH:24][N:23]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:27]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cnc(Cl)cc1C(=O)c1cc(C)c2c(c1)oc(=O)n2C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c(C)cn3)CC1)C(=O)N2
Temperature: 300 °C

Procedure:
0.33 g (1.2 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.13 g (0.40 mmol) 6-(2-chloro-5-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one (mixture) were combined and heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[NH:12][CH:11]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[NH:10][C:9]2=[O:20])=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:20])[NH:10][CH:11]([N:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:21](=[O:23])[CH3:22])[NH:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N2C(=O)NC(NCC(C)C)NC2=O)cc1
Product: CC(=O)N(CC(C)C)C1NC(=O)N(c2ccc(C)cc2)C(=O)N1
Reaction time: 20 h
Yield: 83 %

Procedure:
A mixture of 3-(4-methylphenyl)-6-isobutylaminotetrahydro-1,3,5-triazine-2,4-dione (20 g.) and acetic anhydride (150 ml.) was heated under reflux with slow distillation for 6 hours, cooled and evaporated. The residual oil solidified in 20 hours and was recrystallised from ethanol (100 ml.) to give 3-(4-methylphenyl)-6-[(N-acetyl) isobutylamino]tetrahydro-1,3,5-triazine-2,4dione (19.4 g., 83%) m.p. 159°-160° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:24]3[C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=[O:26])[C:15]=3[C:14]([NH2:27])=[C:13](Cl)[CH:12]=2)=[CH:6][CH:5]=1.[SH:29][CH2:30][CH2:31][OH:32].[OH-].[Na+]>CN(C)C=O>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:24]3[C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=[O:26])[C:15]=3[C:14]([NH2:27])=[C:13]([S:29][CH2:30][CH2:31][OH:32])[CH:12]=2)=[CH:6][CH:5]=1
Reactant: Nc1c(Cl)cc(Nc2ccc(CCO)cc2)c2c1C(=O)c1ccccc1C2=O
Reactant: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1c(SCCO)cc(Nc2ccc(CCO)cc2)c2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 50.4 g of 1-[4-(2-hydroxyethyl)phenylamino]-3-chloro-4-aminoanthraquinone Ic from Example 3 and 100 ml of dimethylformamide (DMF) is heated to 80° C. in a laboratory reaction apparatus. A further 50 ml of DMF and 11 g of 2-mercaptoethanol are then added. At an internal temperature of 83° C., 18.6 g of 30% aqueous sodium hydroxide solution are then slowly added dropwise and the mixture is stirred for 3 hours at 80° C. After cooling to RT, the precipitate is filtered off, washed with ethanol and dried in a vacuum drying chamber.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].Cl.CCOCC>C1COCC1>[ClH:1].[Cl:24][C:25]1[CH:26]=[C:27]([C:28]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:29])[CH:31]=[CH:32][CH:33]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1cccc(Cl)c1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.9 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). 3-Chlorobenzoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 mL) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 21 (56 mg, 61% yield) as a pale yellow solid. LC-MS (M+H=347, obsd.=347).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C(=O)=O.CC(O)C.[Li]CCCC.CN(/[CH:19]=[N:20]/[C:21]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:22]=1[C:23]([O:25]C)=O)C>C1COCC1.C(O)(=O)C>[OH:25][C:23]1[C:22]2[C:21](=[CH:30][CH:29]=[C:28]([O:31][CH3:32])[CH:27]=2)[N:20]=[CH:19][C:2]=1[C:1]#[N:3]
Reactant: COC(=O)c1cc(OC)ccc1/N=C/N(C)C
Reactant: CC#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2ncc(C#N)c(O)c2c1
Temperature: -72 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a cold solution of acetonitrile (2 mL, 38 mmol, 2.8 eq) in THF (30 mL) at −72° C. (Dry-ice/IPA) was added dropwise nBuLi (12 mL, 30 mmol, 2.2 eq) under argon atmosphere. The reaction mixture became an orange suspension after 1 h. A solution of methyl 2-{[(1E)-(dimethylamino)methylidene]amino}-5-(methyloxy)benzoate (3.2 g, 13.6 mmol, 1 eq) in THF (30 mL) was then added dropwise while the internal temperature was maintained at −72° C. The resulting mixture was slowly warmed to RT overnight. To the resulting light-brown suspension was added glacial acetic acid (6 mL) with slight cooling. After stirring for 1 h, the suspension was then quenched with water (60 mL) and filtered to give the titled compound (2.3 g, 85% yield).