Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)cc2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncnc(-c2ccc(C(=O)O)cc2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.25 g (6.28 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-benzoic acid methyl ester using 1.32 g (31.4 mmol.) LiOH in 5 mL water and 50 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and taken up in water. After freeze drying 2.3 g of crude product are obtained which is used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][OH:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][O:13][C:29](=[O:30])[NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
2 g of 7-chloro-2-hydroxyamino-5-phenyl-3H-1,4-benzodiazepine are reacted with 1 g of 4-chlorophenyl isocyanate, analogously to Experiment 1a. Melting point 200° to 203° C. (from methanol); yield 2.1 g.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8](Br)[CH:7]=1)=[O:5])C.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.Cl.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:7]=[C:6]([C:4]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:5])[N:11]2[N:12]=1)=[O:17])[CH3:20]
Reactant: C1CCNC1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(N3CCCC3)cc(C(=O)N3CCCC3)n2n1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester prepared as in Example 16, Step 1 (0.080 g, 0.22 mmol) in dimethylsulfoxide (1 mL) was added pyrrolidine (0.2 mL). The reaction was stirred at 23° C. for 30 minutes, then 80° C. for 3 days. The reaction was then diluted with 2 volumes of water, acidified with 1N aqueous hydrogen chloride, then neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give a colorless oily solid that was purified by silica gel chromatography (gradient elution: 0-20% isopropanol/dichloromethane) to give 1-ethyl-3-[5-(pyrrolidine-1-carbonyl)-7-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea MS (APCI)=372.2 [M+H]
Reaction SMILES: [OH:1][C@@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].F[C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:22]=[CH:21][C:20]=1[N+:32]([O-:34])=[O:33]>C1COCC1>[N+:32]([C:20]1[CH:21]=[CH:22][C:23]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)=[CH:24][C:19]=1[O:1][C@@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(OCc2ccsc2)cc1F
Reactant: Cc1ccccc1[C@H](O)CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1[C@@H](CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 18.9 %

Procedure:
A stirred suspension of sodium (R)-4-hydroxy-4-(2-methylphenyl)butanoate (190 mg) in THF (15 mL) is treated with 60% sodium hydride (35 mg) and maintained at 25° for 0.5 hours. The mixture is treated with 2-fluoro-4-(thiophen-3-ylmethoxy)nitrobenzene (220 mg) and maintained at 50° C. for 3 hours. The solution is evaporated. The residue is dissolved in ethyl acetate, washed with water, dried and evaporated. The residue is purified by flash chromatography on silica, eluting with dichloromethane followed by ethyl acetate, followed by recrystallisation from ethyl acetate/pentane to give (R)-4-[2-nitro-5-(thiophen-3-ylmethoxy)phenoxy]-4-(2-methylphenyl)butyric acid (70 mg), a tan coloured solid, mp. 130-131° C. 1H NMR (CHCl3) 2.2-2.9 (4H,m), 2.4 (3H,s), 4.9 (2H, q), 5.5 (1H, q), 6.2 (1H,s), 6.5 (1H,d), 7.0-7.4 (7H,m), 7.9 (1H,d).
Reaction SMILES: [ClH:1].C([S@@]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][C@@H:21]1[CH2:25][CH2:24][O:23][CH2:22]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][C@@H:21]2[CH2:25][CH2:24][O:23][CH2:22]2)=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:18]=1
Reactant: CC(C)(C)[S@](=O)N1CCCC1c1cc(F)ccc1O[C@@H]1CCOC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(O[C@@H]2CCOC2)c(C2CCCN2)c1
Reaction time: 4 h

Procedure:
4M HCl solution (in Dioxane) (20 mL) was added to stirred solution of 1-((S)-tert-butylsulfinyl)-2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidine (4.1 g, 11.54 mmol) in Dioxane (25 mL) and stirring was continued at 20-35° C. for 4 h. After which the reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by washing with diethyl ether to afford 3.2 g of the title compound as a white solid. MS (ESI): 288.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4](=[O:10])[C:3]1=[O:11]>Cl>[OH:10][C:4]1[C:3](=[O:11])[C:2]([CH3:12])([CH3:1])[C:7](=[O:8])[C:6](=[CH:9][CH:9]=[C:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[C:3](=[O:11])[C:4]([OH:10])=[CH:5]2)[CH:5]=1
Reactant: CC1=CC(=O)C(=O)C(C)(C)C1=O
Agent: Cl
Product: CC1(C)C(=O)C(O)=CC(=CC=C2C=C(O)C(=O)C(C)(C)C2=O)C1=O
Reaction time: 0.25 h

Procedure:
In a 2-1 three-neck flask equipped with an intensive condenser and a stirrer, 50 g of 3,3,5-trimethylcyclohex-5-ene-1,2,4-trione (from Example 2) were dissolved in 300 ml of concentrated hydrochloric acid at room temperature. The flask was then dipped into a hot oil bath at 100° C. for 15 minutes, in the course of which the reaction mixture turned dark and an orange precipitate formed. This solid precipitate was filtered off with suction while hot and washed with water, ethanol, acetone, ethyl acetate and ether. The resulting product was freed of adhering solvent residues in a desiccator. (It is pure enough in this state for further reactions. If desired, it can be recrystallized from dioxane.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Cl)nc3)c2cc1OC
Temperature: 140 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
2-Chloro-5-hydroxypyridine (100 mg), 4-chloro-6,7-dimethoxyquinoline (861 mg), and 4-dimethylaminopyridine (283 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (164 mg, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:65])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:62]=[CH:61][C:34]([C:35]([O:37][CH:38]([O:40][C:41]([O:43][C@@H:44]3[C@H:48]4[O:49]C(C)(C)[O:51][C@H:47]4[O:46][C@@H:45]3[C@H:54]3[CH2:58][O:57]C(C)(C)[O:55]3)=[O:42])[CH3:39])=[O:36])=[CH:33][C:32]=2[O:63][CH3:64])=[O:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.O>>[OH:55][C@@H:54]([C@@H:45]1[C@H:44]([O:43][C:41]([O:40][CH:38]([O:37][C:35](=[O:36])[C:34]2[CH:61]=[CH:62][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:65])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:63][CH3:64])[CH:33]=2)[CH3:39])=[O:42])[C@@H:48]([OH:49])[C@@H:47]([OH:51])[O:46]1)[CH2:58][OH:57]
Reactant: COc1cc(C(=O)OC(C)OC(=O)O[C@@H]2[C@H]3OC(C)(C)O[C@H]3O[C@@H]2[C@H]2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)OC(C)OC(=O)O[C@@H]2[C@@H](O)[C@@H](O)O[C@@H]2[C@H](O)CO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 15 mL round-bottomed flask was charged with 1-(((3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-yloxy)carbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (111 mg, 117 μmol). The mix of trifluoroacetic acid (1.48 g, 1 mL, 13.0 mmol) and water (375 mg, 375 μl, 20.8 mmol) was added. LC-MS indicated the completion of the reaction after stirring at room temperature for 1 h.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH2:34][NH:35][C:36]([NH:38][CH3:39])=[O:37])[C:30]([O:32]C)=[O:31])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C1COCC1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH2:34][NH:35][C:36]([NH:38][CH3:39])=[O:37])[C:30]([OH:32])=[O:31])=[CH:27][CH:28]=1)=[O:22])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC(=O)NCC(C(=O)OC)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)NCC(C(=O)O)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[4-({[2-[(tert-butoxycarbonyl)amino]-5-(3-thienyl)phenyl]amino}carbonyl)phenyl]-3-{[(methylamino)carbonyl]-amino}propanoate (420 mg, 0.76 mmol) in THF (4 mL) and MeOH (1.5 mL) was added KOH (1N, 0.91 mL, 0.91 mmol). After stirring at room temperature for 1 h, the mixture was diluted with 1 M citric acid and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and concentrated to yield 2-[4-({[2-[(tert-butoxycarbonyl)amino]-5-(3-thienyl)phenyl]amino}carbonyl)-phenyl]-3-{[(methylamino)carbonyl]amino}propanoic acid as an off-white powder. MS (ESI) calcd [M+H]+ 539.2, found 539.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[H-].[Na+].CS(O[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>>[C:32]([O:31][C:29](=[O:30])[NH:28][CH:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][N:9]2[C:8](=[O:12])[CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[N:11][C:10]2=3)[CH2:23][CH2:24]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=C1COc2ccc(Br)nc2N1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(Br)nc32)CC1
Yield: 92 %

Procedure:
6-Bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (WO 2004/058144) (935 mg, 4.08 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (5.6 mmol) as described for Intermediate 2, but chromatography was omitted, to give the product as a solid in 92% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC(N(C)C)C(C)C.C(OC([N:31]1[CH2:36][CH2:35][NH:34][C:33]([CH3:38])([CH3:37])[CH2:32]1)=O)(C)(C)C>C1COCC1>[CH3:37][C:33]1([CH3:38])[CH2:32][NH:31][CH2:36][CH2:35][N:34]1[C:13]([C:10]1[N:11]=[CH:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]=1)=[O:15]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)c1ncn(-c2cccc(F)c2)n1
Agent: CC(C)C(Cl)N(C)C
Solvent: C1CCOC1
Product: CC1(C)CNCCN1C(=O)c1ncn(-c2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 460 mg (2.22 mmol) 1-(3-fluoro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid and 330 μL (2.49 mmol) 1-chloro-N,N,2-trimethylpropylamine in 10 mL THF was stirred at RT for 30 min, 500 mg (2.22 mmol) 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 620 μL (4.45 mmol) TEA were added and the mixture was stirred at RT for 1 h. The solvent was removed by distillation and the residue was purified by HPLC.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1O>>[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2F)C1
Yield: 23 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and 2-fluoro-4-nitrophenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 23%). MS (m/e): 467.4 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C-:28]#[N:29].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:28]#[N:29])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(CCCCCBr)oc2-c2ccc(OC)cc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc(CCCCCC#N)oc2-c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
A solution of 5 g of 4,5-Bis(4-methoxyphenyl)-2-(5-bromopentyl)oxazole in 23 cm3 of ethanol and 1.1 g of potassium cyanide dissolved in 9 cm3 of water are brought to reflux for 15 hours. After evaporation of the solvent, the organic/inorganic residue is dissolved in 40 cm3 of diethyl ether and 10 cm3 of water, and the ether phase is separated and washed with 10 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness. The viscous residue (4.4 g) is chromatographed on a column of useful diameter 2 cm containing 80 g of silica gel (50 to 200μ). The column is eluted with 1.2 liters of diazopropyl ether, collecting 50 cm3 fractions. The fractions emerging at between 0.2 and 1.2 liters are concentrated to dryness. 3.5 g (80%) of 6-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]hexanenitrile are obtained in the form of a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:13](=[O:16])(=[O:15])[NH2:14])=[C:5]([C:9](OC)=[O:10])[S:6][C:7]=1[CH3:8])#[N:2].NC1C(C#N)=C(C)SC=1C(OC)=O.O.[NH2:31][NH2:32]>C(O)C>[C:1]([C:3]1[C:4]([S:13]([NH2:14])(=[O:16])=[O:15])=[C:5]([C:9]([NH:31][NH2:32])=[O:10])[S:6][C:7]=1[CH3:8])#[N:2]
Reactant: COC(=O)c1sc(C)c(C#N)c1S(N)(=O)=O
Reactant: NN
Agent: COC(=O)c1sc(C)c(C#N)c1N
Solvent: O
Solvent: CCO
Product: Cc1sc(C(=O)NN)c(S(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-cyano-5-methyl-3-sulfamoyl-thiophene-2-carboxylate (2.9 g), prepared from methyl 3-amino-4-cyano-5-methyl-thiophene-2-carboxylate in analogy with known procedures, e.g. F. Junquera et al., Eur.J.Med.Chem. 23, 329 (1988), was suspended in 10 ml of ethanol. Hydrazine monohydrate (2 ml) was added and the mixture was stirred for 1 h at room temperature and then evaporated. The oily residue (3.3 g) was triturated with 10 ml of water and the precipitating crystals were collected by filtration, washed with water and dried to give the title compoundas yellow crystals (yield 1.62 g); m.p. 186-91° C.; 1H-NMR (DMSO-d6), δ(ppm): 7.25 (br, 5H, NH/NH2), 2.51 (s, 3H, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][CH3:11])[C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[H-].[Na+].[CH3:22][O:23][CH2:24]Cl.O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:4]([CH2:9][CH2:10][CH3:11])[C:5]([O:8][CH2:22][O:23][CH3:24])=[CH:6][CH:7]=1
Reactant: CCCc1c(O)ccc(Br)c1COC1CCCCO1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCOC)ccc(Br)c1COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of 4-bromo-2-propyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenol (972 mg, 2.95 mmol) in N,N-dimethylformamide (5 mL), sodium hydride (55% in oil, 257 mg, 5.90 mmol) and chloromethyl methyl ether (475 mg, 5.90 mmol) were added at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (910 mg, 83%) was obtained as colorless oil.
Reaction SMILES: O.[OH-].[Li+].[N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:16]3[N:20]4[N:21]=[C:22]([C:25]5[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=5)[CH:23]=[N:24][C:19]4=[N:18][CH:17]=3)[CH3:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.Cl>C1COCC1.CO.O>[N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:16]3[N:20]4[N:21]=[C:22]([C:25]5[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=5)[CH:23]=[N:24][C:19]4=[N:18][CH:17]=3)[CH3:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2cnc3ncc(C(C)c4ccc5ncccc5c4)n3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(c1ccc2ncccc2c1)c1cnc2ncc(-c3ccc(C(=O)O)cc3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide monohydrate (24 mg, 0.57 mmol) was added to a solution of methyl 4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate (47 mg, 0.115 mmol) in THF (0.5 mL) and methanol (0.5 mL) and water (0.2 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The mixture was adjusted with conc. HCl to pH 2. The volatiles were removed under reduced pressure to provide the crude product which was directly used in next step. LCMS: (M+H)=396.1.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][CH2:16][C:15]([OH:19])([CH3:18])[CH2:14][C@@H:13]1[NH:20]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:19][C:15]1([CH3:18])[CH2:16][CH2:17][C@@H:12]([NH2:11])[C@@H:13]([NH2:20])[CH2:14]1
Reactant: CC1(O)CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](NC(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(O)CC[C@@H](N)[C@@H](N)C1

Procedure:
10% Palladium on carbon (350 mg) was suspended in a methanol solution (100 ml) of (1R*,2S*)-N1,N2-bis(benzyloxycarbonyl)-4-hydroxy-4-methyl-1,2-cyclohexanediamine (Stereoisomer A) (780 mg), and the suspension was stirred for 5 hours in a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. After the residue was dissolved in dichloromethane (100 ml), and the solution was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain the title compound (Stereoisomer A) (190 mg) as a colorless oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[C:19]([CH3:31])([CH3:30])[C:20](=[O:29])[N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[C:19]([CH3:31])([CH3:30])[C:20](=[O:29])[N:21]([CH:23]3[CH2:24][CH2:25][N:26]([S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([CH3:32])[CH:34]=4)(=[O:41])=[O:40])[CH2:27][CH2:28]3)[N:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCc1ccccc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc1OCc1ccccc1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-[3-(benzyloxy)-4-methoxyphenyl]-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B4*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][CH:36]=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:17]=[C:16]([N:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[CH3:33])[N:15]=2)[C@H:10]([CH3:34])[CH2:9]1.[CH3:38][NH:39][CH3:40]>ClCCCl.CC(O)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][CH2:36][N:39]([CH3:40])[CH3:38])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:17]=[C:16]([N:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[CH3:33])[N:15]=2)[C@H:10]([CH3:34])[CH2:9]1
Reactant: CNC
Reactant: C[C@@H]1CN(c2ncc(CC=O)cc2Cl)CCN1c1cc(-c2ccc(F)c(Cl)c2)nc(N2CCC[C@H]2C)n1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H]1CN(c2ncc(CCN(C)C)cc2Cl)CCN1c1cc(-c2ccc(F)c(Cl)c2)nc(N2CCC[C@H]2C)n1
Reaction time: 8 h

Procedure:
To a solution of 2-(5-chloro-6-((R)-4-(6-(3-chloro-4-fluorophenyl)-2-((R)-2-methylpyrrolidin-1-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)pyridin-3-yl)acetaldehyde (64 mg, 0.118 mmol) in DCE, add dimethylamine (3.87M in THF, 40 μL) followed by 1 drop of HOAc. Stir the mixture overnight, and then dilute with DCM and wash (2×) with 10% NaOH solution. Concentrate under reduced pressure and add EtOAc, followed by a solution of HCl in ether. Concentrate and triturate the hydrochloride salt with fresh EtOAc to afford the title compound. 1H NMR (400 MHz, CDCl3): δ1.31 (d, 3H, J=6.23 Hz, CH3), 1.39 (d, 3H, J=6.6 Hz, CH3), 1.68 (m, 1H), 1.91 (m, 1H), 2.05 (m, 5H), 2.68 (s, 6H, N(CH3)2), 2.9-3.1 (m, 4H), 3.65 (m, 1H), 3.63-3.9 (m, 4H), 4.34 (m, 2H), 4.67 (br s, 1H), 6.20 (s, 1H), 7.18 (t, 1H), 7.55 (s, 1H), 7.88 (m, 1H), 8.06 (s, 2H).